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c3aa2c07b069ab5d545097894539e2c1799bc07b | wikidoc | Real gas | Real gas
Real gas effects refers to an assumption base where the following are taken into account:
- Compressibility effects
- Variable heat capacity
- Van der Waals forces
- Non-equilibrium thermodynamic effects
- Issues with molecular dissociation and elementary reactions with variable composition.
For most applications, such a detailed analysis is "over-kill". An example where "Real Gas effects" would have a significant impact would be on the Space Shuttle re-entry where extremely high temperatures and pressures are present.
# Van der Waals modelisation
Real gases are often modelized by taking into account their molar weight and molar volume
RT=(P+\frac{a}{V_m^2})(V_m-b)
Where P is the pressure, T is the temperature, R the ideal gas constant, and Vm the molar mass. a and b are parameters that are determined empirically for each gas, but are sometimes estimated from their critical temperature (Tc) and critical pressure (Pc) using these relations:
a=\frac{27R^2T_c}{64P_c}
b=\frac{RT_c}{8P_c}
See Van der Waals equation
# Redlich-Kwong modelisation
The Redlich-Kwong equation is another two-parameters equation that is used to modelize real gases. It is almost always more accurate than the Van der Waals equation, and ofter more accurate than some equation with more than two parameters. The equation is
RT=P+\frac{a}{V_m(V_m+b)T^\frac{1}{2}}(V_m-b)
where a and b two empirical parameters that are not the same parameters as in the Van der Waals equation.
See Redlich-Kwong equation of state
# Berthelot and modified Berthelot modelisation
The Berthelot Equation is very rarely used,
P=\frac{RT}{V-b}-\frac{a}{TV^2}
but the modified version is somewhat more accurate
P=\frac{RT}{V}\left(1+\frac{9PT_c}{128P_cT}\frac{(1-6T_c^2)}{T^2}\right)
# Dieterici modelisation
This modelisation fell out of usage in recent years
P=RT\frac{\exp{(\frac{-a}{V_mRT})}}{V_m-b}
# Clausius modelisation
The Clausius equation is a very simply three-parameter equation used to modelize gases.
RT=\left(P+\frac{a}{T(V_m+C)^2}\right)(V_m-b)
where
a=\frac{V_c-RT_c}{4P_c}
b=\frac{3RT_c}{8P_c}-V_c
c=\frac{27R^2T_c^3}{64P_c}
# Virial Modelisation
The Virial equation derives from a perturbative treatment of statistical mechanics.
PV_m=RT\left(1+\frac{B(T)}{V_m}+\frac{C(T)}{V_m^2}+\frac{D(T)}{V_m^3}+...\right)
-r alternatively
PV_m=RT\left(1+\frac{B^\prime(T)}{P}+\frac{C^\prime(T)}{P^2}+\frac{D^\prime(T)}{P^3}+...\right)
where A,B,C and A′,B′,C′ are temperature dependent constants.
# Peng-Robinson Modelisation
This two parameter equation has the interesting property being useful in modelizing some liquids as well as real gases.
P=\frac{RT}{V_m-b}-\frac{a(T)}{V_m(V_m+b)+b(Vm-b)}
# Wohl modelisation
The Wohl equation is formulated in terms of critial values, making it useful when real gas constants are not available.
RT=\left(P+\frac{a}{TV_m(V_m-b)}-\frac{c}{T^2V_m^3}\right)(V_m-b)
where
a=6P_cT_cV_c^2
b=\frac{V_c}{4}
c=4P_cT_c^2V_c^3
# Beatte-Bridgeman Modelisation
The Beattie-Bridgeman equation
P=RTd+(BRT-A-\frac{Rc}{T^2})d^2+(-BbRT+Aa-\frac{RBc}{T^2})d^3+\frac{RBbcd^4}{T^2}
where d is the molal density and a,b,c,A, and B are empirical parameters.
# Benedict-Webb-Rubin Modelisation
The BWR equation, sometimes referred to as the BWRS equation
P=RTd+d^2\left(RT(B+bd)-(A+ad-a{\alpha}d^4)-\frac{1}{T^2}\right)
Where d is the molal density and where a,b,c,A,B,C,α,γ are empirical constants. | Real gas
Real gas effects refers to an assumption base where the following are taken into account:
- Compressibility effects
- Variable heat capacity
- Van der Waals forces
- Non-equilibrium thermodynamic effects
- Issues with molecular dissociation and elementary reactions with variable composition.
For most applications, such a detailed analysis is "over-kill". An example where "Real Gas effects" would have a significant impact would be on the Space Shuttle re-entry where extremely high temperatures and pressures are present.
# Van der Waals modelisation
Real gases are often modelized by taking into account their molar weight and molar volume
<math>RT=(P+\frac{a}{V_m^2})(V_m-b)</math>
Where P is the pressure, T is the temperature, R the ideal gas constant, and Vm the molar mass. a and b are parameters that are determined empirically for each gas, but are sometimes estimated from their critical temperature (Tc) and critical pressure (Pc) using these relations:
<math>a=\frac{27R^2T_c}{64P_c}</math>
<math>b=\frac{RT_c}{8P_c}</math>
See Van der Waals equation
# Redlich-Kwong modelisation
The Redlich-Kwong equation is another two-parameters equation that is used to modelize real gases. It is almost always more accurate than the Van der Waals equation, and ofter more accurate than some equation with more than two parameters. The equation is
<math>RT=P+\frac{a}{V_m(V_m+b)T^\frac{1}{2}}(V_m-b)</math>
where a and b two empirical parameters that are not the same parameters as in the Van der Waals equation.
See Redlich-Kwong equation of state
# Berthelot and modified Berthelot modelisation
The Berthelot Equation is very rarely used,
<math>P=\frac{RT}{V-b}-\frac{a}{TV^2}</math>
but the modified version is somewhat more accurate
<math>P=\frac{RT}{V}\left(1+\frac{9PT_c}{128P_cT}\frac{(1-6T_c^2)}{T^2}\right)</math>
# Dieterici modelisation
This modelisation fell out of usage in recent years
<math>P=RT\frac{\exp{(\frac{-a}{V_mRT})}}{V_m-b}</math>
# Clausius modelisation
The Clausius equation is a very simply three-parameter equation used to modelize gases.
<math>RT=\left(P+\frac{a}{T(V_m+C)^2}\right)(V_m-b)</math>
where
<math>a=\frac{V_c-RT_c}{4P_c}</math>
<math>b=\frac{3RT_c}{8P_c}-V_c</math>
<math>c=\frac{27R^2T_c^3}{64P_c}</math>
# Virial Modelisation
The Virial equation derives from a perturbative treatment of statistical mechanics.
<math>PV_m=RT\left(1+\frac{B(T)}{V_m}+\frac{C(T)}{V_m^2}+\frac{D(T)}{V_m^3}+...\right)</math>
or alternatively
<math>PV_m=RT\left(1+\frac{B^\prime(T)}{P}+\frac{C^\prime(T)}{P^2}+\frac{D^\prime(T)}{P^3}+...\right)</math>
where A,B,C and A′,B′,C′ are temperature dependent constants.
# Peng-Robinson Modelisation
This two parameter equation has the interesting property being useful in modelizing some liquids as well as real gases.
<math>P=\frac{RT}{V_m-b}-\frac{a(T)}{V_m(V_m+b)+b(Vm-b)}</math>
# Wohl modelisation
The Wohl equation is formulated in terms of critial values, making it useful when real gas constants are not available.
<math>RT=\left(P+\frac{a}{TV_m(V_m-b)}-\frac{c}{T^2V_m^3}\right)(V_m-b)</math>
where
<math>a=6P_cT_cV_c^2</math>
<math>b=\frac{V_c}{4}</math>
<math>c=4P_cT_c^2V_c^3</math>
# Beatte-Bridgeman Modelisation
The Beattie-Bridgeman equation
<math>P=RTd+(BRT-A-\frac{Rc}{T^2})d^2+(-BbRT+Aa-\frac{RBc}{T^2})d^3+\frac{RBbcd^4}{T^2}</math>
where d is the molal density and a,b,c,A, and B are empirical parameters.
# Benedict-Webb-Rubin Modelisation
The BWR equation, sometimes referred to as the BWRS equation
<math>P=RTd+d^2\left(RT(B+bd)-(A+ad-a{\alpha}d^4)-\frac{1}{T^2}[C-cd(1+{\gamma}d^2)\exp(-{\gamma}d^2)]\right)</math>
Where d is the molal density and where a,b,c,A,B,C,α,γ are empirical constants. | https://www.wikidoc.org/index.php/Real_gas | |
e93fe1c18940a295051f8ccefc57623dc01f3dd9 | wikidoc | Tenesmus | Tenesmus
Tenesmus is a feeling of incomplete defecation. It is experienced as an inability or difficulty to empty the bowel at defecation. It is frequently painful and may be accompanied by involuntary straining and other gastrointestinal symptoms.
"Vesical tenesmus" is a similar condition, referring to difficult or failed attempts to urinate despite the bladder feeling full.
"Rectal tenesmus" is sometimes used as a retronym to further distinguish defecation-related tenesmus from vesical tenesmus.
# Considerations
Tenesmus is characterized by a sensation of needing to pass stool, accompanied by pain, cramping, and straining. Despite straining, little stool is passed. Tenesmus is generally associated with inflammatory diseases of the bowel, which may be caused by either infectious or noninfectious conditions. Conditions associated with tenesmus include:
- Irritable bowel syndrome
- Inflammatory bowel disease
- Radiation proctitis
- Rectal Gonorrhoea
- Rectal Lymphogranuloma venereum
- Shigellosis
- Ulcerative colitis
- Rectal carcinoma
- Rectal Lower GI parasitic infection, particularly Trichuris Trichiura aka whipworm | Tenesmus
Template:SignSymptom infobox
Tenesmus is a feeling of incomplete defecation. It is experienced as an inability or difficulty to empty the bowel at defecation. It is frequently painful and may be accompanied by involuntary straining and other gastrointestinal symptoms.
"Vesical tenesmus" is a similar condition, referring to difficult or failed attempts to urinate despite the bladder feeling full.
"Rectal tenesmus" is sometimes used as a retronym to further distinguish defecation-related tenesmus from vesical tenesmus.[1]
# Considerations
Tenesmus is characterized by a sensation of needing to pass stool, accompanied by pain, cramping, and straining. Despite straining, little stool is passed. Tenesmus is generally associated with inflammatory diseases of the bowel, which may be caused by either infectious or noninfectious conditions. Conditions associated with tenesmus include:
- Irritable bowel syndrome
- Inflammatory bowel disease
- Radiation proctitis
- Rectal Gonorrhoea
- Rectal Lymphogranuloma venereum
- Shigellosis
- Ulcerative colitis
- Rectal carcinoma
- Rectal Lower GI parasitic infection, particularly Trichuris Trichiura aka whipworm | https://www.wikidoc.org/index.php/Rectal_tenesmus | |
bd9aaab3bdebc3cf7e9c02cf155723dba12c2a86 | wikidoc | Red tide | Red tide
"Red Tide" is a common name for a phenomenon known as an algal bloom, an event in which estuarine, marine, or fresh water algae accumulate rapidly in the water column, or "bloom". These algae, more specifically phytoplankton, are microscopic, single-celled protists, plant-like organisms that can form dense, visible patches near the water's surface. Certain species of phytoplankton contain photosynthetic pigments that vary in color from green to brown to red, and when the algae are present in high concentrations, the water appears to be discolored or murky, varying in color from white to almost black, normally being red or brown. Not all algal blooms are dense enough to cause water discoloration, and not all discolored waters associated with algal blooms are red. Additionally, red tides are not typically associated with tidal movement of water, hence the preference among scientists to use the term algal bloom.
The most conspicuous effects of red tides are the associated wildlife mortalities among marine and coastal species of fish, birds, marine mammals and other organisms. In the case of Florida red tides, these mortalities are caused by exposure to a potent neurotoxin produced naturally by Karenia brevis, called brevetoxin.
# Usage
The term "red tide" is often used in the United States of America to describe a particular type of algal bloom common to the eastern Gulf of Mexico, and is also called "Florida red tide". This type of bloom is caused by a species of dinoflagellate known as Karenia brevis, and these blooms occur almost annually along Florida waters. The density of these organisms during a bloom can exceed tens of millions of cells per liter of seawater, and often discolor the water a deep reddish-brown hue.
The term "Red tide" is also commonly used on the northern east coast of the United States, and particularly in the Gulf of Maine. This type of bloom is caused by another species of dinoflagellate known as Alexandrium fundyense. These blooms of organisms cause severe disruptions in fisheries of these waters as the toxins in these organism cause filter-feeding shellfish in affected waters to become poisonous for human consumption due to saxitoxin.
# Causes
It is unclear what causes red tides; their occurrence in some locations appears to be entirely natural, while in others they appear to be a result of human activities The frequency and severity of algal blooms in some parts of the world have been linked to increased nutrient loading from human activities. In other areas, algal blooms are a seasonal occurrence resulting from coastal upwelling, a natural result of the movement of certain ocean currents. The growth of marine phytoplankton is generally limited by the availability of nitrates and phosphates, which can be abundant in agricultural run-off as well as coastal upwelling zones. Coastal water pollution produced by humans and systematic increase in sea water temperature have also been implicated as contributing factors in red tides. Other factors such as iron-rich dust influx from large desert areas such as the Saharan desert are thought to play a major role in causing red tides. Some algal blooms on the Pacific coast have also been linked to occurrences of large-scale climatic oscillations such as El Niño events. While red tides in the Gulf of Mexico have been occurring since the time of early explorers such as Cabeza de Vaca. it is unclear what initiates these blooms, and how large a role anthropogenic and natural factors play in their development. It is also debated whether the apparent increase in frequency and severity of algal blooms in various parts of the world is in fact a real increase or is due to increased observation effort and advances in species identification methods
# Associated illnesses
Some organisms that can cause red tide naturally produce potent toxins, such as saxitoxin, domoic acid, or brevetoxin, and such red tides composed of toxic phytoplankton are commonly referred to as "harmful algal blooms" or "HABs". The various red tide toxins each have different modes of action, such as disrupting the proper function of ion channels in neurons, mimicking of neurotransmitters, or inhibiting enzymatic activity. Domoic acid, a toxin produced by diatoms of the genus Pseudo-nitzschia, has been linked to neurological damage in certain marine mammals, and is frequently found in algal blooms on the U.S. West Coast. Some red tide toxins can become highly concentrated in various marine organisms that have the ability to filter and consume large quantities of toxic plankton directly from seawater, which include shellfish, finfish, baleen whales, and benthic crustaceans. Frequently, shellfish collected in areas affected by algal blooms can be potentially dangerous for human consumption, leading to closures of shellfish beds for harvesting.
# Notable Occurrences
- On August 30, 2007, Japanese music producer N-Kei Enzaki was reported as being found dead in his hotel room in Osaka, Japan after eating mussels contaminated with red tide toxin. The story was later revealed to be a hoax propagated by TV Tokyo staff. An apology statement was aired shortly after.
- On August 23, 2007, 5 year-old boy was killed and 12 others were hospitalized after eating mussels shellfish contaminated with red tide toxin in Sorsogon, Philippines. The BFAR also raised red tide alerts in the coastal waters of Milagros Bay in Masbate; Juag Lagoon in Matnog; Bislig Bay in Bislig City in Surigao del Sur; Hinatuan Bay in Surigao del Sur; and Dumanguilas Bay in Zamboanga del Sur.
- In June, 2 children were killed and 5 others were hospitalized in Casiguran, Sorsogon, after eating red tide-contaminated mussels.
- In 1972 a red tide was caused in New England by a toxic dinoflagellate Alexandrium (Gonyaulax) tamarense. | Red tide
"Red Tide" is a common name for a phenomenon known as an algal bloom, an event in which estuarine, marine, or fresh water algae accumulate rapidly in the water column, or "bloom". These algae, more specifically phytoplankton, are microscopic, single-celled protists, plant-like organisms that can form dense, visible patches near the water's surface. Certain species of phytoplankton contain photosynthetic pigments that vary in color from green to brown to red, and when the algae are present in high concentrations, the water appears to be discolored or murky, varying in color from white to almost black, normally being red or brown. Not all algal blooms are dense enough to cause water discoloration, and not all discolored waters associated with algal blooms are red. Additionally, red tides are not typically associated with tidal movement of water, hence the preference among scientists to use the term algal bloom.
The most conspicuous effects of red tides are the associated wildlife mortalities among marine and coastal species of fish, birds, marine mammals and other organisms. In the case of Florida red tides, these mortalities are caused by exposure to a potent neurotoxin produced naturally by Karenia brevis, called brevetoxin.
# Usage
The term "red tide" is often used in the United States of America to describe a particular type of algal bloom common to the eastern Gulf of Mexico, and is also called "Florida red tide". This type of bloom is caused by a species of dinoflagellate known as Karenia brevis, and these blooms occur almost annually along Florida waters. The density of these organisms during a bloom can exceed tens of millions of cells per liter of seawater, and often discolor the water a deep reddish-brown hue.
The term "Red tide" is also commonly used on the northern east coast of the United States, and particularly in the Gulf of Maine. This type of bloom is caused by another species of dinoflagellate known as Alexandrium fundyense. These blooms of organisms cause severe disruptions in fisheries of these waters as the toxins in these organism cause filter-feeding shellfish in affected waters to become poisonous for human consumption due to saxitoxin.
# Causes
It is unclear what causes red tides; their occurrence in some locations appears to be entirely natural[1], while in others they appear to be a result of human activities[2] The frequency and severity of algal blooms in some parts of the world have been linked to increased nutrient loading from human activities. In other areas, algal blooms are a seasonal occurrence resulting from coastal upwelling, a natural result of the movement of certain ocean currents[3]. The growth of marine phytoplankton is generally limited by the availability of nitrates and phosphates, which can be abundant in agricultural run-off as well as coastal upwelling zones. Coastal water pollution produced by humans and systematic increase in sea water temperature have also been implicated as contributing factors in red tides. Other factors such as iron-rich dust influx from large desert areas such as the Saharan desert are thought to play a major role in causing red tides[4]. Some algal blooms on the Pacific coast have also been linked to occurrences of large-scale climatic oscillations such as El Niño events. While red tides in the Gulf of Mexico have been occurring since the time of early explorers such as Cabeza de Vaca[5]. it is unclear what initiates these blooms, and how large a role anthropogenic and natural factors play in their development. It is also debated whether the apparent increase in frequency and severity of algal blooms in various parts of the world is in fact a real increase or is due to increased observation effort and advances in species identification methods [6]
[7].
# Associated illnesses
Some organisms that can cause red tide naturally produce potent toxins, such as saxitoxin, domoic acid, or brevetoxin, and such red tides composed of toxic phytoplankton are commonly referred to as "harmful algal blooms" or "HABs". The various red tide toxins each have different modes of action, such as disrupting the proper function of ion channels in neurons, mimicking of neurotransmitters, or inhibiting enzymatic activity[8]. Domoic acid, a toxin produced by diatoms of the genus Pseudo-nitzschia, has been linked to neurological damage in certain marine mammals, and is frequently found in algal blooms on the U.S. West Coast[9]. Some red tide toxins can become highly concentrated in various marine organisms that have the ability to filter and consume large quantities of toxic plankton directly from seawater, which include shellfish, finfish, baleen whales, and benthic crustaceans. Frequently, shellfish collected in areas affected by algal blooms can be potentially dangerous for human consumption, leading to closures of shellfish beds for harvesting.
# Notable Occurrences
- On August 30, 2007, Japanese music producer N-Kei Enzaki was reported as being found dead in his hotel room in Osaka, Japan after eating mussels contaminated with red tide toxin. The story was later revealed to be a hoax propagated by TV Tokyo staff. An apology statement was aired shortly after.[citation needed]
- On August 23, 2007, 5 year-old boy was killed and 12 others were hospitalized after eating mussels shellfish contaminated with red tide toxin in Sorsogon, Philippines. The BFAR also raised red tide alerts in the coastal waters of Milagros Bay in Masbate; Juag Lagoon in Matnog; Bislig Bay in Bislig City in Surigao del Sur; Hinatuan Bay in Surigao del Sur; and Dumanguilas Bay in Zamboanga del Sur.[citation needed]
- In June, 2 children were killed and 5 others were hospitalized in Casiguran, Sorsogon, after eating red tide-contaminated mussels.[10]
- In 1972 a red tide was caused in New England by a toxic dinoflagellate Alexandrium (Gonyaulax) tamarense.[citation needed] | https://www.wikidoc.org/index.php/Red_tide | |
c9f0f6db2819941b6a3a5d29fe49b23efdff8649 | wikidoc | Trospium | Trospium
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# Overview
Trospium is a muscarinic antagonist that is FDA approved for the treatment of overactive bladder. Common adverse reactions include dry mouth, constipation, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- SANCTURA® is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
### Dosage
- The recommended dose is 20 mg twice daily. SANCTURA® should be dosed at least one hour before meals or given on an empty stomach.
- For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime.
- In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability
### DOSAGE FORMS AND STRENGTHS
- SANCTURA® is supplied as 20 mg tablets (brownish yellow, biconvex, glossy coated tablets printed with S in black ink)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trospium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trospium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Trospium in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trospium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trospium in pediatric patients.
# Contraindications
- SANCTURA® is contraindicated in patients with:
# Warnings
- SANCTURA® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention
- Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in SANCTURA®. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, SANCTURA® should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.
- SANCTURA® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. SANCTURA®, like other antimuscarinic agents, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis.
- In patients being treated for narrow-angle glaucoma, SANCTURA® should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring.
- SANCTURA® is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how SANCTURA® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
- Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on systemic exposure are not known, but systemic exposure is likely increased. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate renal impairment
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of SANCTURA® was evaluated in controlled clinical trials in a total of 2975 patients, who were treated with SANCTURA® (N=1673), placebo (N=1056) or active control medications (N=246). Of this total, 1181 patients participated in two, 12-week, U.S., efficacy and safety studies and a 9-month open-label extension. Of this total, 591 patients received SANCTURA® 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with SANCTURA® for at least 24 and 52 weeks, respectively.
- In all placebo-controlled trials combined, the incidence of serious adverse events was 2.9% among patients receiving SANCTURA® 20 mg twice daily and 1.5% among patients receiving placebo. TABLE 1 lists adverse reactions from the combined 12-week U.S. safety and efficacy trials were reported by at least 1% of patients, and were reported more frequently in the SANCTURA® group than in the placebo group.
- The two most common adverse reactions reported by patients receiving SANCTURA® 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse reaction for SANCTURA®, dry mouth, occurred in 20.1% of SANCTURA® treated patients and 5.8% of patients receiving placebo. In the two U.S. studies, dry mouth led to discontinuation in 1.9% of patients treated with SANCTURA® 20 mg twice daily. For the patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.
- Other adverse reactions from the U.S., placebo-controlled trials , occurring in greater than or equal to 0.5% and less than 1.0% of SANCTURA® treated patients, and more common with SANCTURA® than placebo are: tachycardia, blurred vision , abdominal distension, vomiting, dysgeusia, dry throat, and dry skin.
- During controlled clinical studies, one adverse reaction of angioneurotic edema was reported.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of trospium chloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- gastritis
- palpitations
- supraventricular tachycardia
- chest pain
- syncope
- hypertensive crisis
- Stevens-Johnson syndrome
- anaphylactic reaction
- angioedema
- dizziness
- confusion
- abnormal vision
- hallucinations
- somnolence
- delirium
- rhabdomyolysis
- rash
# Drug Interactions
- Concomitant use of SANCTURA® and digoxin did not affect the pharmacokinetics of either drug.
- Although demonstrated in a drug-drug interaction study not to affect the pharmacokinetics of digoxin, SANCTURA® has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g., procainamide, pancuronium, morphine, vancomycin, and tenofovir). Coadministration of SANCTURA® with these drugs may increase the serum concentration of SANCTURA® and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs.
- The concomitant use of SANCTURA® with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. SANCTURA® may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
- Co-administration of 500 mg metformin immediate release tablets twice daily with SANCTURA XR® (trospium chloride 60 mg extended release) reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of SANCTURA® in pregnant women. SANCTURA® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during SANCTURA® treatment are encouraged to contact their physician.
- Based on animal data, trospium chloride is predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk. Adverse developmental findings were not observed to correlate with dose in rats or in rabbits. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.
- In a rat embryo/fetal development study, pregnant rats received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate, with maternal systemic exposures corresponding to approximately nine times the exposure of women treated at the MRHD of 40 mg, based on AUC. No malformations or fetal toxicity were observed.
- The offspring of female rats exposed orally, pre- and post-natally, to trospium chloride up to 200 mg/kg/day showed no increased developmental toxicity over background in surviving pups. However, maternal toxicity (death, irregular breathing, increased excitability) was observed at 200 mg/kg/day. A no-effect level for maternal and pup toxicity (survival to Day 4) was 20 mg/kg/day, an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.
- In a rabbit embryo/fetal development study, pregnant rabbits received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate. At 200 mg/kg/day, maternal systemic exposures corresponded to approximately 16 times the exposure of women treated at the MRHD of 40 mg, based on AUC. However, one fetus in each of the three treated dose groups (0.3 to 16 times exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A maternal no-effect level was set at 20 mg/kg/day, at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg, due to clinical signs (reduced feces, hunched posture, diarrhea) observed in a pharmacokinetic study at 200 mg/kg/day.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trospium in women who are pregnant.
### Labor and Delivery
- The effect of SANCTURA® tablets on labor and delivery is unknown.
### Nursing Mothers
- Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, SANCTURA® should be used during lactation only if the potential benefit justifies the potential risk to the newborn.
### Pediatric Use
- The safety and effectiveness of SANCTURA® in pediatric patients have not been established.
### Geriatic Use
- Of the 591 patients with overactive bladder who received treatment with SANCTURA® in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight SANCTURA® treated patients (15%) were greater than or equal to 75 years of age.
In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with SANCTURA® (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. This effect may be related to an enhanced sensitivity to anticholinergic agents in this patient population. Therefore, based upon tolerability, the dose frequency of SANCTURA® may be reduced to 20 mg once daily in patients 75 years of age and older.
### Gender
There is no FDA guidance on the use of Trospium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trospium with respect to specific racial populations.
### Renal Impairment
Severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of SANCTURA®. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of SANCTURA® in patients with severe renal impairment necessitates adjustment of dosage frequency. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30-80 mL/min.
- Trospium is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.
### Hepatic Impairment
- There is no information regarding the effect of severe hepatic impairment on exposure to SANCTURA®. In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution should be used when administering SANCTURA® to patients with moderate and severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trospium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trospium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose.
# IV Compatibility
There is limited information regarding IV Compatibility of Trospium in the drug label.
# Overdosage
- Overdosage with antimuscarinic agents, including SANCTURA®, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, electrocardiographic monitoring is recommended.
- A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium 10 mg given by a sibling. The baby's weight was reported as 5 kg. Following admission into the hospital and about 1 hour after ingestion of the trospium, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats per minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.
# Pharmacology
## Mechanism of Action
- SANCTURA® is a muscarinic antagonist.
- Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder.
- Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.
## Structure
- SANCTURA® (trospium chloride) is a quaternary ammonium compound with the chemical name of Spirooctane-8,1'-pyrrolidinium], 3--, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:
- Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g per 2 mL.
- Each SANCTURA® tablet contains 20 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each tablet also contains the following inactive ingredients: sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, carboxymethylcellulose sodium, white wax, magnesium stearate, and carnauba wax.
## Pharmacodynamics
- Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that SANCTURA® increases maximum cystometric bladder capacity and volume at first detrusor contraction.
- The effect of 20 mg twice daily and up to 100 mg twice daily SANCTURA® on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg once daily) controlled 5 day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. The 100 mg twice daily dose of SANCTURA® was chosen because this achieves the Cmax expected in severe renal impairment. SANCTURA® was not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.
- In this study, asymptomatic, non-specific T wave inversions were observed more often in subjects receiving SANCTURA® than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 SANCTURA® treated overactive bladder patients. The clinical significance of T wave inversion in this study is unknown. SANCTURA® is associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, SANCTURA® demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18 bpm for the 100 mg dose. In the two U.S. placebo-controlled trials in patients with overactive bladder, the mean increase in heart rate compared to placebo in Study 1 was observed to be 3 bpm and in Study 2 was 4 bpm.
## Pharmacokinetics
- After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4-16.1%). Peak plasma concentrations (Cmax) occur between 5 to 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. SANCTURA® exhibits diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.
- Administration with a high (50%) fat-content meal resulted in reduced absorption, with AUC and Cmax values 70-80% lower than those obtained when SANCTURA® was administered while fasting. Therefore, it is recommended that SANCTURA® should be taken at least one hour prior to meals or on an empty stomach.
- A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of SANCTURA® is provided in TABLE 2.
- Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5-50 ng/mL) were incubated with human serum in vitro.
- The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma.
- The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.
- The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 (CYP) is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven CYP isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.
- The plasma half-life for SANCTURA® following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium.
- The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated.
- Concomitant use of 20 mg SANCTURA® (trospium chloride immediate release) twice daily at steady state and a single dose of 0.5 mg digoxin in a crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.
- A drug interaction study was conducted in which SANCTURA XR® 60 mg once daily was co-administered with Glucophage® (metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax. The effect of decrease in trospium exposure on the efficacy of SANCTURA XR® is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg SANCTURA XR® once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.
- Age: Age did not appear to significantly affect the pharmacokinetics of SANCTURA®, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients greater than or equal to 75 years of age.
- Pediatric: The pharmacokinetics of SANCTURA® were not evaluated in pediatric patients.
- Race: Pharmacokinetic differences due to race have not been studied.
- Gender: Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg SANCTURA® dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg SANCTURA® was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and Cmax were 26% and 68% higher, respectively, in females without hormone replacement therapy than in males.
- Renal Impairment: In a clinical pharmacokinetic study where a single dose of 40 mg immediate release trospium chloride was administered to 12 healthy males and 12 males with severe renal impairment, severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of SANCTURA®. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hours vs. 18 hours) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of SANCTURA® in patients with severe renal impairment necessitates adjustment of dosage frequency. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30-80 mL/min.
- Hepatic Impairment: In a clinical pharmacokinetic study in patients with mild (Child-Pugh score 5-6) and with moderate (Child-Pugh score 7-8) hepatic impairment, given a single dose of 40 mg immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. There is no information regarding the effect of severe hepatic impairment on exposure to SANCTURA®.
## Nonclinical Toxicology
- Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day, approximately 9 times the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 40 mg.
- Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the rat micronucleus test.
- No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).
# Clinical Studies
- SANCTURA® was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension.
- Study 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received SANCTURA® 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range: 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and greater than 70 micturitions per week. The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and SANCTURA® treatment groups are summarized in TABLE 3 and FIGURES 2 and 3.
# How Supplied
- SANCTURA® tablets 20 mg (brownish yellow, biconvex, glossy coated tablets printed with S in black ink) are supplied as follows: 60 count HDPE bottle - NDC 0023-3513-60
## Storage
- Store at controlled room temperature 20° - 25°C (68° - 77°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be informed that trospium chloride, the active ingredient in SANCTURA®, may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue SANCTURA® and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.
- Prior to treatment, patients should fully understand the risks and benefits of SANCTURA®. In particular, patients should be informed not to take SANCTURA® tablets if they:
- have urinary retention;
- gastric retention;
- uncontrolled narrow-angle glaucoma;
- are allergic to any component of SANCTURA®.
- Patients should be instructed regarding the recommended dosing and administration of SANCTURA®:
- Take one SANCTURA® tablet twice daily with water.
- Take SANCTURA® on an empty stomach or at least 1 hour before a meal.
- Patients should be informed that the most common side effects with SANCTURA® are dry mouth and constipation and that other less common side effects include trouble emptying the bladder, blurred vision, and heat prostration. Because anticholinergics, such as SANCTURA®, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.
### PATIENT PACKAGE INSERT
# Precautions with Alcohol
- Alcohol-Trospium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sanctura®
# Look-Alike Drug Names
There is limited information regarding Trospium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Trospium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Trospium is a muscarinic antagonist that is FDA approved for the treatment of overactive bladder. Common adverse reactions include dry mouth, constipation, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- SANCTURA® is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
### Dosage
- The recommended dose is 20 mg twice daily. SANCTURA® should be dosed at least one hour before meals or given on an empty stomach.
- For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime.
- In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability
### DOSAGE FORMS AND STRENGTHS
- SANCTURA® is supplied as 20 mg tablets (brownish yellow, biconvex, glossy coated tablets printed with S in black ink)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trospium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trospium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Trospium in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trospium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trospium in pediatric patients.
# Contraindications
- SANCTURA® is contraindicated in patients with:
# Warnings
- SANCTURA® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention
- Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in SANCTURA®. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, SANCTURA® should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.
- SANCTURA® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. SANCTURA®, like other antimuscarinic agents, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis.
- In patients being treated for narrow-angle glaucoma, SANCTURA® should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring.
- SANCTURA® is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how SANCTURA® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
- Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on systemic exposure are not known, but systemic exposure is likely increased. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate renal impairment
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of SANCTURA® was evaluated in controlled clinical trials in a total of 2975 patients, who were treated with SANCTURA® (N=1673), placebo (N=1056) or active control medications (N=246). Of this total, 1181 patients participated in two, 12-week, U.S., efficacy and safety studies and a 9-month open-label extension. Of this total, 591 patients received SANCTURA® 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with SANCTURA® for at least 24 and 52 weeks, respectively.
- In all placebo-controlled trials combined, the incidence of serious adverse events was 2.9% among patients receiving SANCTURA® 20 mg twice daily and 1.5% among patients receiving placebo. TABLE 1 lists adverse reactions from the combined 12-week U.S. safety and efficacy trials were reported by at least 1% of patients, and were reported more frequently in the SANCTURA® group than in the placebo group.
- The two most common adverse reactions reported by patients receiving SANCTURA® 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse reaction for SANCTURA®, dry mouth, occurred in 20.1% of SANCTURA® treated patients and 5.8% of patients receiving placebo. In the two U.S. studies, dry mouth led to discontinuation in 1.9% of patients treated with SANCTURA® 20 mg twice daily. For the patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.
- Other adverse reactions from the U.S., placebo-controlled trials , occurring in greater than or equal to 0.5% and less than 1.0% of SANCTURA® treated patients, and more common with SANCTURA® than placebo are: tachycardia, blurred vision , abdominal distension, vomiting, dysgeusia, dry throat, and dry skin.
- During controlled clinical studies, one adverse reaction of angioneurotic edema was reported.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of trospium chloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- gastritis
- palpitations
- supraventricular tachycardia
- chest pain
- syncope
- hypertensive crisis
- Stevens-Johnson syndrome
- anaphylactic reaction
- angioedema
- dizziness
- confusion
- abnormal vision
- hallucinations
- somnolence
- delirium
- rhabdomyolysis
- rash
# Drug Interactions
- Concomitant use of SANCTURA® and digoxin did not affect the pharmacokinetics of either drug.
- Although demonstrated in a drug-drug interaction study not to affect the pharmacokinetics of digoxin, SANCTURA® has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g., procainamide, pancuronium, morphine, vancomycin, and tenofovir). Coadministration of SANCTURA® with these drugs may increase the serum concentration of SANCTURA® and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs.
- The concomitant use of SANCTURA® with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. SANCTURA® may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
- Co-administration of 500 mg metformin immediate release tablets twice daily with SANCTURA XR® (trospium chloride 60 mg extended release) reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of SANCTURA® in pregnant women. SANCTURA® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during SANCTURA® treatment are encouraged to contact their physician.
- Based on animal data, trospium chloride is predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk. Adverse developmental findings were not observed to correlate with dose in rats or in rabbits. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.
- In a rat embryo/fetal development study, pregnant rats received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate, with maternal systemic exposures corresponding to approximately nine times the exposure of women treated at the MRHD of 40 mg, based on AUC. No malformations or fetal toxicity were observed.
- The offspring of female rats exposed orally, pre- and post-natally, to trospium chloride up to 200 mg/kg/day showed no increased developmental toxicity over background in surviving pups. However, maternal toxicity (death, irregular breathing, increased excitability) was observed at 200 mg/kg/day. A no-effect level for maternal and pup toxicity (survival to Day 4) was 20 mg/kg/day, an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.
- In a rabbit embryo/fetal development study, pregnant rabbits received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate. At 200 mg/kg/day, maternal systemic exposures corresponded to approximately 16 times the exposure of women treated at the MRHD of 40 mg, based on AUC. However, one fetus in each of the three treated dose groups (0.3 to 16 times exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A maternal no-effect level was set at 20 mg/kg/day, at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg, due to clinical signs (reduced feces, hunched posture, diarrhea) observed in a pharmacokinetic study at 200 mg/kg/day.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trospium in women who are pregnant.
### Labor and Delivery
- The effect of SANCTURA® tablets on labor and delivery is unknown.
### Nursing Mothers
- Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, SANCTURA® should be used during lactation only if the potential benefit justifies the potential risk to the newborn.
### Pediatric Use
- The safety and effectiveness of SANCTURA® in pediatric patients have not been established.
### Geriatic Use
- Of the 591 patients with overactive bladder who received treatment with SANCTURA® in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight SANCTURA® treated patients (15%) were greater than or equal to 75 years of age.
In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with SANCTURA® (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. This effect may be related to an enhanced sensitivity to anticholinergic agents in this patient population. Therefore, based upon tolerability, the dose frequency of SANCTURA® may be reduced to 20 mg once daily in patients 75 years of age and older.
### Gender
There is no FDA guidance on the use of Trospium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trospium with respect to specific racial populations.
### Renal Impairment
Severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of SANCTURA®. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of SANCTURA® in patients with severe renal impairment necessitates adjustment of dosage frequency. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30-80 mL/min.
- Trospium is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.
### Hepatic Impairment
- There is no information regarding the effect of severe hepatic impairment on exposure to SANCTURA®. In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution should be used when administering SANCTURA® to patients with moderate and severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trospium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trospium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose.
# IV Compatibility
There is limited information regarding IV Compatibility of Trospium in the drug label.
# Overdosage
- Overdosage with antimuscarinic agents, including SANCTURA®, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, electrocardiographic monitoring is recommended.
- A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium 10 mg given by a sibling. The baby's weight was reported as 5 kg. Following admission into the hospital and about 1 hour after ingestion of the trospium, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats per minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.
# Pharmacology
## Mechanism of Action
- SANCTURA® is a muscarinic antagonist.
- Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder.
- Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.
## Structure
- SANCTURA® (trospium chloride) is a quaternary ammonium compound with the chemical name of Spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:
- Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g per 2 mL.
- Each SANCTURA® tablet contains 20 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each tablet also contains the following inactive ingredients: sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, carboxymethylcellulose sodium, white wax, magnesium stearate, and carnauba wax.
## Pharmacodynamics
- Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that SANCTURA® increases maximum cystometric bladder capacity and volume at first detrusor contraction.
- The effect of 20 mg twice daily and up to 100 mg twice daily SANCTURA® on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg once daily) controlled 5 day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. The 100 mg twice daily dose of SANCTURA® was chosen because this achieves the Cmax expected in severe renal impairment. SANCTURA® was not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.
- In this study, asymptomatic, non-specific T wave inversions were observed more often in subjects receiving SANCTURA® than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 SANCTURA® treated overactive bladder patients. The clinical significance of T wave inversion in this study is unknown. SANCTURA® is associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, SANCTURA® demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18 bpm for the 100 mg dose. In the two U.S. placebo-controlled trials in patients with overactive bladder, the mean increase in heart rate compared to placebo in Study 1 was observed to be 3 bpm and in Study 2 was 4 bpm.
## Pharmacokinetics
- After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4-16.1%). Peak plasma concentrations (Cmax) occur between 5 to 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. SANCTURA® exhibits diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.
- Administration with a high (50%) fat-content meal resulted in reduced absorption, with AUC and Cmax values 70-80% lower than those obtained when SANCTURA® was administered while fasting. Therefore, it is recommended that SANCTURA® should be taken at least one hour prior to meals or on an empty stomach.
- A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of SANCTURA® is provided in TABLE 2.
- Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5-50 ng/mL) were incubated with human serum in vitro.
- The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma.
- The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.
- The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 (CYP) is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven CYP isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.
- The plasma half-life for SANCTURA® following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium.
- The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated.
- Concomitant use of 20 mg SANCTURA® (trospium chloride immediate release) twice daily at steady state and a single dose of 0.5 mg digoxin in a crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.
- A drug interaction study was conducted in which SANCTURA XR® 60 mg once daily was co-administered with Glucophage® (metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax. The effect of decrease in trospium exposure on the efficacy of SANCTURA XR® is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg SANCTURA XR® once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.
- Age: Age did not appear to significantly affect the pharmacokinetics of SANCTURA®, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients greater than or equal to 75 years of age.
- Pediatric: The pharmacokinetics of SANCTURA® were not evaluated in pediatric patients.
- Race: Pharmacokinetic differences due to race have not been studied.
- Gender: Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg SANCTURA® dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg SANCTURA® was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and Cmax were 26% and 68% higher, respectively, in females without hormone replacement therapy than in males.
- Renal Impairment: In a clinical pharmacokinetic study where a single dose of 40 mg immediate release trospium chloride was administered to 12 healthy males and 12 males with severe renal impairment, severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of SANCTURA®. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hours vs. 18 hours) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of SANCTURA® in patients with severe renal impairment necessitates adjustment of dosage frequency. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30-80 mL/min.
- Hepatic Impairment: In a clinical pharmacokinetic study in patients with mild (Child-Pugh score 5-6) and with moderate (Child-Pugh score 7-8) hepatic impairment, given a single dose of 40 mg immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. There is no information regarding the effect of severe hepatic impairment on exposure to SANCTURA®.
## Nonclinical Toxicology
- Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day, approximately 9 times the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 40 mg.
- Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the rat micronucleus test.
- No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).
# Clinical Studies
- SANCTURA® was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension.
- Study 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received SANCTURA® 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range: 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and greater than 70 micturitions per week. The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and SANCTURA® treatment groups are summarized in TABLE 3 and FIGURES 2 and 3.
# How Supplied
- SANCTURA® tablets 20 mg (brownish yellow, biconvex, glossy coated tablets printed with S in black ink) are supplied as follows: 60 count HDPE bottle - NDC 0023-3513-60
## Storage
- Store at controlled room temperature 20° - 25°C (68° - 77°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be informed that trospium chloride, the active ingredient in SANCTURA®, may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue SANCTURA® and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.
- Prior to treatment, patients should fully understand the risks and benefits of SANCTURA®. In particular, patients should be informed not to take SANCTURA® tablets if they:
- have urinary retention;
- gastric retention;
- uncontrolled narrow-angle glaucoma;
- are allergic to any component of SANCTURA®.
- Patients should be instructed regarding the recommended dosing and administration of SANCTURA®:
- Take one SANCTURA® tablet twice daily with water.
- Take SANCTURA® on an empty stomach or at least 1 hour before a meal.
- Patients should be informed that the most common side effects with SANCTURA® are dry mouth and constipation and that other less common side effects include trouble emptying the bladder, blurred vision, and heat prostration. Because anticholinergics, such as SANCTURA®, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.
### PATIENT PACKAGE INSERT
# Precautions with Alcohol
- Alcohol-Trospium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sanctura®[1]
# Look-Alike Drug Names
There is limited information regarding Trospium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Regurin | |
02804acafa3b6f3f4033d685efc30bc7e28781a3 | wikidoc | Relacore | Relacore
Relacore is a herbal supplement marketed by the Carter Reed Company, a brand for Basic Research of Salt Lake City, Utah. Some companies had suggested that cortisol is the primary cause of the occurrence of body fat in women over 30. In October 2004, the US Federal Trade Commission (FTC) alleged that marketers of CortiSlim and CortiStress (similar products to Relacore) were making false or unsubstantiated claims in their advertising. Since then, those makers have changed their marketing claims.
Advertisements in January 2006 tout Relacore vaguely as a "feel-good pill" that can "reduce stress" by unspecified means. The idea is that excess cortisol is a product of stress. The main ingredient, as it pertains to cortisol control, is Magnolia bark.
Relacore's website claims that its product is stimulant free.
# Sales
Basic Research marketing claims that Relacore is the top-selling dietary supplement as of June 26, 2006, with sales of US $ 23.9 million and 900,000 bottles sold.
# Notes
- ↑ "Basic Research has launched Relacore, a nonsedating, mild anti-anxiety mood enhancer that reduces stress-induced cortisol production by helping to minimize stress". OTC Drug Store News. 27 (7): 44. 2005. ISSN 0191-7587. Unknown parameter |month= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Some weighty advice on diet aids". Herald News: C03. 2005. Unknown parameter |month= ignored (help)
- ↑ According to Supplement Watch, "a small dose of honokiol, or a magnolia bark extract standardized for honokiol content, can help to "de-stress" you without making you sleepy, while a larger dose might have the effect of knocking you out. When compared to pharmaceutical agents such as Valium (diazepam), honokiol appears to be as effective in its anti-anxiety activity, yet not nearly as powerful in its sedative ability." | Relacore
Relacore is a herbal supplement marketed by the Carter Reed Company, a brand for Basic Research of Salt Lake City, Utah.[1] Some companies had suggested that cortisol is the primary cause of the occurrence of body fat in women over 30. In October 2004, the US Federal Trade Commission (FTC) alleged that marketers of CortiSlim and CortiStress (similar products to Relacore) were making false or unsubstantiated claims in their advertising. Since then, those makers have changed their marketing claims.[2]
Advertisements in January 2006 tout Relacore vaguely as a "feel-good pill" that can "reduce stress" by unspecified means. The idea is that excess cortisol is a product of stress. The main ingredient, as it pertains to cortisol control, is Magnolia bark. [3]
Relacore's website claims that its product is stimulant free.[1]
# Sales
Basic Research marketing claims that Relacore is the top-selling dietary supplement as of June 26, 2006, with sales of US $ 23.9 million and 900,000 bottles sold.[citation needed][dubious – discuss]
# Notes
- ↑ "Basic Research has launched Relacore, a nonsedating, mild anti-anxiety mood enhancer that reduces stress-induced cortisol production by helping to minimize stress". OTC Drug Store News. 27 (7): 44. 2005. ISSN 0191-7587. Unknown parameter |month= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Some weighty advice on diet aids". Herald News: C03. 2005. Unknown parameter |month= ignored (help)
- ↑ According to Supplement Watch, "a small dose of honokiol, or a magnolia bark extract standardized for honokiol content, can help to "de-stress" you without making you sleepy, while a larger dose might have the effect of knocking you out. When compared to pharmaceutical agents such as Valium (diazepam), honokiol appears to be as effective in its anti-anxiety activity, yet not nearly as powerful in its sedative ability."
# External links
- http://www.relacore.com/
- http://www.ftc.gov/opa/2007/01/weightloss.htm
Template:Pharma-stub | https://www.wikidoc.org/index.php/Relacore | |
0c29573d0f27b9ec8353b7010d292cad17ea62d5 | wikidoc | Renalase | Renalase
Renalase, FAD-dependent amine oxidase is an enzyme that in humans is encoded by the RNLS gene. Renalase is a flavin adenine dinucleotide-dependent amine oxidase that is secreted into the blood from the kidney.
# Structure
## Gene
The gene encoding this protein is called RNLS (also known as C10orf59 or FLJ11218). The renalase gene has 9 exons spanning approximately 311,000 bp and resides on chromosome 10 at q23.33.
## Protein
The renalase protein consists of a putative secretory signal peptide (SignalP score of 0.4), a flavin adenine dinucleotide (FAD)-binding region, and an oxidase domain. At least four alternative splicing isoforms have been identified in humans (hRenalase1 to hRenalase4). Only hRenalase1 is detected in human blood samples, which means that hRenalase2 to 4 probably have different functions than hRenalase1.
Analysis of the primary structure of renalase shows that it is an FAD-dependent oxidase. The X-ray crystal structure of hRenalase1 reveals structural similarity between renalase and p-hydroxybenzoate hydroxylase.
# Function
Renalase has been claimed to degrade catecholamines like adrenaline (epinephrine) and noradrenaline (norepinephrine) in the blood circulation.
Dr. Gary Desir's laboratory at Yale School of Medicine discovered and named renalase in 2005 suggest that the human kidney releases this protein into the bloodstream to regulate blood pressure (in addition to other possible, as yet undiscovered, functions).
Whether renalase actually oxidizes catecholamine substrates has been widely disputed. The primary evidence for catecholamine oxidation is the detection of H2O2, however catecholamines emanate H2O2 in the presence of O2 in a natural decomposition reaction. In 2013, renalase was claimed to oxidize α-NADH (the normal form of NADH is the β anomer) to β-NAD+, with concomitant reduction of O2 (dioxygen) to H2O2 (hydrogen peroxide). This reaction was proposed to repair aberrant NADH and NADPH forms that are not accepted as cofactors by most nicotinamide-dependent oxidoreductase enzymes.
It transpired that α-NAD(P)H molecules are not substrates for renalase; instead 6-dihydroNAD (6DHNAD) was identified as the substrate, a molecule with highly similar spectrophotometric characteristics and equilibrium concentrations as those reported for α-NAD(P)H. 6DHNAD is an isomeric form of β-NADH that carries the hydride in the 6-position of the nicotinamide base as opposed to the metabolically active 4-position. This form of NAD is one of three products that are formed from non-enzymatic reduction of β-NAD+ in addition to 4-dihydroNAD (β-NADH), 2-dihydroNAD (2DHNAD). Both 2DHNAD and 6DHNAD were shown to be substrates for renalase. These molecules react rapidly to reduce the enzyme's flavin cofactor forming β-NAD+. The renalase flavin then delivers the electrons harvested to O2 (dioxygen) forming H2O2 (hydrogen peroxide), completing the catalytic cycle. It was shown that both 6DHNAD and 2DHNAD are tight binding inhibitors of specific primary metabolism dehydrogenases, thereby defining a clear metabolic function for renalase in the alleviation of this inhibition.
Extracellular renalase functions as a survival and growth factor, independent of its enzymatic activity. Either naturally folded renalase or a 20 amino acid renalase peptide can activate the phosphoinositide 3-kinase (PI3K)and the mitogen-activated protein kinase (MAPK) pathways in a manner that protects cells against apoptosis.
# Catalysis
Renalase isolated in native form, that is, without refolding steps, catalyzes the oxidation of 6DHNAD(P) or 2DHNAD(P), the isomeric forms of β-NAD(P)H . In contrast to clear evidence for catalysis of this activity, the native renalase used in these experiments did not catalyze the conversion of the catecholamine epinephrine to adrenochrome.
Renalase is secreted in plasma, and functions as an anti-apoptotic survival factor. The Plasma membrane Ca2+ ATPase PMCA4b is a putative receptor for extracellular renalase. The binding of renalase to PMCA4b stimulates calcium efflux with subsequent activation of the PI3K and MAPK pathways, increased expression of the anti-apoptotic factor Bcl-2, and decreased caspase3-mediated apoptosis. Administration of recombinant renalase protects against acute kidney injury (AKI), and against cardiac ischemia in animal models.
# Clinical significance
Renalase levels are markedly reduced in patients with severe chronic kidney disease (end-stage renal disease, ESRD). Since hormones like erythropoietin are secreted less in ESRD, renalase may also be a kidney hormone, although it is also expressed in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles.
Renalase has been controversially proposed to degrade catecholamines, which are hormones involved in the acute stress (fight-or-flight) response. Injection of renalase in rodents transiently decreases blood pressure, heart rate, heart muscle contractility, and blood vessel resistance. Under normal conditions, renalase is present but inactive in the bloodstream. When catecholamines are released into the bloodstream however, renalase activity increases about tenfold within 30 seconds, and remains high for an hour or longer. Activation of circulating renalase is probably responsible for early activation, while secretion into the bloodstream occurs after 15 minutes.
polymorphisms in the renalase gene is a risk factor for essential hypertension.
Single nucleotide polymorphisms in the renalase gene are associated with type 1 diabetes. A genome-wide association study and meta-analysis found that approximately 42 loci affect the risk of diabetes The data confirmed linkage with most of the 24 previously identified loci, and identified 27 novel loci. The strongest evidence of association among these novel regions was achieved for the renalase gene.
# Animal studies
In mice, hearts exposed to oxygen shortage (ischemia), myocardial infarction size was decreased and heart function better preserved when renalase was administered. Renalase knock-out mice are also more sensitive to damage to the heart muscle. Renalase expression in the heart is also decreased in the rat model of end-stage renal disease. The scientists who discovered renalase believe that it might explain some of the susceptibility to heart disease among patients with chronic kidney disease.
Using small inhibitory RNAs or knock-out mice, the consequences of loss of renalase function have been studied. These include raised blood pressure (hypertension), increased heart rate (tachycardia), increased blood vessel resistance (vasoconstriction) and an increased catecholamine response.
In a rat model of chronic kidney disease (in which 85% of kidney tissue is surgically removed), renalase deficiency and defective renalase activation develops 2–3 weeks after surgery.
# Interactions
Renalase has been shown to interact with PMCA4b. | Renalase
Renalase, FAD-dependent amine oxidase is an enzyme that in humans is encoded by the RNLS gene. Renalase is a flavin adenine dinucleotide-dependent amine oxidase that is secreted into the blood from the kidney.[1]
# Structure
## Gene
The gene encoding this protein is called RNLS (also known as C10orf59 or FLJ11218).[1] The renalase gene has 9 exons spanning approximately 311,000 bp and resides on chromosome 10 at q23.33.[2]
## Protein
The renalase protein consists of a putative secretory signal peptide (SignalP score of 0.4), a flavin adenine dinucleotide (FAD)-binding region, and an oxidase domain. At least four alternative splicing isoforms have been identified in humans (hRenalase1 to hRenalase4). Only hRenalase1 is detected in human blood samples, which means that hRenalase2 to 4 probably have different functions than hRenalase1.[3]
Analysis of the primary structure of renalase shows that it is an FAD-dependent oxidase. The X-ray crystal structure of hRenalase1 reveals structural similarity between renalase and p-hydroxybenzoate hydroxylase.[4]
# Function
Renalase has been claimed to degrade catecholamines like adrenaline (epinephrine) and noradrenaline (norepinephrine) in the blood circulation.[3]
Dr. Gary Desir's laboratory at Yale School of Medicine discovered and named renalase in 2005[2] suggest that the human kidney releases this protein into the bloodstream to regulate blood pressure (in addition to other possible, as yet undiscovered, functions).[3]
Whether renalase actually oxidizes catecholamine substrates has been widely disputed.[5][6] The primary evidence for catecholamine oxidation is the detection of H2O2, however catecholamines emanate H2O2 in the presence of O2 in a natural decomposition reaction. In 2013, renalase was claimed to oxidize α-NADH (the normal form of NADH is the β anomer) to β-NAD+, with concomitant reduction of O2 (dioxygen) to H2O2 (hydrogen peroxide).[7] This reaction was proposed to repair aberrant NADH and NADPH forms that are not accepted as cofactors by most nicotinamide-dependent oxidoreductase enzymes.
It transpired that α-NAD(P)H molecules are not substrates for renalase; instead 6-dihydroNAD (6DHNAD) was identified as the substrate, a molecule with highly similar spectrophotometric characteristics and equilibrium concentrations as those reported for α-NAD(P)H.[8] 6DHNAD is an isomeric form of β-NADH that carries the hydride in the 6-position of the nicotinamide base as opposed to the metabolically active 4-position. This form of NAD is one of three products that are formed from non-enzymatic reduction of β-NAD+ in addition to 4-dihydroNAD (β-NADH), 2-dihydroNAD (2DHNAD). Both 2DHNAD and 6DHNAD were shown to be substrates for renalase. These molecules react rapidly to reduce the enzyme's flavin cofactor forming β-NAD+. The renalase flavin then delivers the electrons harvested to O2 (dioxygen) forming H2O2 (hydrogen peroxide), completing the catalytic cycle. It was shown that both 6DHNAD and 2DHNAD are tight binding inhibitors of specific primary metabolism dehydrogenases, thereby defining a clear metabolic function for renalase in the alleviation of this inhibition.
Extracellular renalase functions as a survival and growth factor, independent of its enzymatic activity.[9] Either naturally folded renalase or a 20 amino acid renalase peptide can activate the phosphoinositide 3-kinase (PI3K)and the mitogen-activated protein kinase (MAPK) pathways in a manner that protects cells against apoptosis.
# Catalysis
Renalase isolated in native form, that is, without refolding steps, catalyzes the oxidation of 6DHNAD(P) or 2DHNAD(P), the isomeric forms of β-NAD(P)H .[7] In contrast to clear evidence for catalysis of this activity, the native renalase used in these experiments did not catalyze the conversion of the catecholamine epinephrine to adrenochrome.[7]
Renalase is secreted in plasma, and functions as an anti-apoptotic survival factor. The Plasma membrane Ca2+ ATPase PMCA4b is a putative receptor for extracellular renalase.[10] The binding of renalase to PMCA4b stimulates calcium efflux with subsequent activation of the PI3K and MAPK pathways, increased expression of the anti-apoptotic factor Bcl-2, and decreased caspase3-mediated apoptosis. Administration of recombinant renalase protects against acute kidney injury (AKI), and against cardiac ischemia in animal models.
# Clinical significance
Renalase levels are markedly reduced in patients with severe chronic kidney disease (end-stage renal disease, ESRD). Since hormones like erythropoietin are secreted less in ESRD, renalase may also be a kidney hormone, although it is also expressed in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles.[3][11]
Renalase has been controversially proposed to degrade catecholamines, which are hormones involved in the acute stress (fight-or-flight) response. Injection of renalase in rodents transiently decreases blood pressure, heart rate, heart muscle contractility, and blood vessel resistance.[2] Under normal conditions, renalase is present but inactive in the bloodstream. When catecholamines are released into the bloodstream however, renalase activity increases about tenfold within 30 seconds, and remains high for an hour or longer. Activation of circulating renalase is probably responsible for early activation, while secretion into the bloodstream occurs after 15 minutes.[12]
polymorphisms in the renalase gene is a risk factor for essential hypertension.[13]
Single nucleotide polymorphisms in the renalase gene are associated with type 1 diabetes. A genome-wide association study and meta-analysis found that approximately 42 loci affect the risk of diabetes[14] The data confirmed linkage with most of the 24 previously identified loci, and identified 27 novel loci. The strongest evidence of association among these novel regions was achieved for the renalase gene.
# Animal studies
In mice, hearts exposed to oxygen shortage (ischemia), myocardial infarction size was decreased and heart function better preserved when renalase was administered.[15] Renalase knock-out mice are also more sensitive to damage to the heart muscle.[3] Renalase expression in the heart is also decreased in the rat model of end-stage renal disease. The scientists who discovered renalase believe that it might explain some of the susceptibility to heart disease among patients with chronic kidney disease.[3]
Using small inhibitory RNAs or knock-out mice, the consequences of loss of renalase function have been studied. These include raised blood pressure (hypertension), increased heart rate (tachycardia), increased blood vessel resistance (vasoconstriction) and an increased catecholamine response.[16][17]
In a rat model of chronic kidney disease (in which 85% of kidney tissue is surgically removed), renalase deficiency and defective renalase activation develops 2–3 weeks after surgery.[12]
# Interactions
Renalase has been shown to interact with PMCA4b.[18] | https://www.wikidoc.org/index.php/Renalase | |
07981d8f40992cf0b98f695f429f39aa0f78de9c | wikidoc | Research | Research
# Overview
Research is a human activity based on intellectual investigation and aimed at discovering, interpreting, and revising human knowledge on different aspects of the world. Research can use the scientific method, but need not do so.
Scientific research relies on the application of the scientific method, a harnessing of curiosity. This research provides scientific information and theories for the explanation of the nature and the properties of humans. It makes practical applications possible. Scientific research is funded by public authorities, by charitable organisations and by private groups, including many companies. Scientific research can be subdivided into different classifications.
Historical research is embodied in the historical method.
The term research is also used to describe an entire collection of information about a particular subject.
# Basic research
Basic research (also called fundamental or pure research) has as its primary objective the advancement of knowledge and the theoretical understanding of the relations among variables (see statistics). It is exploratory and often driven by the researcher’s curiosity, interest, or intuition. It is conducted without any practical end in mind, although it may have unexpected results pointing to practical applications. The terms “basic” or “fundamental” indicate that, through theory generation, basic research provides the foundation for further, sometimes applied research. As there is no guarantee of short-term practical gain, researchers may find it difficult to obtain funding for basic research. Research is a subset of invention.
Examples of questions asked in basic research:
- Does string theory provide physics with a grand unification theory?
- Which aspects of genomes explain organismal complexity?
- Is it possible to prove or disprove Goldbach's conjecture? (i.e. that every even integer greater than 2 can be written as the sum of two, not necessarily distinct primes)
Traditionally, basic research was considered as an activity that preceded applied research, which in turn preceded development into practical applications. Recently, these distinctions have become much less clear-cut, and it is sometimes the case that all stages will intermix. This is particularly the case in fields such as biotechnology and electronics, where fundamental discoveries may be made alongside work intended to develop new products, and in areas where public and private sector partners collaborate in order to develop greater insight into key areas of interest. For this reason, some now prefer the term frontier research.
# Research processes
## Scientific research
Generally, research is understood to follow a certain structural process. Though step order may vary depending on the subject matter and researcher, the following steps are usually part of most formal research, both basic and applied:
- Formation of the topic
- Hypothesis
- Conceptual definitions
- Operational definitions
- Gathering of data
- Analysis of data
- Test, revising of hypothesis
- Conclusion, iteration if necessary
A common misunderstanding is that by this method a hypothesis can be proven. Generally a hypothesis is used to make predictions that can be tested by observing the outcome of an experiment. If the outcome is inconsistent with the hypothesis, then the hypothesis is rejected. However, if the outcome is consistent with the hypothesis, the experiment is said to support the hypothesis. This careful language is used because researchers recognize that alternative hypotheses may also be consistent with the observations. In this sense, a hypothesis can never be proven, but rather only supported by surviving rounds of scientific testing and, eventually, becoming widely thought of as true (or better, predictive), but this is not the same as it having been proven.
A useful hypothesis allows prediction and within the accuracy of observation of the time, the prediction will be verified. As the accuracy of observation improves with time, the hypothesis may no longer provide an accurate prediction. In this case a new hypothesis will arise to challenge the old, and to the extent that the new hypothesis makes more accurate predictions than the old, the new will supplant it.
## Historical
The historical method comprises the techniques and guidelines by which historians use historical sources and other evidence to research and then to write history. There are various history guidelines commonly used by historians in their work, under the headings of external criticism, internal criticism, and synthesis. This includes higher criticism and textual criticism. Though items may vary depending on the subject matter and researcher, the following concepts are usually part of most formal historical research:
- Identification of origin date
- Evidence of localization
- Recognition of authorship
- Analysis of data
- Identification of integrity
- Attribution of credibility
# Research methods
The goal of the research process is to produce new knowledge, which takes three main forms (although, as previously discussed, the boundaries between them may be fuzzy):
- Exploratory research, which structures and identifies new problems
- Constructive research, which develops solutions to a problem
- Empirical research, which tests the feasibility of a solution using empirical evidence
Research can also fall into two distinct types:
- Primary research
- Secondary research.
Research methods used by scholars include:
- Action research
- Cartography
- Case study
- Classification
- Experience and intuition
- Experiments
- Interviews
- Mathematical models
- Participant observation
- Simulation
- Statistical analysis
- Statistical surveys
- Content or Textual Analysis
- Ethnography
Research is often conducted using the hourglass model. The hourglass model starts with a broad spectrum for research, focusing in on the required information through the methodology of the project (like the neck of the hourglass), then expands the research in the form of discussion and results.
# Publishing
Academic publishing describes a system that is necessary in order for academic scholars to peer review the work and make it available for a wider audience. The 'system', which is probably disorganised enough not to merit the title, varies widely by field, and is also always changing, if often slowly. Most academic work is published in journal article or book form. In publishing, STM publishing is an abbreviation for academic publications in science, technology, and medicine.
Most established academic fields have their own journals and other outlets for publication, though many academic journals are somewhat interdisciplinary, and publish work from several distinct fields or subfields. The kinds of publications that are accepted as contributions of knowledge or research vary greatly between fields.
Academic publishing is undergoing major changes, emerging from the transition from the print to the electronic format. Business models are different in the electronic environment. Since about the early 1990s, licensing of electronic resources, particularly journals, has been very common. Presently, a major trend, particularly with respect to scholarly journals, is open access. There are two main forms of open access: open access publishing, in which the articles or the whole journal is freely available from the time of publication, and self-archiving, where the author makes a copy of their own work freely available on the web.
# Research funding
Most funding for scientific research comes from two major sources, corporations (through research and development departments) and government (primarily through universities and in some cases through military contractors). Many senior researchers (such as group leaders) spend more than a trivial amount of their time applying for grants for research funds. These grants are necessary not only for researchers to carry out their research, but also as a source of merit. Some faculty positions require that the holder has received grants from certain institutions, such as the US National Institutes of Health (NIH). Government-sponsored grants (e.g. from the NIH, the National Health Service in Britain or any of the European research councils) generally have a high status.
# Etymology
The word research derives from the French recherche, from rechercher, to search closely where "chercher" means "to search" (see French language); its literal meaning is 'to investigate thoroughly'. | Research
# Overview
Research is a human activity based on intellectual investigation and aimed at discovering, interpreting, and revising human knowledge on different aspects of the world. Research can use the scientific method, but need not do so.
Scientific research relies on the application of the scientific method, a harnessing of curiosity. This research provides scientific information and theories for the explanation of the nature and the properties of humans. It makes practical applications possible. Scientific research is funded by public authorities, by charitable organisations and by private groups, including many companies. Scientific research can be subdivided into different classifications.
Historical research is embodied in the historical method.
The term research is also used to describe an entire collection of information about a particular subject.
# Basic research
Basic research (also called fundamental or pure research) has as its primary objective the advancement of knowledge and the theoretical understanding of the relations among variables (see statistics). It is exploratory and often driven by the researcher’s curiosity, interest, or intuition. It is conducted without any practical end in mind, although it may have unexpected results pointing to practical applications. The terms “basic” or “fundamental” indicate that, through theory generation, basic research provides the foundation for further, sometimes applied research. As there is no guarantee of short-term practical gain, researchers may find it difficult to obtain funding for basic research. Research is a subset of invention.
Examples of questions asked in basic research:
- Does string theory provide physics with a grand unification theory?
- Which aspects of genomes explain organismal complexity?
- Is it possible to prove or disprove Goldbach's conjecture? (i.e. that every even integer greater than 2 can be written as the sum of two, not necessarily distinct primes)
Traditionally, basic research was considered as an activity that preceded applied research, which in turn preceded development into practical applications. Recently, these distinctions have become much less clear-cut, and it is sometimes the case that all stages will intermix. This is particularly the case in fields such as biotechnology and electronics, where fundamental discoveries may be made alongside work intended to develop new products, and in areas where public and private sector partners collaborate in order to develop greater insight into key areas of interest. For this reason, some now prefer the term frontier research.
# Research processes
## Scientific research
Generally, research is understood to follow a certain structural process. Though step order may vary depending on the subject matter and researcher, the following steps are usually part of most formal research, both basic and applied:
- Formation of the topic
- Hypothesis
- Conceptual definitions
- Operational definitions
- Gathering of data
- Analysis of data
- Test, revising of hypothesis
- Conclusion, iteration if necessary
A common misunderstanding is that by this method a hypothesis can be proven. Generally a hypothesis is used to make predictions that can be tested by observing the outcome of an experiment. If the outcome is inconsistent with the hypothesis, then the hypothesis is rejected. However, if the outcome is consistent with the hypothesis, the experiment is said to support the hypothesis. This careful language is used because researchers recognize that alternative hypotheses may also be consistent with the observations. In this sense, a hypothesis can never be proven, but rather only supported by surviving rounds of scientific testing and, eventually, becoming widely thought of as true (or better, predictive), but this is not the same as it having been proven.
A useful hypothesis allows prediction and within the accuracy of observation of the time, the prediction will be verified. As the accuracy of observation improves with time, the hypothesis may no longer provide an accurate prediction. In this case a new hypothesis will arise to challenge the old, and to the extent that the new hypothesis makes more accurate predictions than the old, the new will supplant it.
## Historical
The historical method comprises the techniques and guidelines by which historians use historical sources and other evidence to research and then to write history. There are various history guidelines commonly used by historians in their work, under the headings of external criticism, internal criticism, and synthesis. This includes higher criticism and textual criticism. Though items may vary depending on the subject matter and researcher, the following concepts are usually part of most formal historical research:
- Identification of origin date
- Evidence of localization
- Recognition of authorship
- Analysis of data
- Identification of integrity
- Attribution of credibility
# Research methods
The goal of the research process is to produce new knowledge, which takes three main forms (although, as previously discussed, the boundaries between them may be fuzzy):
- Exploratory research, which structures and identifies new problems
- Constructive research, which develops solutions to a problem
- Empirical research, which tests the feasibility of a solution using empirical evidence
Research can also fall into two distinct types:
- Primary research
- Secondary research.
Research methods used by scholars include:
- Action research
- Cartography
- Case study
- Classification
- Experience and intuition
- Experiments
- Interviews
- Mathematical models
- Participant observation
- Simulation
- Statistical analysis
- Statistical surveys
- Content or Textual Analysis
- Ethnography
Research is often conducted using the hourglass model.[1] The hourglass model starts with a broad spectrum for research, focusing in on the required information through the methodology of the project (like the neck of the hourglass), then expands the research in the form of discussion and results.
# Publishing
Academic publishing describes a system that is necessary in order for academic scholars to peer review the work and make it available for a wider audience. The 'system', which is probably disorganised enough not to merit the title, varies widely by field, and is also always changing, if often slowly. Most academic work is published in journal article or book form. In publishing, STM publishing is an abbreviation for academic publications in science, technology, and medicine.
Most established academic fields have their own journals and other outlets for publication, though many academic journals are somewhat interdisciplinary, and publish work from several distinct fields or subfields. The kinds of publications that are accepted as contributions of knowledge or research vary greatly between fields.
Academic publishing is undergoing major changes, emerging from the transition from the print to the electronic format. Business models are different in the electronic environment. Since about the early 1990s, licensing of electronic resources, particularly journals, has been very common. Presently, a major trend, particularly with respect to scholarly journals, is open access. There are two main forms of open access: open access publishing, in which the articles or the whole journal is freely available from the time of publication, and self-archiving, where the author makes a copy of their own work freely available on the web.
# Research funding
Most funding for scientific research comes from two major sources, corporations (through research and development departments) and government (primarily through universities and in some cases through military contractors). Many senior researchers (such as group leaders) spend more than a trivial amount of their time applying for grants for research funds. These grants are necessary not only for researchers to carry out their research, but also as a source of merit. Some faculty positions require that the holder has received grants from certain institutions, such as the US National Institutes of Health (NIH). Government-sponsored grants (e.g. from the NIH, the National Health Service in Britain or any of the European research councils) generally have a high status.
# Etymology
The word research derives from the French recherche, from rechercher, to search closely where "chercher" means "to search" (see French language); its literal meaning is 'to investigate thoroughly'. | https://www.wikidoc.org/index.php/Research | |
27e3a0d9b5bbb49edc3d1b4d3e0064691cbd2651 | wikidoc | Resistin | Resistin
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich adipose-derived peptide hormone that in humans is encoded by the RETN gene.
In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue. The length of the resistin pre-peptide in human is 108 amino acid residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa. Resistin is an adipose-derived hormone (similar to a cytokine) whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes mellitus (T2DM).
Resistin has been shown to cause "high levels of 'bad' cholesterol (low-density lipoprotein or LDL), increasing the risk of heart disease resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in arteries, increasing the risk of heart disease. resistin adversely impacts the effects of statins, the main cholesterol-reducing drug used in the treatment and prevention of cardiovascular disease."
# Discovery
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine. It was called "resistin" because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, rats, and mice). Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.
This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects.
# Inflammation
Inflammation is the first innate immune response to infection or irritation resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine, prostaglandin, and pro-inflammatory cytokines. As cited, it has recently been discovered that resistin also participates in the inflammatory response.
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion. It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide, which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation, which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with lowered renal function and inflammation, but not with insulin resistance. Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
# Obesity and insulin resistance
## Arguments for
Much of what is hypothesized about a resistin role in energy metabolism and T2DM can be derived from studies showing strong correlations between resistin and obesity. The underlying belief among those in support of this theory is that serum resistin levels will increase with increased adiposity. Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment. Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin. This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance that appears to be associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance. This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM. If resistin does contribute to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects might deliver immense therapeutic benefits.
## Arguments against
The amount of evidence supporting the resistin link theory between obesity and T2DM is vast. Nevertheless, this theory lacks support from the entire scientific community, as the number of studies presenting evidence against it continues to expand. Such studies have found significantly decreased serum concentrations of resistin with increased adiposity, suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between obesity and T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented; such studies instead report that weight loss is associated with marked increases in serum resistin. The idea that resistin links obesity to T2DM is now under even more scrutiny, as recent investigations have confirmed ubiquitous expression of resistin in many tissues, rather than those only characteristic of obesity, such as adipocytes.
Although nearly as many scientists oppose the theory as those who support it, there is sufficient evidence to support the idea that resistin does have some incompletely defined role in energy homeostasis, while also demonstrating properties that help to incite inflammatory responses to sites of infection.
# Structure
Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions that make up its structure. The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. Each protein subunit comprises a carboxy-terminal disulfide-rich beta sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. The globular domain from resistin contains five disulfide bonds (Cys35-Cys88, Cys47-Cys87, Cys56-Cys73, Cys58-Cys75, and Cys62-Cys77). This suggests that the disulfide pattern will be conserved.
The interchain disulfide bonds of resistin and resistin-like molecule β (RELMß) are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds is 9.9%, and 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin’s disulfides in high-resolution.
A Cys6Ser resistin mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect a mandatory step toward activation. Other results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver. | Resistin
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich adipose-derived peptide hormone that in humans is encoded by the RETN gene.[1]
In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue. The length of the resistin pre-peptide in human is 108 amino acid residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa. Resistin is an adipose-derived hormone (similar to a cytokine) whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes mellitus (T2DM).[2]
Resistin has been shown to cause "high levels of 'bad' cholesterol (low-density lipoprotein or LDL), increasing the risk of heart disease [...] resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in arteries, increasing the risk of heart disease. [...] resistin adversely impacts the effects of statins, the main cholesterol-reducing drug used in the treatment and prevention of cardiovascular disease."[3]
# Discovery
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine.[4] It was called "resistin" because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, rats, and mice).[4][5][6][7][8] Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.[9][10][11]
This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects.
# Inflammation
Inflammation is the first innate immune response to infection or irritation resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine, prostaglandin, and pro-inflammatory cytokines. As cited, it has recently been discovered that resistin also participates in the inflammatory response.[12][13][14][15]
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion.[16][17] It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection.[18] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[19] which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.[20]
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation,[21][22] which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with lowered renal function and inflammation, but not with insulin resistance.[23] Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
# Obesity and insulin resistance
## Arguments for
Much of what is hypothesized about a resistin role in energy metabolism and T2DM can be derived from studies showing strong correlations between resistin and obesity. The underlying belief among those in support of this theory is that serum resistin levels will increase with increased adiposity.[5][11][24][25] Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment.[26] Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.[27] This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.[6][28]
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance that appears to be associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance.[29][30][31][32] This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM.[4][24][33][34] If resistin does contribute to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects might deliver immense therapeutic benefits.[35]
## Arguments against
The amount of evidence supporting the resistin link theory between obesity and T2DM is vast.[citation needed] Nevertheless, this theory lacks support from the entire scientific community, as the number of studies presenting evidence against it continues to expand.[36][37][38] Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,[39][40][41] suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between obesity and T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented; such studies instead report that weight loss is associated with marked increases in serum resistin.[16] The idea that resistin links obesity to T2DM is now under even more scrutiny, as recent investigations have confirmed ubiquitous expression of resistin in many tissues, rather than those only characteristic of obesity, such as adipocytes.
Although nearly as many scientists oppose the theory as those who support it, there is sufficient evidence to support the idea that resistin does have some incompletely defined role in energy homeostasis, while also demonstrating properties that help to incite inflammatory responses to sites of infection.
# Structure
Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions that make up its structure. The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. Each protein subunit comprises a carboxy-terminal disulfide-rich beta sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. The globular domain from resistin contains five disulfide bonds (Cys35-Cys88, Cys47-Cys87, Cys56-Cys73, Cys58-Cys75, and Cys62-Cys77). This suggests that the disulfide pattern will be conserved.
The interchain disulfide bonds of resistin and resistin-like molecule β (RELMß) are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds is 9.9%, and 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin’s disulfides in high-resolution.
A Cys6Ser resistin mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect a mandatory step toward activation. Other results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver. | https://www.wikidoc.org/index.php/Resistin | |
3205a4cc06ee1daebd93c41d09591dff1f83a5ee | wikidoc | Resistor | Resistor
A resistor is a two-terminal electrical or electronic component that opposes an electric current by producing a voltage drop between its terminals in proportion to the current, that is, in accordance with Ohm's law: V = I R.
The electrical resistance R is equal to the voltage drop V across the resistor divided by the current I through the resistor. Resistors are used as part of electrical networks and electronic circuits.
# Identifying resistors
Most axial resistors use a pattern of colored stripes to indicate resistance. Surface-mount resistors are marked numerically. Cases are usually brown, blue, or green, though other colors are occasionally found such as dark red or dark grey.
One can also use a multimeter or ohmmeter to test the values of a resistor.
## Four-band axial resistors
Four-band identification is the most commonly used color coding scheme on all resistors. It consists of four colored bands that are painted around the body of the resistor. The scheme is simple: The first two numbers are the first two significant digits of the resistance value, the third is a multiplier, and the fourth is the tolerance of the value (e.g. green-blue-yellow red : 56 x (10^4) ohms = 56 x 10000 ohms = 560 kohms ±2%). Each color corresponds to a certain number, shown in the chart below. The tolerance for a 4-band resistor will be 1%, 5%, or 10%.
## Preferred values
Resistors are manufactured in values from a few milliohms to about a gigaohm; only a limited range of values from the IEC 60063 preferred number series are commonly available. These series are called E6, E12, E24, E96 and E192. The number tells how many standardized values exist in each decade (e.g. between 10 and 100, or between 100 and 1000). So resistors conforming to the E12 series, can have 12 distinct values between 10 and 100, whereas those confirming to the E24 series would have 24 distinct values. In practice, the discrete component sold as a "resistor" is not a perfect resistance, as defined above. Resistors are often marked with their tolerance (maximum expected variation from the marked resistance). These E numbers correspond to the formula R= 10^(N/E), So for an 1.21 ohm E96 series resistor, N=8 and 10^(8/96)=1.21 ohm. Each multiple of 96 added to the remainder gives the next decade. So a 12.1 ohm resistor would have a N= 8+96 = 104. N can also be found by using the formula E*LOG10(R) = N.
## 5-band axial resistors
5-band identification is used for higher precision (lower tolerance) resistors (1%, 0.5%, 0.25%, 0.1%), to notate the extra digit. The first three bands represent the significant digits, the fourth is the multiplier, and the fifth is the tolerance. 5-band standard tolerance resistors are sometimes encountered, generally on older or specialized resistors. They can be identified by noting a standard tolerance color in the 4th band. The 5th band in this case is the temperature coefficient
## SMT resistors
Surface mounted resistors are printed with numerical values in a code related to that used on axial resistors. Standard-tolerance Surface Mount Technology (SMT) resistors are marked with a three-digit code, in which the first two digits are the first two significant digits of the value and the third digit is the power of ten (the number of zeroes). For example:
Resistances less than 100 ohms are written: 100, 220, 470. The final zero represents ten to the power zero, which is 1. For example:
Sometimes these values are marked as "10" or "22" to prevent a mistake.
Resistances less than 10 ohms have 'R' to indicate the position of the decimal point (radix point). For example:
Precision resistors are marked with a four-digit code, in which the first three digits are the significant figures and the fourth is the power of ten. For example:
"000" and "0000" sometimes appear as values on surface-mount zero-ohm links, since these have (approximately) zero resistance.
## Industrial type designation
Format:
The operational temperature range distinguishes commercial grade, industrial grade and military grade components.
- Commercial grade: 0 °C to 70 °C
- Industrial grade: −40 °C to 85 °C (sometimes −25 °C to 85 °C)
- Military grade: −55 °C to 125 °C (sometimes -65 °C to 275 °C)
- Standard Grade -5°C to 60°C
# Resistor standards
- MIL-R-11
- MIL-R-39008
- MIL-R-39017
- MIL-PRF-26
- MIL-PRF-39007
- MIL-PRF-55342
- MIL-PRF-914
- BS 1852
- EIA-RS-279
There are other United States military procurement MIL-R- standards.
## Power dissipation
The power dissipated by a resistor is the voltage across the resistor multiplied by the current through the resistor:
P = I^2 R = I \cdot V = \frac{V^2}{R}
All three equations are equivalent. The first is derived from Joule's law, and the other two are derived from that by Ohm's Law.
The total amount of heat energy released is the integral of the power over time:
W = \int_{t_1}^{t_2} v(t) i(t)\, dt.
If the average power dissipated exceeds the power rating of the resistor, the resistor may depart from its nominal resistance, and may be damaged by overheating. Significantly excessive power dissipation may raise the temperature of the resistor to a point where it burns out, which could cause a fire in adjacent components and materials.
## Series and parallel circuits
Resistors in a parallel configuration each have the same potential difference (voltage). To find their total equivalent resistance (Req):
\frac{1}{R_\mathrm{eq}} = \frac{1}{R_1} + \frac{1}{R_2} + \cdots + \frac{1}{R_n}
The parallel property can be represented in equations by two vertical lines "||" (as in geometry) to simplify equations. For two resistors,
R_\mathrm{eq} = R_1 \| R_2 = {R_1 R_2 \over R_1 + R_2}
The current through resistors in series stays the same, but the voltage across each resistor can be different. The sum of the potential differences (voltage) is equal to the total voltage. To find their total resistance:
R_\mathrm{eq} = R_1 + R_2 + \cdots + R_n
A resistor network that is a combination of parallel and series can sometimes be broken up into smaller parts that are either one or the other. For instance,
R_\mathrm{eq} = \left( R_1 \| R_2 \right) + R_3 = {R_1 R_2 \over R_1 + R_2} + R_3
However, many resistor networks cannot be split up in this way. Consider a cube, each edge of which has been replaced by a resistor. For example, determining the resistance between two opposite vertices requires matrix methods for the general case. However, if all twelve resistors are equal, the corner-to-corner resistance is 5⁄6 of any one of them.
# Technology
## Carbon composition
Carbon composition resistors consist of a solid cylindrical resistive element with embedded wire leadouts or metal end caps to which the leadout wires are attached, which is protected with paint or plastic.
The resistive element is made from a mixture of finely ground (powdered) carbon and an insulating material (usually ceramic). The mixture is held together by a resin. The resistance is determined by the ratio of the
fill material (the powdered ceramic) and the carbon. Higher concentrations of carbon, a weak conductor, result in lower resistance. Carbon composition resistors were commonly used in the 1960s and earlier, but are not so popular for general use now as other types have better specifications, such as tolerance, voltage dependence, and stress (carbon composition resistors will change value when stressed with over-voltages).
## Carbon film
A spiral is used to increase the length and decrease the width of the film, which increases the resistance. Varying shapes, coupled with the resistivity of carbon, (ranging from 9 to 40 µΩm) can make for a variety of resistances.
## Thick and thin film
Thick film resistors became popular during the 1970s, and most SMD resistors today are of this type. The principal difference between "thin film" and "thick film resistors" isn't necessarily the "thickness" of the film, but rather, how the film is applied to the cylinder (axial resistors) or the surface (SMD resistors). In thick film resistors the "film" is applied using traditional screen-printing technology.
Thin film resistors are made by sputtering the resistive material onto the surface of the resistor. Sputtering is a method used in vacuum deposition. The thin film is then etched in a similar manner to the old (subtractive) process for making printed circuit boards: ie the surface is coated with a photo-sensitive material, then covered by a film, irradiated with ultraviolet light, and then the exposed photo-sensitive coating, and underlying thin film, are etched away.
Thin film resistors, like their thick film counterparts, are then usually trimmed to an accurate value by abrasive or laser trimming.
Because the time during which the sputtering is performed can be controlled, the thickness of the film of a thin-film resistor can be accurately controlled. The type of the material is also usually different consisting of one or more ceramic (cermet) conductors such as tantalum nitride (TaN), ruthenium dioxide (RuO2), lead oxide (PbO), bismuth ruthenate (Bi2Ru2O7), nickel chromium (NiCr), and/or bismuth iridate (Bi2Ir2O7).
By contrast, thick film resistors, may use the same conductive ceramics, but they are mixed with sintered (powdered) glass, and some kind of liquid so that the composite can be screen-printed. This composite of glass and conductive ceramic (cermet) material is then fused (baked) in an oven at about 850 °C.
Traditionally thick film resistors had tolerances of 5%, but in the last few decades, standard tolerances have improved to 2% and 1%. But beware, temperature coefficients of thick film resistors are tyically ±200 ppm, or ±250 ppm, depending on the resistance. Thus a 40 degree Celsius (70 °F) temperature change can add another 1% variation to a 1% resistor.
Thin film resistors are usually specified with tolerances of 0.1, 0.2, 0.5, and 1%, and with temperature coefficients of 5 to 25 ppm. They are usually far more expensive than their thick film cousins. Note, though, that SMD thin film resistors, with 0.5% tolerances, and with 25 ppm temperature coefficients, when bought in full size reel quantities, are about twice the cost of a 1%, 250 ppm thick film resistors.
## Metal film
A common type of axial resistor today is referred to as a metal-film resistor. MELF (Metal Electrode Leadless Face) resistors often use the same technology, but are a cylindrically shaped resistor designed for surface mounting. .
Metal film resistors are usually coated with nickel chromium (NiCr), but might be coated with any of the cermet materials listed above for thin film resistors. Unlike thin film resistors, the material may be applied using different techniques than sputtering (though that is one such technique). Also, unlike thin-film resistors, the resistance value is determined by cutting a helix through the coating rather than by etching. The result is a reasonable tolerance (0.5, 1, or 2%) and a temperature coefficient of (usually) 25 or 50 ppm.
## Wirewound
Wirewound resistors are commonly made by winding a metal wire around a ceramic, plastic, or fiberglass core. The ends of the wire are soldered or welded to two caps, attached to the ends of the core. The assembly is protected with a layer of paint, molded plastic, or an enamel coating baked at high temperature. The wire leads are usually between 0.6 and 0.8 mm in diameter and tinned for ease of soldering. For higher power wirewound resistors, either a ceramic outer case or an aluminium outer case on top of an insulating layer is used. The aluminium cased types are designed to be attached to a heatsink to dissipate the heat; the rated power is dependent on being used with a suitable heatsink, e.g., a 50 W power rated resistor will overheat at around one fifth of the power dissipation if not used with a heatsink.
Because wirewound resistors are coils they have more inductance than other types of resistor, although this property can be minimized by winding the wire in sections with alternately reversed direction.
## Foil resistor
Foil resistors have had the best precision and stability ever since they were introduced in 1958 by Felix Zandman. One of the important parameters influencing stability is the temperature coefficient of resistance (TCR). Although the TCR of foil resistors is considered extremely low, this characteristic has been further refined over the years.
## Grid resistor
The term "grid resistor" can mean two things:
In tube or valve electronic circuit design, a grid resistor or "grid stopper" is used to limit grid current and prevent high frequencies from entering or oscillating the circuit. Such a resistor can be composed of any one of a number of resistor technologies. One application that uses grid resistors is electric guitar amplifier circuitry.
In heavy duty, industrial, high-current applications, a grid resistor is a large convection-cooled lattice of stamped metal alloy strips connected in rows between two electrodes. Such industrial grade resistors can be as large as a refrigerator; some designs can handle over 500 amps of current, with a range of resistances extending lower than 0.04 Ohms. They are used in applications such as dynamic braking for locomotives and trams, neutral grounding for industrial AC distribution, control loads for cranes and heavy equipment, load testing of generators and harmonic filtering for electric substations.
## Other types
- Metal-oxide resistor
- Cermet
- Phenolic
- Tantalum
- Liquid-filled
# Noise
In precision circuits, electronic noise becomes of utmost concern. As dissipative elements, resistors will naturally produce a fluctuating "noise" voltage across their terminals. This Johnson–Nyquist noise is predicted by the fluctuation–dissipation theorem and is a fundamental noise source present in all resistors which must be considered in constructing low-noise electronics. For example, the gain in a simple (non-)inverting amplifier is set using a voltage divider. Noise considerations dictate that the smallest practical resistance should be used, since the noise voltage scales with resistance, and any resistor noise in the voltage divider will be impressed upon the amplifier's output.
Although Johnson–Nyquist noise is a fundamental noise source, resistors frequently exhibit other, "non-fundamental" sources of noise. Noise due to these sources is called "excess noise." Thick-film and carbon composition resistors are notorious for excess noise at low frequencies. Wire-wound and thin-film resistors, though much more expensive, are often utilized for their better noise characteristics.
# Failure modes and pitfalls
Like every part, resistors can fail; the usual way depends on their construction. Carbon composition resistors and metal film resistors typically fail as open circuits. Carbon-film resistors typically fail as short circuits. Carbon film and composition resistors can burn if too much power is dissipated. This is also possible but less likely with metal film and wirewound resistors. If not enclosed, wirewound resistors can corrode. Carbon -composition resistors are prone to drifting over time and are easily damaged by excessive heat in soldering (the binder evaporates).
Various effects become important in high-precision applications. Small voltage differentials may appear on the resistors due to thermoelectric effect if their ends are not kept at the same temperature. The voltages appear in the junctions of the resistor leads with the circuit board and with the resistor body. Common metal film resistors show such effect at magnitude of about 20 µV/°C. Some carbon composition resistors can go as high as 400 µV/°C, and specially constructed resistors can go as low as 0.05 µV/°C. In applications where thermoelectric effects may become important, care has to be taken to e.g. mount the resistors horizontally to avoid temperature gradients and to mind the air flow over the board. | Resistor
Template:Float begin
Template:Float end
Template:Float begin
Template:Float end
A resistor is a two-terminal electrical or electronic component that opposes an electric current by producing a voltage drop between its terminals in proportion to the current, that is, in accordance with Ohm's law: <math>V = I R</math>.
The electrical resistance <math>R</math> is equal to the voltage drop <math>V</math> across the resistor divided by the current <math>I</math> through the resistor. Resistors are used as part of electrical networks and electronic circuits.
# Identifying resistors
Most axial resistors use a pattern of colored stripes to indicate resistance. Surface-mount resistors are marked numerically. Cases are usually brown, blue, or green, though other colors are occasionally found such as dark red or dark grey.
One can also use a multimeter or ohmmeter to test the values of a resistor.
## Four-band axial resistors
Four-band identification is the most commonly used color coding scheme on all resistors. It consists of four colored bands that are painted around the body of the resistor. The scheme is simple: The first two numbers are the first two significant digits of the resistance value, the third is a multiplier, and the fourth is the tolerance of the value (e.g. green-blue-yellow red : 56 x (10^4) ohms = 56 x 10000 ohms = 560 kohms ±2%). Each color corresponds to a certain number, shown in the chart below. The tolerance for a 4-band resistor will be 1%, 5%, or 10%.
## Preferred values
Resistors are manufactured in values from a few milliohms to about a gigaohm; only a limited range of values from the IEC 60063 preferred number series are commonly available. These series are called E6, E12, E24, E96 and E192. The number tells how many standardized values exist in each decade (e.g. between 10 and 100, or between 100 and 1000). So resistors conforming to the E12 series, can have 12 distinct values between 10 and 100, whereas those confirming to the E24 series would have 24 distinct values. In practice, the discrete component sold as a "resistor" is not a perfect resistance, as defined above. Resistors are often marked with their tolerance (maximum expected variation from the marked resistance). These E numbers correspond to the formula R= 10^(N/E), So for an 1.21 ohm E96 series resistor, N=8 and 10^(8/96)=1.21 ohm. Each multiple of 96 added to the remainder gives the next decade. So a 12.1 ohm resistor would have a N= 8+96 = 104. N can also be found by using the formula E*LOG10(R) = N.
## 5-band axial resistors
5-band identification is used for higher precision (lower tolerance) resistors (1%, 0.5%, 0.25%, 0.1%), to notate the extra digit. The first three bands represent the significant digits, the fourth is the multiplier, and the fifth is the tolerance. 5-band standard tolerance resistors are sometimes encountered, generally on older or specialized resistors. They can be identified by noting a standard tolerance color in the 4th band. The 5th band in this case is the temperature coefficient
## SMT resistors
Surface mounted resistors are printed with numerical values in a code related to that used on axial resistors. Standard-tolerance Surface Mount Technology (SMT) resistors are marked with a three-digit code, in which the first two digits are the first two significant digits of the value and the third digit is the power of ten (the number of zeroes). For example:
Resistances less than 100 ohms are written: 100, 220, 470. The final zero represents ten to the power zero, which is 1. For example:
Sometimes these values are marked as "10" or "22" to prevent a mistake.
Resistances less than 10 ohms have 'R' to indicate the position of the decimal point (radix point). For example:
Precision resistors are marked with a four-digit code, in which the first three digits are the significant figures and the fourth is the power of ten. For example:
"000" and "0000" sometimes appear as values on surface-mount zero-ohm links, since these have (approximately) zero resistance.
## Industrial type designation
Format: [two letters]<space>[resistance value (three digit)]<nospace>[tolerance code(numerical - one digit)]
[1]
The operational temperature range distinguishes commercial grade, industrial grade and military grade components.
- Commercial grade: 0 °C to 70 °C
- Industrial grade: −40 °C to 85 °C (sometimes −25 °C to 85 °C)
- Military grade: −55 °C to 125 °C (sometimes -65 °C to 275 °C)
- Standard Grade -5°C to 60°C
# Resistor standards
- MIL-R-11
- MIL-R-39008
- MIL-R-39017
- MIL-PRF-26
- MIL-PRF-39007
- MIL-PRF-55342
- MIL-PRF-914
- BS 1852
- EIA-RS-279
There are other United States military procurement MIL-R- standards.
## Power dissipation
The power dissipated by a resistor is the voltage across the resistor multiplied by the current through the resistor:
P = I^2 R = I \cdot V = \frac{V^2}{R}
</math>
All three equations are equivalent. The first is derived from Joule's law, and the other two are derived from that by Ohm's Law.
The total amount of heat energy released is the integral of the power over time:
W = \int_{t_1}^{t_2} v(t) i(t)\, dt.
</math>
If the average power dissipated exceeds the power rating of the resistor, the resistor may depart from its nominal resistance, and may be damaged by overheating. Significantly excessive power dissipation may raise the temperature of the resistor to a point where it burns out, which could cause a fire in adjacent components and materials.
## Series and parallel circuits
Resistors in a parallel configuration each have the same potential difference (voltage). To find their total equivalent resistance (Req):
\frac{1}{R_\mathrm{eq}} = \frac{1}{R_1} + \frac{1}{R_2} + \cdots + \frac{1}{R_n}
</math>
The parallel property can be represented in equations by two vertical lines "||" (as in geometry) to simplify equations. For two resistors,
R_\mathrm{eq} = R_1 \| R_2 = {R_1 R_2 \over R_1 + R_2}
</math>
The current through resistors in series stays the same, but the voltage across each resistor can be different. The sum of the potential differences (voltage) is equal to the total voltage. To find their total resistance:
R_\mathrm{eq} = R_1 + R_2 + \cdots + R_n
</math>
A resistor network that is a combination of parallel and series can sometimes be broken up into smaller parts that are either one or the other. For instance,
R_\mathrm{eq} = \left( R_1 \| R_2 \right) + R_3 = {R_1 R_2 \over R_1 + R_2} + R_3
</math>
However, many resistor networks cannot be split up in this way. Consider a cube, each edge of which has been replaced by a resistor. For example, determining the resistance between two opposite vertices requires matrix methods for the general case. However, if all twelve resistors are equal, the corner-to-corner resistance is 5⁄6 of any one of them.
# Technology
## Carbon composition
Carbon composition resistors consist of a solid cylindrical resistive element with embedded wire leadouts or metal end caps to which the leadout wires are attached, which is protected with paint or plastic.
The resistive element is made from a mixture of finely ground (powdered) carbon and an insulating material (usually ceramic). The mixture is held together by a resin. The resistance is determined by the ratio of the
fill material (the powdered ceramic) and the carbon. Higher concentrations of carbon, a weak conductor, result in lower resistance. Carbon composition resistors were commonly used in the 1960s and earlier, but are not so popular for general use now as other types have better specifications, such as tolerance, voltage dependence, and stress (carbon composition resistors will change value when stressed with over-voltages).
## Carbon film
A spiral is used to increase the length and decrease the width of the film, which increases the resistance. Varying shapes, coupled with the resistivity of carbon, (ranging from 9 to 40 µΩm) can make for a variety of resistances.[2]
## Thick and thin film
Thick film resistors became popular during the 1970s, and most SMD resistors today are of this type. The principal difference between "thin film" and "thick film resistors" isn't necessarily the "thickness" of the film, but rather, how the film is applied to the cylinder (axial resistors) or the surface (SMD resistors). In thick film resistors the "film" is applied using traditional screen-printing technology.
Thin film resistors are made by sputtering the resistive material onto the surface of the resistor. Sputtering is a method used in vacuum deposition. The thin film is then etched in a similar manner to the old (subtractive) process for making printed circuit boards: ie the surface is coated with a photo-sensitive material, then covered by a film, irradiated with ultraviolet light, and then the exposed photo-sensitive coating, and underlying thin film, are etched away.
Thin film resistors, like their thick film counterparts, are then usually trimmed to an accurate value by abrasive or laser trimming.
Because the time during which the sputtering is performed can be controlled, the thickness of the film of a thin-film resistor can be accurately controlled. The type of the material is also usually different consisting of one or more ceramic (cermet) conductors such as tantalum nitride (TaN), ruthenium dioxide (RuO2), lead oxide (PbO), bismuth ruthenate (Bi2Ru2O7), nickel chromium (NiCr), and/or bismuth iridate (Bi2Ir2O7).
By contrast, thick film resistors, may use the same conductive ceramics, but they are mixed with sintered (powdered) glass, and some kind of liquid so that the composite can be screen-printed. This composite of glass and conductive ceramic (cermet) material is then fused (baked) in an oven at about 850 °C.
Traditionally thick film resistors had tolerances of 5%, but in the last few decades, standard tolerances have improved to 2% and 1%. But beware, temperature coefficients of thick film resistors are tyically ±200 ppm, or ±250 ppm, depending on the resistance. Thus a 40 degree Celsius (70 °F) temperature change can add another 1% variation to a 1% resistor.
Thin film resistors are usually specified with tolerances of 0.1, 0.2, 0.5, and 1%, and with temperature coefficients of 5 to 25 ppm. They are usually far more expensive than their thick film cousins. Note, though, that SMD thin film resistors, with 0.5% tolerances, and with 25 ppm temperature coefficients, when bought in full size reel quantities, are about twice the cost of a 1%, 250 ppm thick film resistors.
## Metal film
A common type of axial resistor today is referred to as a metal-film resistor. MELF (Metal Electrode Leadless Face) resistors often use the same technology, but are a cylindrically shaped resistor designed for surface mounting. [Note that other types of resistors, eg carbon composition, are also available in "MELF" packages].
Metal film resistors are usually coated with nickel chromium (NiCr), but might be coated with any of the cermet materials listed above for thin film resistors. Unlike thin film resistors, the material may be applied using different techniques than sputtering (though that is one such technique). Also, unlike thin-film resistors, the resistance value is determined by cutting a helix through the coating rather than by etching. [This is similar to the way carbon resistors are made.] The result is a reasonable tolerance (0.5, 1, or 2%) and a temperature coefficient of (usually) 25 or 50 ppm.
## Wirewound
Wirewound resistors are commonly made by winding a metal wire around a ceramic, plastic, or fiberglass core. The ends of the wire are soldered or welded to two caps, attached to the ends of the core. The assembly is protected with a layer of paint, molded plastic, or an enamel coating baked at high temperature. The wire leads are usually between 0.6 and 0.8 mm in diameter and tinned for ease of soldering. For higher power wirewound resistors, either a ceramic outer case or an aluminium outer case on top of an insulating layer is used. The aluminium cased types are designed to be attached to a heatsink to dissipate the heat; the rated power is dependent on being used with a suitable heatsink, e.g., a 50 W power rated resistor will overheat at around one fifth of the power dissipation if not used with a heatsink.
Because wirewound resistors are coils they have more inductance than other types of resistor, although this property can be minimized by winding the wire in sections with alternately reversed direction.
## Foil resistor
Foil resistors have had the best precision and stability ever since they were introduced in 1958 by Felix Zandman. One of the important parameters influencing stability is the temperature coefficient of resistance (TCR). Although the TCR of foil resistors is considered extremely low, this characteristic has been further refined over the years.[3]
## Grid resistor
The term "grid resistor" can mean two things:
In tube or valve electronic circuit design, a grid resistor or "grid stopper" is used to limit grid current and prevent high frequencies from entering or oscillating the circuit. Such a resistor can be composed of any one of a number of resistor technologies. One application that uses grid resistors is electric guitar amplifier circuitry.[4][5]
In heavy duty, industrial, high-current applications, a grid resistor is a large convection-cooled lattice of stamped metal alloy strips connected in rows between two electrodes. Such industrial grade resistors can be as large as a refrigerator; some designs can handle over 500 amps of current, with a range of resistances extending lower than 0.04 Ohms. They are used in applications such as dynamic braking for locomotives and trams, neutral grounding for industrial AC distribution, control loads for cranes and heavy equipment, load testing of generators and harmonic filtering for electric substations.[6][7][8]
## Other types
- Metal-oxide resistor
- Cermet
- Phenolic
- Tantalum
- Liquid-filled
# Noise
In precision circuits, electronic noise becomes of utmost concern. As dissipative elements, resistors will naturally produce a fluctuating "noise" voltage across their terminals. This Johnson–Nyquist noise is predicted by the fluctuation–dissipation theorem and is a fundamental noise source present in all resistors which must be considered in constructing low-noise electronics. For example, the gain in a simple (non-)inverting amplifier is set using a voltage divider. Noise considerations dictate that the smallest practical resistance should be used, since the noise voltage scales with resistance, and any resistor noise in the voltage divider will be impressed upon the amplifier's output.
Although Johnson–Nyquist noise is a fundamental noise source, resistors frequently exhibit other, "non-fundamental" sources of noise. Noise due to these sources is called "excess noise." Thick-film and carbon composition resistors are notorious for excess noise at low frequencies. Wire-wound and thin-film resistors, though much more expensive, are often utilized for their better noise characteristics.
# Failure modes and pitfalls
Like every part, resistors can fail; the usual way depends on their construction. Carbon composition resistors and metal film resistors typically fail as open circuits. Carbon-film resistors typically fail as short circuits[citation needed]. Carbon film and composition resistors can burn if too much power is dissipated. This is also possible but less likely with metal film and wirewound resistors. If not enclosed, wirewound resistors can corrode. Carbon -composition resistors are prone to drifting over time and are easily damaged by excessive heat in soldering (the binder evaporates).
Various effects become important in high-precision applications. Small voltage differentials may appear on the resistors due to thermoelectric effect if their ends are not kept at the same temperature. The voltages appear in the junctions of the resistor leads with the circuit board and with the resistor body. Common metal film resistors show such effect at magnitude of about 20 µV/°C. Some carbon composition resistors can go as high as 400 µV/°C, and specially constructed resistors can go as low as 0.05 µV/°C. In applications where thermoelectric effects may become important, care has to be taken to e.g. mount the resistors horizontally to avoid temperature gradients and to mind the air flow over the board. [9] | https://www.wikidoc.org/index.php/Resistor | |
fa23a921542fa2965bf8b82bd89ee1c95271f596 | wikidoc | Rev-ErbA | Rev-ErbA
The Rev-ErbA proteins are members of the nuclear receptor family of intracellular transcription factors. There are two forms of the receptor, alpha and beta, each encoded by a separate gene (NR1D1 and NR1D2 respectively).
The rev-Erb-α gene is highly unusual in that it is encoded on the opposite strand of the alpha-thyroid hormone receptor (TR) gene.
The rev-Erb-α protein is a key regulatory component of the circadian clock. In addition, rev-Erb-α appears also to regulate the breakdown of cartilage.
# Ligands
- SR9009 (aka Stenabolic) is listed as an agonist | Rev-ErbA
The Rev-ErbA proteins are members of the nuclear receptor family of intracellular transcription factors. There are two forms of the receptor, alpha and beta, each encoded by a separate gene (NR1D1 and NR1D2 respectively).[1][2]
The rev-Erb-α gene is highly unusual in that it is encoded on the opposite strand of the alpha-thyroid hormone receptor (TR) gene.[1]
The rev-Erb-α protein is a key regulatory component of the circadian clock.[3][4] In addition, rev-Erb-α appears also to regulate the breakdown of cartilage.[5]
# Ligands
- SR9009 (aka Stenabolic) is listed as an agonist | https://www.wikidoc.org/index.php/Rev-ErbA | |
664c9b912753941fea93178e822ff976a6d67813 | wikidoc | Rhamnose | Rhamnose
Rhamnose is a naturally-occurring deoxy sugar. It can be classified either as a methyl-pentose or a 6-deoxy-hexose. Rhamnose occurs in nature in its L-form as L-rhamnose (6-deoxy-L-mannose). This is unusual since most of the naturally-occurring sugars are in D-form. Exceptions are the methyl pentoses L-fucose and L-rhamnose and the pentose L-arabinose.
L-Rhamnose can be isolated from Buckthorn (Rhamnus) and poison sumac. It is also found as a glycoside in a variety of other plants.
Rhamnose is a component of the outer cell membrane of acid-fast bacteria in the Mycobacterium genus, which includes the organsism that causes tuberculosis. | Rhamnose
Template:Chembox new
Rhamnose is a naturally-occurring deoxy sugar. It can be classified either as a methyl-pentose or a 6-deoxy-hexose. Rhamnose occurs in nature in its L-form as L-rhamnose (6-deoxy-L-mannose). This is unusual since most of the naturally-occurring sugars are in D-form. Exceptions are the methyl pentoses L-fucose and L-rhamnose and the pentose L-arabinose.
L-Rhamnose can be isolated from Buckthorn (Rhamnus) and poison sumac. It is also found as a glycoside in a variety of other plants.
Rhamnose is a component of the outer cell membrane of acid-fast bacteria in the Mycobacterium genus, which includes the organsism that causes tuberculosis.[1] | https://www.wikidoc.org/index.php/Rhamnose | |
b84371d8ea3d11155b99678a94b61a5c931f98d4 | wikidoc | Rheobase | Rheobase
In neuroscience, rheobase is the minimal electric current of infinite duration (practically, a few hundred milliseconds) that results in an action potential or the contraction of a muscle.
In the case of a nerve or single muscle cell, rheobase is half the current that needs to be applied for the duration of chronaxie to result in an action potential or muscle twitch. This can be understood better by looking at a strength duration relationship.
This is in short the : "Minimal Electrical current that results in an action potential"
# Links
Chronaxie | Rheobase
In neuroscience, rheobase is the minimal electric current of infinite duration (practically, a few hundred milliseconds) that results in an action potential or the contraction of a muscle.
In the case of a nerve or single muscle cell, rheobase is half the current that needs to be applied for the duration of chronaxie to result in an action potential or muscle twitch. [1] This can be understood better by looking at a strength duration relationship. [2]
This is in short the : "Minimal Electrical current that results in an action potential"
# Links
Chronaxie | https://www.wikidoc.org/index.php/Rheobase | |
5f259826bc46828753ad36105aeea9a7c0157f9a | wikidoc | Rhizaria | Rhizaria
# Overview
The Rhizaria are a major line of protists. They vary considerably in form, but for the most part they are amoeboids with filose, reticulose, or microtubule-supported pseudopods. Many produce shells or skeletons, which may be quite complex in structure, and these make up the vast majority of protozoan fossils. Nearly all have mitochondria with tubular cristae. There are three main groups of Rhizaria:
Cercozoa - Various amoebae and flagellates, usually with filose pseudopods and common in soil
Foraminifera - Amoeboids with reticulose pseudopods, common as marine benthos
Radiolaria - Amoeboids with axopods, common as marine plankton
A few other groups may be included in the Cercozoa, but on some trees appear closer to the Foraminifera. These are the Phytomyxea and Ascetosporea, parasites of plants and animals respectively, and the peculiar amoeba Gromia. The different groups of Rhizaria are considered close relatives based mainly on genetic similarities, and have been regarded as an extension of the Cercozoa. The name Rhizaria for the expanded group was introduced by Cavalier-Smith in 2002, who also included the centrohelids and Apusozoa.
# Evolutionary relationship
Rhizaria is part of the bikont clade, which also comprises the Archaeplastida, the Chromalveolata, the Excavata, and some smaller, unresolved groups such as the Apusozoa and the Centrohelida. As bikonts, they all descend from a heterotrophic eukaryote with two flagella. It is also thought that the Rhizaria share a closer relationship with the Excavata than with the other groups, in a clade some call Cabozoa.
Historically, many rhizarians were considered animals, with their motility and heterotrophy as justification. However, when the five-kingdom system took prevalence over the animal-plant dichotomy, the rhizarians were put into the kingdom Protista. Then, after Woese published his three-domain system, because of the paraphyly of the kingdom Monera, taxonomists turned their attention to the eukaryote domain, and the inherent paraphyly of Protista. After much debate, which continues to this day, Rhizaria emerged as a monophyletic group. | Rhizaria
# Overview
The Rhizaria are a major line of protists. They vary considerably in form, but for the most part they are amoeboids with filose, reticulose, or microtubule-supported pseudopods. Many produce shells or skeletons, which may be quite complex in structure, and these make up the vast majority of protozoan fossils. Nearly all have mitochondria with tubular cristae. There are three main groups of Rhizaria:
Cercozoa - Various amoebae and flagellates, usually with filose pseudopods and common in soil
Foraminifera - Amoeboids with reticulose pseudopods, common as marine benthos
Radiolaria - Amoeboids with axopods, common as marine plankton
A few other groups may be included in the Cercozoa, but on some trees appear closer to the Foraminifera. These are the Phytomyxea and Ascetosporea, parasites of plants and animals respectively, and the peculiar amoeba Gromia. The different groups of Rhizaria are considered close relatives based mainly on genetic similarities, and have been regarded as an extension of the Cercozoa. The name Rhizaria for the expanded group was introduced by Cavalier-Smith in 2002, who also included the centrohelids and Apusozoa.
# Evolutionary relationship
Rhizaria is part of the bikont clade, which also comprises the Archaeplastida, the Chromalveolata, the Excavata, and some smaller, unresolved groups such as the Apusozoa and the Centrohelida. As bikonts, they all descend from a heterotrophic eukaryote with two flagella. It is also thought that the Rhizaria share a closer relationship with the Excavata than with the other groups, in a clade some call Cabozoa.
Historically, many rhizarians were considered animals, with their motility and heterotrophy as justification. However, when the five-kingdom system took prevalence over the animal-plant dichotomy, the rhizarians were put into the kingdom Protista. Then, after Woese published his three-domain system, because of the paraphyly of the kingdom Monera, taxonomists turned their attention to the eukaryote domain, and the inherent paraphyly of Protista. After much debate, which continues to this day, Rhizaria emerged as a monophyletic group. | https://www.wikidoc.org/index.php/Rhizaria | |
549ae6f0cf1c00f318b1a67ff7e2b31a4c766384 | wikidoc | Rhizobia | Rhizobia
Rhizobia (from the Greek words rhiza = root and bios = Life) are soil bacteria that fix nitrogen (diazotrophy) after becoming established inside root nodules of legumes (Fabaceae). The rhizobia cannot independently fix nitrogen, and require a plant host. Morphologically they are generally gram negative, motile, non-sporulating rods.
# History
The first species (R. leguminosarum) was identified in 1889, and all further species placed in the Rhizobium genus. However, more advanced methods of analysis have revised this classification and now there are many in other genera. Rhizobium is still sometimes used as the singular of rhizobia. Most research has been done on crop and forage legumes such as clover, beans, and soy. However, recently more work is occurring on indigenous legumes.
# Taxonomy
Rhizobia consist of 57 species found in 12 genera. Most belong to the Rhizobiales, a probably-monophyletic group of proteobacteria. Within that group, however, they are scattered among several different families:
These groups also include a variety of other bacteria. For instance, the plant pathogen Agrobacterium is a closer relative of Rhizobium than the rhizobia that nodulate soybean (and may not really be a separate genus). The genes responsible for the symbiosis with plants, however, may be closer than the organisms themselves, acquired by horizontal transfer (via bacterial conjugation) rather than from a common ancestor.
# Importance in agriculture
Although much of the nitrogen is removed when protein-rich grain or hay is harvested, significant amounts can remain in the soil for future crops. This is especially important when nitrogen fertilizer is not used, as in organic rotation schemes or some less-industrialized countries. Nitrogen is the most commonly deficient nutrient in many soils around the world and it is the most commonly supplied plant nutrient. Supply of nitrogen through fertilizers has severe environmental concerns. Nitrogen fixation by Rhizobium is also beneficial to the environment.
they are rod shaped and flagellated, non - sporulating.
at times they are covered all over by flagella.
they enter leguminous plants through the root hair .
# Symbiosis
Rhizobia are unique because they live in a symbiotic relationship with legumes. Common crop and forage legumes are peas, beans, clover, and soy. Rhizobia live in the soil where they encounter the root of a legume, and if that bacteria has the correct nod or nodulating genes, symbiosis can occur. The rhizobia enter a root hair and travel down a tube to the reletively anoxic centre of the root hair cell. Here proliferating plant cells form a nodule. The bacteria differentiate morphologically into bacteroids and fix nitrogen from the atmosphere in to a plant usable form, ammonium (NH4+), utilising the enzyme nitrogenase. In return the plant supplies the bacteria with carbohydrates, proteins, and sufficient enough oxygen so as not to interfere with the fixation process.
The legume – Rhizobia symbiosis is a classic example of mutualism — rhizobia supply ammonia or amino acids to the plant and in return receive organic acids (principally as the dicarboxylic acids malate and succinate) as a carbon and energy source — but its evolutionary persistence is actually somewhat surprising. Because several unrelated strains infect each individual plant, any one strain could redirect resources from nitrogen fixation to its own reproduction without killing the host plant upon which they all depend. But this form of cheating should be equally tempting for all strains, a classic tragedy of the commons. It turns out that legume plants guide the evolution of rhizobia towards greater mutualism by reducing the oxygen supply to nodules that fix less nitrogen, thereby reducing the frequency of cheaters in the next generation.
# Other diazotrophs
Many other species of bacteria are able to fix nitrogen (diazotrophs), including Frankia which is symbiotic and Azospirillum which is free-living. | Rhizobia
Rhizobia (from the Greek words rhiza = root and bios = Life) are soil bacteria that fix nitrogen (diazotrophy) after becoming established inside root nodules of legumes (Fabaceae). The rhizobia cannot independently fix nitrogen, and require a plant host. Morphologically they are generally gram negative, motile, non-sporulating rods.
# History
The first species (R. leguminosarum) was identified in 1889, and all further species placed in the Rhizobium genus. However, more advanced methods of analysis have revised this classification and now there are many in other genera. Rhizobium is still sometimes used as the singular of rhizobia. Most research has been done on crop and forage legumes such as clover, beans, and soy. However, recently more work is occurring on indigenous legumes.
# Taxonomy
Rhizobia consist of 57 species found in 12 genera.[1] Most belong to the Rhizobiales, a probably-monophyletic group of proteobacteria. Within that group, however, they are scattered among several different families:
These groups also include a variety of other bacteria. For instance, the plant pathogen Agrobacterium is a closer relative of Rhizobium than the rhizobia that nodulate soybean (and may not really be a separate genus). The genes responsible for the symbiosis with plants, however, may be closer than the organisms themselves, acquired by horizontal transfer (via bacterial conjugation) rather than from a common ancestor.
# Importance in agriculture
Although much of the nitrogen is removed when protein-rich grain or hay is harvested, significant amounts can remain in the soil for future crops. This is especially important when nitrogen fertilizer is not used, as in organic rotation schemes or some less-industrialized countries. Nitrogen is the most commonly deficient nutrient in many soils around the world and it is the most commonly supplied plant nutrient. Supply of nitrogen through fertilizers has severe environmental concerns. Nitrogen fixation by Rhizobium is also beneficial to the environment.
they are rod shaped and flagellated, non - sporulating.
at times they are covered all over by flagella.
they enter leguminous plants through the root hair .
# Symbiosis
Rhizobia are unique because they live in a symbiotic relationship with legumes. Common crop and forage legumes are peas, beans, clover, and soy. Rhizobia live in the soil where they encounter the root of a legume, and if that bacteria has the correct nod or nodulating genes, symbiosis can occur. The rhizobia enter a root hair and travel down a tube to the reletively anoxic centre of the root hair cell. Here proliferating plant cells form a nodule. The bacteria differentiate morphologically into bacteroids and fix nitrogen from the atmosphere in to a plant usable form, ammonium (NH4+), utilising the enzyme nitrogenase. In return the plant supplies the bacteria with carbohydrates, proteins, and sufficient enough oxygen so as not to interfere with the fixation process.
The legume – Rhizobia symbiosis is a classic example of mutualism — rhizobia supply ammonia or amino acids to the plant and in return receive organic acids (principally as the dicarboxylic acids malate and succinate) as a carbon and energy source — but its evolutionary persistence is actually somewhat surprising. Because several unrelated strains infect each individual plant, any one strain could redirect resources from nitrogen fixation to its own reproduction without killing the host plant upon which they all depend. But this form of cheating should be equally tempting for all strains, a classic tragedy of the commons. It turns out that legume plants guide the evolution of rhizobia towards greater mutualism by reducing the oxygen supply to nodules that fix less nitrogen, thereby reducing the frequency of cheaters in the next generation.
# Other diazotrophs
Many other species of bacteria are able to fix nitrogen (diazotrophs), including Frankia which is symbiotic and Azospirillum which is free-living.
# External links
- Legume sanctions maintain Rhizobium mutualism
- Current list of rhizobia species
- Nitrogen Fixation and Inoculation of Forage Legumes | https://www.wikidoc.org/index.php/Rhizobia | |
bdc355fe1a150e6ca9b0bafda7efa551a31d002b | wikidoc | Rhizomes | Rhizomes
In botany, a rhizome is a horizontal stem of a plant that is usually found underground, often sending out roots and shoots from its nodes. Plants with underground rhizomes include ginger, hops, and turmeric, significant for their medicinal properties, and the weeds Johnson grass, bermuda grass, and purple nut sedge. Some plants have rhizomes that grow above ground or that sit at the soil surface, including some Iris species, and ferns, whose spreading stems are rhizomes. Rhizomes may also be referred to as creeping rootstalks, or rootstocks. A stolon is similar to a rhizome, but, unlike a rhizome, which is the main stem of the plant, a stolon sprouts from an existing stem, has long internodes, and generates new shoots at the end, e.g., the strawberry plant. In general, rhizomes have short internodes; they send out roots from the bottom of the nodes and new upward-growing shoots from the top of the nodes.
For many plants, the rhizome is used by gardeners to propagate the plants by a process known as vegetative reproduction. Examples of plants that are propagated this way include asparagus, ginger, irises, Lily of the Valley, Cannas, and sympodial orchids.
A stem tuber is a thickened part of a rhizome or stolon that has been enlarged for use as a storage organ. In general, a tuber is high in starch, for example, the common potato, which is a modified stolon. The term tuber is often used imprecisely, and is sometimes applied to plants with rhizomes.
The rhizome is a key metaphor in the philosophy of Gilles Deleuze and Felix Guattari. | Rhizomes
In botany, a rhizome is a horizontal stem of a plant that is usually found underground, often sending out roots and shoots from its nodes. Plants with underground rhizomes include ginger, hops, and turmeric, significant for their medicinal properties, and the weeds Johnson grass, bermuda grass, and purple nut sedge. Some plants have rhizomes that grow above ground or that sit at the soil surface, including some Iris species, and ferns, whose spreading stems are rhizomes. Rhizomes may also be referred to as creeping rootstalks, or rootstocks. A stolon is similar to a rhizome, but, unlike a rhizome, which is the main stem of the plant, a stolon sprouts from an existing stem, has long internodes, and generates new shoots at the end, e.g., the strawberry plant. In general, rhizomes have short internodes; they send out roots from the bottom of the nodes and new upward-growing shoots from the top of the nodes.
For many plants, the rhizome is used by gardeners to propagate the plants by a process known as vegetative reproduction. Examples of plants that are propagated this way include asparagus, ginger, irises, Lily of the Valley, Cannas, and sympodial orchids.
A stem tuber is a thickened part of a rhizome or stolon that has been enlarged for use as a storage organ. [1] In general, a tuber is high in starch, for example, the common potato, which is a modified stolon. The term tuber is often used imprecisely, and is sometimes applied to plants with rhizomes.
The rhizome is a key metaphor in the philosophy of Gilles Deleuze and Felix Guattari. | https://www.wikidoc.org/index.php/Rhizomes | |
8f73f090a75a581f3acb3208fff90432837f2bde | wikidoc | Rhizopus | Rhizopus
# Overview
Rhizopus is a genus of common saprobic fungi on plants and specialized parasites on animals. They are found on a wide variety of organic substrates, including "mature fruits and vegetables", faeces, jellies, syrups, leather, bread, peanuts and tobacco. Some Rhizopus species are opportunistic agents of human zygomycosis (fungal infection) and can be fatal. Rhizopus infections are also an associated complication of diabetic ketoacidosis. The widespread genus contains about nine species.
Rhizopus reproduces by vegetative, asexual and sexual methods by spores. The asexual sporangiospores are produced inside a pinhead-like structure, the sporangium, and are genetically identical to their parent. In Rhizopus, the sporangia are supported by a large apophysate columella, and the sporangiophores arise among distinctive rhizoids. Dark zygospores are produced after two compatible mycelia fuse during sexual reproduction producing colonies that may be genetically different from their parents.
- R. arrhizus causes fruit rot on apples.
- R. artocarpi causes fruit drop on jack fruit.
- R. nigricans is a common bread mold.
- R. oligosporus is used to make tempeh, a fermented food derived from soybeans.
- R. oryzae is used in the production of alcoholic beverages in parts of Asia and Africa.
- R. stolonifer (black bread mold) causes fruit rot on strawberry, tomato, and sweet potato and used in commercial production of fumaric acid and cortisone.
# Species
- Rhizopus arrhizus
- Rhizopus azygosporus
- Rhizopus circinans
- Rhizopus microsporus
- Rhizopus nigricans
- Rhizopus oligosporus
- Rhizopus oryzae
- Rhizopus schipperae
- Rhizopus sexualis
- Rhizopus stolonifer
# Plant body or mycelium
- The plant body of rhizopus is known as mycelium.It is made up of long tubular branched thread or filament like structure called hyphae.The mycelium can be distinguished into three types of hyphae namely
- stolons
- rhizoids
- Sporangiospores | Rhizopus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rhizopus is a genus of common saprobic fungi on plants and specialized parasites on animals. They are found on a wide variety of organic substrates, including "mature fruits and vegetables", faeces, jellies, syrups, leather, bread, peanuts and tobacco. Some Rhizopus species are opportunistic agents of human zygomycosis (fungal infection) and can be fatal. Rhizopus infections are also an associated complication of diabetic ketoacidosis. The widespread genus contains about nine species.
Rhizopus reproduces by vegetative, asexual and sexual methods by spores. The asexual sporangiospores are produced inside a pinhead-like structure, the sporangium, and are genetically identical to their parent. In Rhizopus, the sporangia are supported by a large apophysate columella, and the sporangiophores arise among distinctive rhizoids. Dark zygospores are produced after two compatible mycelia fuse during sexual reproduction producing colonies that may be genetically different from their parents.
- R. arrhizus causes fruit rot on apples.
- R. artocarpi causes fruit drop on jack fruit.
- R. nigricans is a common bread mold.
- R. oligosporus is used to make tempeh, a fermented food derived from soybeans.
- R. oryzae is used in the production of alcoholic beverages in parts of Asia and Africa.
- R. stolonifer (black bread mold) causes fruit rot on strawberry, tomato, and sweet potato and used in commercial production of fumaric acid and cortisone.
# Species
- Rhizopus arrhizus
- Rhizopus azygosporus
- Rhizopus circinans
- Rhizopus microsporus
- Rhizopus nigricans
- Rhizopus oligosporus
- Rhizopus oryzae
- Rhizopus schipperae
- Rhizopus sexualis
- Rhizopus stolonifer
# Plant body or mycelium
- The plant body of rhizopus is known as mycelium.It is made up of long tubular branched thread or filament like structure called hyphae.The mycelium can be distinguished into three types of hyphae namely
- stolons
- rhizoids
- Sporangiospores | https://www.wikidoc.org/index.php/Rhizopus | |
7841b8dc788f1362ef5e7bbfa252db47c98cf317 | wikidoc | Ribulose | Ribulose
Ribulose is a ketopentose — a monosaccharide containing five carbon atoms, and including a ketone functional group. It has chemical formula Template:Carbon5Template:Hydrogen10Template:Oxygen5. Two enantiomers are possible, D-ribulose (D-erythro-pentulose) and L-ribulose (L-erythro-pentulose). D-Ribulose is the diastereomer of D-xylulose.
Ribulose sugars are composed in the pentose phosphate pathway. They are important in the formation of many bioactive substances. For example, D-ribulose is an intermediate in the fungal pathway for D-arabitol production. Also, as the 1,5-bisphosphate, D-ribulose combines with carbon dioxide at the start of the photosynthetic process in green plants (carbon dioxide trap).
A synthetic form of ribulose known as sucroribulose is found in many brands of artificial sweeteners. | Ribulose
Template:Chembox new
Ribulose is a ketopentose — a monosaccharide containing five carbon atoms, and including a ketone functional group. It has chemical formula Template:Carbon5Template:Hydrogen10Template:Oxygen5. Two enantiomers are possible, D-ribulose (D-erythro-pentulose) and L-ribulose (L-erythro-pentulose). D-Ribulose is the diastereomer of D-xylulose.
Ribulose sugars are composed in the pentose phosphate pathway. They are important in the formation of many bioactive substances. For example, D-ribulose is an intermediate in the fungal pathway for D-arabitol production. Also, as the 1,5-bisphosphate, D-ribulose combines with carbon dioxide at the start of the photosynthetic process in green plants (carbon dioxide trap).
A synthetic form of ribulose known as sucroribulose is found in many brands of artificial sweeteners. | https://www.wikidoc.org/index.php/Ribulose | |
64aced89b2bfacaaf6c7767e5f1f1434c562af2c | wikidoc | Riluzole | Riluzole
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# Overview
Riluzole is a Glutamate antagonist that is FDA approved for the treatment of amyotrophic lateral sclerosis (ALS). Common adverse reactions include headache, abdominal pain, back pain, vomiting, dyspepsia, diarrhea, dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Riluzole tablets, USP are indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS).
- Riluzole extends survival and/or time to tracheostomy.
# Dosage
- The recommended dose for riluzole tablets is 50 mg every 12 hours. No increased benefit can be expected from higher daily doses, but adverse events are increased.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Riluzole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Riluzole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Riluzole FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Riluzole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Riluzole in pediatric patients.
# Contraindications
- Riluzole tablets are contraindicated in patients who have a history of severe hypersensitivity reactions to riluzole or any of the tablet components.
# Warnings
Liver Injury / Monitoring Liver Chemistries
- Riluzole tablets should be prescribed with care in patients with current evidence or history of abnormal liver function indicated by significant abnormalities in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and/or gamma-glutamate transferase (GGT) levels. Baseline elevations of several LFTs (especially elevated bilirubin) should preclude the use of riluzole.
- Riluzole, even in patients without a prior history of liver disease, causes serum aminotransferase elevations. Treatment should be discontinued if ALT levels are ≥ 5 X ULN or if clinical jaundice develops.
- Experience in almost 800 ALS patients indicates that about 50% of riluzole-treated patients will experience at least one ALT/SGPT level above the upper limit of normal, about 8% will have elevations > 3 × ULN, and about 2% of patients will have elevations > 5 × ULN. A single non-ALS patient with epilepsy treated with concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver enzymes with jaundice (ALT 26 × ULN, AST 17 × ULN, and bilirubin 11 × ULN) four months after starting riluzole; these returned to normal 7 weeks after treatment discontinuation.
- Maximum increases in serum ALT usually occurred within 3 months after the start of riluzole therapy and were usually transient when 5 X ULN, but there is the possibility of increased ALT values reoccurring: Laboratory Tests). Therefore, rechallenge is not recommended.
- In postmarketing experience, cases of clinical hepatitis associated with riluzole have been reported, including with fatal outcome.
Neutropenia
- Among approximately 4000 patients given riluzole for ALS, there were three cases of marked neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 months of riluzole treatment. In one case, neutrophil counts rose on continued treatment. In a second case, counts rose after therapy was stopped. A third case was more complex, with marked anemia as well as neutropenia and the etiology of both is uncertain. Patients should be warned to report any febrile illness to their physicians. The report of a febrile illness should prompt treating physicians to check white blood cell counts.
Interstitial Lung Disease
- Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them severe; upon further investigation, many of these cases were hypersensitivity pneumonitis. If respiratory symptoms develop such as dry cough and/or dyspnea, chest radiography should be performed, and in case of findings suggestive of interstitial lung disease or hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole should be discontinued immediately. In the majority of the reported cases, symptoms resolved after drug discontinuation and symptomatic treatment.
PRECAUTIONS
Use in Patients with Concomitant Disease
- Riluzole should be used with caution in patients with concomitant liver insufficiency. In particular, in cases of riluzole-induced hepatic injury manifested by elevated liver enzymes, the effect of the hepatic injury on riluzole metabolism is unknown.
Special Populations
- Riluzole should be used with caution in elderly patients whose hepatic function may be compromised due to age. Also, female patients may possess a lower metabolic capacity to eliminate riluzole compared to males.
Information for the Patients
- Patients should be advised to report any febrile illness to their physicians: Neutropenia.
- Patients should be advised to report any cough or difficulties in breathing to their physicians: Interstitial Lung Disease.
- Patients and caregivers should be advised that riluzole tablets should be taken on a regular basis and at the same time of the day (e.g., in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned.
- Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on riluzole to gauge whether or not it affects their mental and/or motor performance adversely.
- Whether alcohol increases the risk of serious hepatotoxicity with riluzole is unknown; therefore, patients being treated with riluzole should be discouraged from drinking excessive amounts of alcohol.
- Patients should also be made aware that riluzole tablets should be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) and protected from bright light.
- Riluzole tablets must be kept out of the reach of children.
# Adverse Reactions
## Clinical Trials Experience
- The most commonly observed AEs associated with the use of riluzole more frequently than placebo treated patients were: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, and circumoral paresthesia were dose related.
- Approximately 14% (n = 141) of the 982 individuals with ALS who received riluzole in pre-marketing clinical trials discontinued treatment because of an adverse experience. Of those patients who discontinued due to adverse events, the most commonly reported were: nausea, abdominal pain, constipation, and ALT elevations. In a dose response study in ALS patients, the rates of discontinuation of riluzole for asthenia, nausea, abdominal pain, and ALT elevation were dose related.
Incidence in Controlled ALS Clinical Studies
- Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with ALS treated with riluzole (n=794) participating in placebo-controlled trials and were numerically greater in the patients treated with riluzole 100 mg/day than with placebo or for which a dose response relationship is suggested.
- The prescriber should be aware that these figures cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the AE incidences in the population studied.
Other Adverse Events Observed
- Other events which occurred in more than 2% of patients treated with riluzole 100 mg/day but equally or more frequently in the placebo group included: accidental injury, apnea, bronchitis, constipation, death, dysphagia, dyspnea, flu syndrome, heart arrest, increased sputum, pneumonia, and respiratory disorder.
- The overall adverse event profile for riluzole was similar between females and males, and was independent of age. Because the largest non-white racial subgroup was only 2% of patients exposed to riluzole (18/794) in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. In ALS studies, dizziness did occur more commonly in females (11%) than in males (4%). There was not a difference between females and males in the rates of discontinuation of riluzole for individual adverse experiences.
Other Adverse Events Observed During All Clinical Trials
- Riluzole has been administered to 1713 individuals during all clinical trials, some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 1713 individuals exposed to riluzole who experienced an event of the type cited on at least one occasion while receiving riluzole. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug.
- Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Frequent: Hostility. Infrequent: Abscess, sepsis, photosensitivity reaction, cellulitis, face edema, hernia, peritonitis, attempted suicide, injection site reaction, chills, flu syndrome, intentional injury, enlarged abdomen, neoplasm. Rare: Acrodynia, hypothermia, moniliasis, rheumatoid arthritis.
Digestive System: Infrequent: Increased appetite, intestinal obstruction, fecal impaction, gastrointestinal hemorrhage, gastrointestinal ulceration, gastritis, fecal incontinence, jaundice, hepatitis, glossitis, gum hemorrhage, pancreatitis, tenesmus, esophageal stenosis. Rare: Cheilitis, cholecystitis, hematemesis, melena, biliary pain, proctitis, pseudomembranous enterocolitis, enlarged salivary gland, tongue discoloration, tooth caries.
Immune System Disorders: Infrequent: Anaphylactoid reaction and anaphylaxis.
Nervous System: Frequent: Agitation, tremor. Infrequent: Hallucinations, personality disorder, abnormal thinking, coma, paranoid reaction, manic reaction, ataxia, extrapyramidal syndrome, hypokinesia, urinary retention, emotional lability, delusions, apathy, hypesthesia, incoordination, confusion, convulsion, leg cramps, amnesia, dysarthria, increased libido, stupor, subdural hematoma, abnormal gait, delirium, depersonalization, facial paralysis, hemiplegia, decreased libido, myoclonus. Rare: Abnormal dreams, acute brain syndrome, CNS depression, dementia, cerebral embolism, euphoria, hypotonia, ileus, peripheral neuritis, psychosis, psychotic depression, schizophrenic reaction, trismus, wristdrop.
Skin and Appendages: Infrequent: Skin ulceration, urticaria, psoriasis, seborrhea1, skin disorder, fungal dermatitis. Rare: Angioedema, contact dermatitis, erythema multiforme, furunculosis, skin moniliasis, skin granuloma, skin nodule.
Respiratory System: Infrequent: Hiccup, pleural disorder, asthma, epistaxis, hemoptysis, yawn, hyperventilation, lung edema, hypoventilation, lung carcinoma, hypoxia, laryngitis, pleural effusion, pneumothorax, respiratory moniliasis, stridor, interstitial lung disease, hypersensitivity pneumonitis.
Cardiovascular System: Infrequent: Syncope, hypotension, heart failure, migraine, peripheral vascular disease, angina pectoris, myocardial infarction, ventricular extrasystoles, cerebral hemorrhage, atrial fibrillation, bundle branch block, congestive heart failure, pericarditis, lower extremity embolus, myocardial ischemia, shock. Rare: Bradycardia, cerebral ischemia, hemorrhage, mesenteric artery occlusion, subarachnoid hemorrhage, supraventricular tachycardia, thrombosis, ventricular fibrillation, ventricular tachycardia.
Metabolic and Nutritional Disorders: Infrequent: Gout, respiratory acidosis, edema, thirst, hypokalemia, hyponatremia, weight gain. Rare: Generalized edema, hypercalcemia, hypercholesteremia.
Endocrine System: Infrequent: Diabetes mellitus, thyroid neoplasia. Rare: Diabetes insipidus, parathyroid disorder.
Hemic and Lymphatic System: Infrequent: Anemia, leukocytosis, leukopenia, ecchymosis. Rare: Neutropenia, aplastic anemia, cyanosis, hypochromic anemia, iron deficiency anemia, lymphadenopathy, petechiae1, purpura.
Musculoskeletal System: Infrequent: Arthrosis, myasthenia1, bone neoplasm. Rare: Bone necrosis, osteoporosis, tetany.
Special Senses: Infrequent: Amblyopia, ophthalmitis. Rare: Blepharitis, cataract, deafness, diplopia, ear pain, glaucoma, hyperacusis, photophobia, taste loss, vestibular disorder.
Urogenital System: Infrequent: Urinary urgency, urine abnormality, urinary incontinence, kidney calculus, hematuria, impotence, prostate carcinoma, kidney pain, metrorrhagia, priapism. Rare: Amenorrhea, breast abscess, breast pain, nephritis, nocturia, pyelonephritis, enlarged uterine fibroids, uterine hemorrhage, vaginal moniliasis.
## Postmarketing Experience
There is limited information regarding Riluzole Postmarketing Experience in the drug label.
# Drug Interactions
- There have been no clinical studies designed to evaluate the interaction of riluzole with other drugs.
- As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Hepatotoxic Drugs
The clinical trials in ALS excluded patients on concomitant medications which were potentially hepatotoxic, (e.g., allopurinol, methyldopa, sulfasalazine). Accordingly, there is no information about the safety of administering riluzole in conjunction with such medications. If the practitioner chooses to prescribe such a combination, caution should be exercised.
Drugs Highly Bound To Plasma Proteins
Riluzole is highly bound (96%) to plasma proteins, binding mainly to serum albumin and to lipoproteins. The effect of riluzole (up to 5 mcg/mL) on warfarin (5 mcg/mL) binding did not show any displacement of warfarin. Conversely, riluzole binding was unaffected by the addition of warfarin, digoxin, imipramine and quinine at high therapeutic concentrations.
Effect of Other Drugs On Riluzole Metabolism
In vitro studies using human liver microsomal preparations suggest that CYP 1A2 is the principal isozyme involved in the initial oxidative metabolism of riluzole and, therefore, potential interactions may occur when riluzole is given concurrently with agents that affect CYP 1A2 activity. Potential inhibitors of CYP 1A2 (e.g., caffeine, phenacetin, theophylline, amitriptyline, and quinolones) could decrease the rate of riluzole elimination, while inducers of CYP 1A2 (e.g., cigarette smoke, charcoal-broiled food, rifampicin, and omeprazole) could increase the rate of riluzole elimination.
Effect of Riluzole On the Metabolism of Other Drugs
CYP 1A2 is the principal isoenzyme involved in the initial oxidative metabolism of riluzole; potential interactions may occur when riluzole is given concurrently with other agents which are also metabolized primarily by CYP 1A2 (e.g., theophylline, caffeine, and tacrine). Currently, it is not known whether riluzole has any potential for enzyme induction in humans.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy category C
- Oral administration of riluzole to pregnant animals during the period of organogenesis caused embryotoxicity in rats and rabbits at doses of 27 mg/kg and 60 mg/kg, respectively, or 2.6 and 11.5 times, respectively, the recommended maximum human daily dose on a mg/m2 basis. Evidence of maternal toxicity was also observed at these doses.
- When administered to rats prior to and during mating (males and females) and throughout gestation and lactation (females), riluzole produced adverse effects on pregnancy (decreased implantations, increased intrauterine death) and offspring viability and growth at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.
- There are no adequate and well-controlled studies in pregnant women. Riluzole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Riluzole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Riluzole during labor and delivery.
### Nursing Mothers
- In rat studies, 14C-riluzole was detected in maternal milk. It is not known whether riluzole is excreted in human breast milk. Because many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants from riluzole is unknown, women should be advised not to breast-feed during treatment with riluzole.
### Pediatric Use
- The safety and the effectiveness of riluzole in pediatric patients have not been established.
### Geriatic Use
- Age-related compromised renal and hepatic function may cause a decrease in clearance of riluzole. In controlled clinical trials, about 30% of patients were over 65. There were no differences in adverse effects between younger and older patients.
### Gender
There is no FDA guidance on the use of Riluzole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Riluzole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Riluzole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Riluzole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Riluzole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Riluzole in patients who are immunocompromised.
### Others
(Description)
# Administration and Monitoring
### Administration
- Oral
- Riluzole tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related decrease in bioavailability.
### Monitoring
There is limited information regarding Riluzole Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Riluzole and IV administrations.
# Overdosage
- No specific antidote or information on treatment of overdosage with RILUTEK is available. In the event of overdose, RILUTEK therapy should be discontinued immediately. Experience with riluzole overdose in humans is limited. Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma, and methemoglobinemia have been observed in isolated cases. Treatment should be supportive and directed toward alleviating symptoms.
- Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.
- The estimated oral median lethal dose is 94 mg/kg and 39 mg/kg for male mice and rats, respectively.
# Pharmacology
## Mechanism of Action
There is limited information regarding Riluzole Mechanism of Action in the drug label.
## Structure
There is limited information regarding Riluzole Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Riluzole Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Riluzole Pharmacokinetics in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Riluzole was not carcinogenic in mice or rats when administered for 2 years at daily oral doses up to 20 mg/kg and 10 mg/kg, respectively, which are approximately equivalent to the maximum human dose on a mg/m2 basis.
- The genotoxic potential of riluzole was evaluated in the bacterial mutagenicity (Ames) test, the mouse lymphoma mutation assay in L5178Y cells, the in vitro chromosomal aberration assay in human lymphocytes and the in vivo rat cytogenetic assay and in vivo mouse micronucleus assay in bone marrow. There was no evidence of mutagenic or clastogenic potential in the Ames test, the mouse lymphoma assay, or the in vivo assays in the mouse and rat. There was an equivocal clastogenic response in the in vitro human lymphocyte chromosomal aberration assay, which was not reproduced in a second assay performed at equal or higher concentrations; riluzole was therefore considered non-clastogenic in the human lymphocyte assay.
- N-hydroxyriluzole, the major active metabolite of riluzole, caused chromosomal damage in the in vitro mammalian mouse lymphoma assay and in the in vitro micronucleus assay that used the same mouse lymphoma cell line, L5178Y. N-hydroxyriluzole was not mutagenic in this cell line when tested in the HPRT gene mutation assay, and was negative in the Ames bacterial gene mutation assay (with and without rat or hamster S9), the in vitro UDS assay in rat hepatocytes, the chromosomal aberration test in human lymphocytes, and the in vivo mouse bone marrow micronucleus test.
- Riluzole impaired fertility when administered to male and female rats prior to and during mating at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.
# Clinical Studies
There is limited information regarding Riluzole Clinical Studies in the drug label.
# How Supplied
- Riluzole tablets, USP 50 mg are white to off white colored, round-shaped, biconvex film-coated tablets and debossed with “538” on one side and plain on other side.
They are supplied as follows:
- Unit Dose Box of 30’s ………………...NDC 0179-0150-70
## Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F)and protect from bright light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to report any febrile illness to their physicians.
- Patients should be advised to report any cough or difficulties in breathing to their physicians.
- Patients and caregivers should be advised that riluzole tablets should be taken on a regular basis and at the same time of the day (e.g., in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned.
- Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on riluzole to gauge whether or not it affects their mental and/or motor performance adversely.
- Whether alcohol increases the risk of serious hepatotoxicity with riluzole is unknown; therefore, patients being treated with riluzole should be discouraged from drinking excessive amounts of alcohol.
- Patients should also be made aware that riluzole tablets should be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) and protected from bright light.
- Riluzole tablets must be kept out of the reach of children.
# Precautions with Alcohol
Alcohol-Riluzole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Rilutek
# Look-Alike Drug Names
There is limited information regarding Riluzole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Riluzole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
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# Overview
Riluzole is a Glutamate antagonist that is FDA approved for the treatment of amyotrophic lateral sclerosis (ALS). Common adverse reactions include headache, abdominal pain, back pain, vomiting, dyspepsia, diarrhea, dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Riluzole tablets, USP are indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS).
- Riluzole extends survival and/or time to tracheostomy.
# Dosage
- The recommended dose for riluzole tablets is 50 mg every 12 hours. No increased benefit can be expected from higher daily doses, but adverse events are increased.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Riluzole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Riluzole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Riluzole FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Riluzole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Riluzole in pediatric patients.
# Contraindications
- Riluzole tablets are contraindicated in patients who have a history of severe hypersensitivity reactions to riluzole or any of the tablet components.
# Warnings
Liver Injury / Monitoring Liver Chemistries
- Riluzole tablets should be prescribed with care in patients with current evidence or history of abnormal liver function indicated by significant abnormalities in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and/or gamma-glutamate transferase (GGT) levels. Baseline elevations of several LFTs (especially elevated bilirubin) should preclude the use of riluzole.
- Riluzole, even in patients without a prior history of liver disease, causes serum aminotransferase elevations. Treatment should be discontinued if ALT levels are ≥ 5 X ULN or if clinical jaundice develops.
- Experience in almost 800 ALS patients indicates that about 50% of riluzole-treated patients will experience at least one ALT/SGPT level above the upper limit of normal, about 8% will have elevations > 3 × ULN, and about 2% of patients will have elevations > 5 × ULN. A single non-ALS patient with epilepsy treated with concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver enzymes with jaundice (ALT 26 × ULN, AST 17 × ULN, and bilirubin 11 × ULN) four months after starting riluzole; these returned to normal 7 weeks after treatment discontinuation.
- Maximum increases in serum ALT usually occurred within 3 months after the start of riluzole therapy and were usually transient when < 5 times ULN. In trials, if ALT levels were < 5 times ULN, treatment continued and ALT levels usually returned to below 2 times ULN within 2 to 6 months. Treatment in studies was discontinued, however, if ALT levels exceeded 5 × ULN, so that there is no experience with continued treatment of ALS patients once ALT values exceed 5 times ULN. There were rare instances of jaundice. There is limited experience with rechallenge of patients who have had riluzole discontinued for ALT > 5 X ULN, but there is the possibility of increased ALT values reoccurring: Laboratory Tests). Therefore, rechallenge is not recommended.
- In postmarketing experience, cases of clinical hepatitis associated with riluzole have been reported, including with fatal outcome.
Neutropenia
- Among approximately 4000 patients given riluzole for ALS, there were three cases of marked neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 months of riluzole treatment. In one case, neutrophil counts rose on continued treatment. In a second case, counts rose after therapy was stopped. A third case was more complex, with marked anemia as well as neutropenia and the etiology of both is uncertain. Patients should be warned to report any febrile illness to their physicians. The report of a febrile illness should prompt treating physicians to check white blood cell counts.
Interstitial Lung Disease
- Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them severe; upon further investigation, many of these cases were hypersensitivity pneumonitis. If respiratory symptoms develop such as dry cough and/or dyspnea, chest radiography should be performed, and in case of findings suggestive of interstitial lung disease or hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole should be discontinued immediately. In the majority of the reported cases, symptoms resolved after drug discontinuation and symptomatic treatment.
PRECAUTIONS
Use in Patients with Concomitant Disease
- Riluzole should be used with caution in patients with concomitant liver insufficiency. In particular, in cases of riluzole-induced hepatic injury manifested by elevated liver enzymes, the effect of the hepatic injury on riluzole metabolism is unknown.
Special Populations
- Riluzole should be used with caution in elderly patients whose hepatic function may be compromised due to age. Also, female patients may possess a lower metabolic capacity to eliminate riluzole compared to males.
Information for the Patients
- Patients should be advised to report any febrile illness to their physicians: Neutropenia.
- Patients should be advised to report any cough or difficulties in breathing to their physicians: Interstitial Lung Disease.
- Patients and caregivers should be advised that riluzole tablets should be taken on a regular basis and at the same time of the day (e.g., in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned.
- Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on riluzole to gauge whether or not it affects their mental and/or motor performance adversely.
- Whether alcohol increases the risk of serious hepatotoxicity with riluzole is unknown; therefore, patients being treated with riluzole should be discouraged from drinking excessive amounts of alcohol.
- Patients should also be made aware that riluzole tablets should be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) and protected from bright light.
- Riluzole tablets must be kept out of the reach of children.
# Adverse Reactions
## Clinical Trials Experience
- The most commonly observed AEs associated with the use of riluzole more frequently than placebo treated patients were: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, and circumoral paresthesia were dose related.
- Approximately 14% (n = 141) of the 982 individuals with ALS who received riluzole in pre-marketing clinical trials discontinued treatment because of an adverse experience. Of those patients who discontinued due to adverse events, the most commonly reported were: nausea, abdominal pain, constipation, and ALT elevations. In a dose response study in ALS patients, the rates of discontinuation of riluzole for asthenia, nausea, abdominal pain, and ALT elevation were dose related.
Incidence in Controlled ALS Clinical Studies
- Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with ALS treated with riluzole (n=794) participating in placebo-controlled trials and were numerically greater in the patients treated with riluzole 100 mg/day than with placebo or for which a dose response relationship is suggested.
- The prescriber should be aware that these figures cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the AE incidences in the population studied.
Other Adverse Events Observed
- Other events which occurred in more than 2% of patients treated with riluzole 100 mg/day but equally or more frequently in the placebo group included: accidental injury, apnea, bronchitis, constipation, death, dysphagia, dyspnea, flu syndrome, heart arrest, increased sputum, pneumonia, and respiratory disorder.
- The overall adverse event profile for riluzole was similar between females and males, and was independent of age. Because the largest non-white racial subgroup was only 2% of patients exposed to riluzole (18/794) in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. In ALS studies, dizziness did occur more commonly in females (11%) than in males (4%). There was not a difference between females and males in the rates of discontinuation of riluzole for individual adverse experiences.
Other Adverse Events Observed During All Clinical Trials
- Riluzole has been administered to 1713 individuals during all clinical trials, some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 1713 individuals exposed to riluzole who experienced an event of the type cited on at least one occasion while receiving riluzole. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug.
- Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Frequent: Hostility. Infrequent: Abscess, sepsis, photosensitivity reaction, cellulitis, face edema, hernia, peritonitis, attempted suicide, injection site reaction, chills, flu syndrome, intentional injury, enlarged abdomen, neoplasm. Rare: Acrodynia, hypothermia, moniliasis, rheumatoid arthritis.
Digestive System: Infrequent: Increased appetite, intestinal obstruction, fecal impaction, gastrointestinal hemorrhage, gastrointestinal ulceration, gastritis, fecal incontinence, jaundice, hepatitis, glossitis, gum hemorrhage, pancreatitis, tenesmus, esophageal stenosis. Rare: Cheilitis, cholecystitis, hematemesis, melena, biliary pain, proctitis, pseudomembranous enterocolitis, enlarged salivary gland, tongue discoloration, tooth caries.
Immune System Disorders: Infrequent: Anaphylactoid reaction and anaphylaxis.
Nervous System: Frequent: Agitation, tremor. Infrequent: Hallucinations, personality disorder, abnormal thinking, coma, paranoid reaction, manic reaction, ataxia, extrapyramidal syndrome, hypokinesia, urinary retention, emotional lability, delusions, apathy, hypesthesia, incoordination, confusion, convulsion, leg cramps, amnesia, dysarthria, increased libido, stupor, subdural hematoma, abnormal gait, delirium, depersonalization, facial paralysis, hemiplegia, decreased libido, myoclonus. Rare: Abnormal dreams, acute brain syndrome, CNS depression, dementia, cerebral embolism, euphoria, hypotonia, ileus, peripheral neuritis, psychosis, psychotic depression, schizophrenic reaction, trismus, wristdrop.
Skin and Appendages: Infrequent: Skin ulceration, urticaria, psoriasis, seborrhea1, skin disorder, fungal dermatitis. Rare: Angioedema, contact dermatitis, erythema multiforme, furunculosis, skin moniliasis, skin granuloma, skin nodule.
Respiratory System: Infrequent: Hiccup, pleural disorder, asthma, epistaxis, hemoptysis, yawn, hyperventilation, lung edema, hypoventilation, lung carcinoma, hypoxia, laryngitis, pleural effusion, pneumothorax, respiratory moniliasis, stridor, interstitial lung disease, hypersensitivity pneumonitis.
Cardiovascular System: Infrequent: Syncope, hypotension, heart failure, migraine, peripheral vascular disease, angina pectoris, myocardial infarction, ventricular extrasystoles, cerebral hemorrhage, atrial fibrillation, bundle branch block, congestive heart failure, pericarditis, lower extremity embolus, myocardial ischemia, shock. Rare: Bradycardia, cerebral ischemia, hemorrhage, mesenteric artery occlusion, subarachnoid hemorrhage, supraventricular tachycardia, thrombosis, ventricular fibrillation, ventricular tachycardia.
Metabolic and Nutritional Disorders: Infrequent: Gout, respiratory acidosis, edema, thirst, hypokalemia, hyponatremia, weight gain. Rare: Generalized edema, hypercalcemia, hypercholesteremia.
Endocrine System: Infrequent: Diabetes mellitus, thyroid neoplasia. Rare: Diabetes insipidus, parathyroid disorder.
Hemic and Lymphatic System: Infrequent: Anemia, leukocytosis, leukopenia, ecchymosis. Rare: Neutropenia, aplastic anemia, cyanosis, hypochromic anemia, iron deficiency anemia, lymphadenopathy, petechiae1, purpura.
Musculoskeletal System: Infrequent: Arthrosis, myasthenia1, bone neoplasm. Rare: Bone necrosis, osteoporosis, tetany.
Special Senses: Infrequent: Amblyopia, ophthalmitis. Rare: Blepharitis, cataract, deafness, diplopia, ear pain, glaucoma, hyperacusis, photophobia, taste loss, vestibular disorder.
Urogenital System: Infrequent: Urinary urgency, urine abnormality, urinary incontinence, kidney calculus, hematuria, impotence, prostate carcinoma, kidney pain, metrorrhagia, priapism. Rare: Amenorrhea, breast abscess, breast pain, nephritis, nocturia, pyelonephritis, enlarged uterine fibroids, uterine hemorrhage, vaginal moniliasis.
## Postmarketing Experience
There is limited information regarding Riluzole Postmarketing Experience in the drug label.
# Drug Interactions
- There have been no clinical studies designed to evaluate the interaction of riluzole with other drugs.
- As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Hepatotoxic Drugs
The clinical trials in ALS excluded patients on concomitant medications which were potentially hepatotoxic, (e.g., allopurinol, methyldopa, sulfasalazine). Accordingly, there is no information about the safety of administering riluzole in conjunction with such medications. If the practitioner chooses to prescribe such a combination, caution should be exercised.
Drugs Highly Bound To Plasma Proteins
Riluzole is highly bound (96%) to plasma proteins, binding mainly to serum albumin and to lipoproteins. The effect of riluzole (up to 5 mcg/mL) on warfarin (5 mcg/mL) binding did not show any displacement of warfarin. Conversely, riluzole binding was unaffected by the addition of warfarin, digoxin, imipramine and quinine at high therapeutic concentrations.
Effect of Other Drugs On Riluzole Metabolism
In vitro studies using human liver microsomal preparations suggest that CYP 1A2 is the principal isozyme involved in the initial oxidative metabolism of riluzole and, therefore, potential interactions may occur when riluzole is given concurrently with agents that affect CYP 1A2 activity. Potential inhibitors of CYP 1A2 (e.g., caffeine, phenacetin, theophylline, amitriptyline, and quinolones) could decrease the rate of riluzole elimination, while inducers of CYP 1A2 (e.g., cigarette smoke, charcoal-broiled food, rifampicin, and omeprazole) could increase the rate of riluzole elimination.
Effect of Riluzole On the Metabolism of Other Drugs
CYP 1A2 is the principal isoenzyme involved in the initial oxidative metabolism of riluzole; potential interactions may occur when riluzole is given concurrently with other agents which are also metabolized primarily by CYP 1A2 (e.g., theophylline, caffeine, and tacrine). Currently, it is not known whether riluzole has any potential for enzyme induction in humans.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy category C
- Oral administration of riluzole to pregnant animals during the period of organogenesis caused embryotoxicity in rats and rabbits at doses of 27 mg/kg and 60 mg/kg, respectively, or 2.6 and 11.5 times, respectively, the recommended maximum human daily dose on a mg/m2 basis. Evidence of maternal toxicity was also observed at these doses.
- When administered to rats prior to and during mating (males and females) and throughout gestation and lactation (females), riluzole produced adverse effects on pregnancy (decreased implantations, increased intrauterine death) and offspring viability and growth at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.
- There are no adequate and well-controlled studies in pregnant women. Riluzole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Riluzole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Riluzole during labor and delivery.
### Nursing Mothers
- In rat studies, 14C-riluzole was detected in maternal milk. It is not known whether riluzole is excreted in human breast milk. Because many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants from riluzole is unknown, women should be advised not to breast-feed during treatment with riluzole.
### Pediatric Use
- The safety and the effectiveness of riluzole in pediatric patients have not been established.
### Geriatic Use
- Age-related compromised renal and hepatic function may cause a decrease in clearance of riluzole. In controlled clinical trials, about 30% of patients were over 65. There were no differences in adverse effects between younger and older patients.
### Gender
There is no FDA guidance on the use of Riluzole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Riluzole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Riluzole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Riluzole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Riluzole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Riluzole in patients who are immunocompromised.
### Others
(Description)
# Administration and Monitoring
### Administration
- Oral
- Riluzole tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related decrease in bioavailability.
### Monitoring
There is limited information regarding Riluzole Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Riluzole and IV administrations.
# Overdosage
- No specific antidote or information on treatment of overdosage with RILUTEK is available. In the event of overdose, RILUTEK therapy should be discontinued immediately. Experience with riluzole overdose in humans is limited. Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma, and methemoglobinemia have been observed in isolated cases. Treatment should be supportive and directed toward alleviating symptoms.
- Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.
- The estimated oral median lethal dose is 94 mg/kg and 39 mg/kg for male mice and rats, respectively.
# Pharmacology
## Mechanism of Action
There is limited information regarding Riluzole Mechanism of Action in the drug label.
## Structure
There is limited information regarding Riluzole Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Riluzole Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Riluzole Pharmacokinetics in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Riluzole was not carcinogenic in mice or rats when administered for 2 years at daily oral doses up to 20 mg/kg and 10 mg/kg, respectively, which are approximately equivalent to the maximum human dose on a mg/m2 basis.
- The genotoxic potential of riluzole was evaluated in the bacterial mutagenicity (Ames) test, the mouse lymphoma mutation assay in L5178Y cells, the in vitro chromosomal aberration assay in human lymphocytes and the in vivo rat cytogenetic assay and in vivo mouse micronucleus assay in bone marrow. There was no evidence of mutagenic or clastogenic potential in the Ames test, the mouse lymphoma assay, or the in vivo assays in the mouse and rat. There was an equivocal clastogenic response in the in vitro human lymphocyte chromosomal aberration assay, which was not reproduced in a second assay performed at equal or higher concentrations; riluzole was therefore considered non-clastogenic in the human lymphocyte assay.
- N-hydroxyriluzole, the major active metabolite of riluzole, caused chromosomal damage in the in vitro mammalian mouse lymphoma assay and in the in vitro micronucleus assay that used the same mouse lymphoma cell line, L5178Y. N-hydroxyriluzole was not mutagenic in this cell line when tested in the HPRT gene mutation assay, and was negative in the Ames bacterial gene mutation assay (with and without rat or hamster S9), the in vitro UDS assay in rat hepatocytes, the chromosomal aberration test in human lymphocytes, and the in vivo mouse bone marrow micronucleus test.
- Riluzole impaired fertility when administered to male and female rats prior to and during mating at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.
# Clinical Studies
There is limited information regarding Riluzole Clinical Studies in the drug label.
# How Supplied
- Riluzole tablets, USP 50 mg are white to off white colored, round-shaped, biconvex film-coated tablets and debossed with “538” on one side and plain on other side.
They are supplied as follows:
- Unit Dose Box of 30’s ………………...NDC 0179-0150-70
## Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F)and protect from bright light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to report any febrile illness to their physicians.
- Patients should be advised to report any cough or difficulties in breathing to their physicians.
- Patients and caregivers should be advised that riluzole tablets should be taken on a regular basis and at the same time of the day (e.g., in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned.
- Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on riluzole to gauge whether or not it affects their mental and/or motor performance adversely.
- Whether alcohol increases the risk of serious hepatotoxicity with riluzole is unknown; therefore, patients being treated with riluzole should be discouraged from drinking excessive amounts of alcohol.
- Patients should also be made aware that riluzole tablets should be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) and protected from bright light.
- Riluzole tablets must be kept out of the reach of children.
# Precautions with Alcohol
Alcohol-Riluzole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Rilutek
# Look-Alike Drug Names
There is limited information regarding Riluzole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Riluzole | |
28fbfa9d1202b984256eeb737b9cb2900f77d1a7 | wikidoc | Rose oil | Rose oil
Rose oil, meaning either rose otto (attar of rose, attar of roses) or rose absolute, is the essential oil extracted from the petals of various types of rose. Rose ottos are extracted through steam distillation, while rose absolutes are obtained through solvent extraction or supercritical carbon dioxide extraction, with the absolute being used more commonly in perfumery. Even with their prohibitive price and the advent of organic synthesis, rose oils are still perhaps the most widely used essential oil in perfumery.
# Components
Two major species of rose are cultivated for the production of rose oil:
- Rosa damascena, the damask rose, which is widely grown in Bulgaria, Turkey, Russia, India, Iran and China
- Rosa centifolia, the cabbage rose, which is more commonly grown in Morocco, France and Egypt
Most rose oil is produced in Bulgaria, Morocco, Iran and Turkey. Recently, China has begun producing Rose oil as well.
More than 300 compounds have been identified in rose oil. The most common are:
The key compounds that contribute to the distinctive scent of rose oil, however, are beta-damascenone, beta-damascone, beta-ionone, and rose oxide. Even though these compounds exist in less than 1% quantity of rose oil, they make up for slightly more than 90% of the odor content due to their low odor detection thresholds.
# Production
Due to the labor-intensive production process and the low content of oil in the rose blooms, rose oil commands a very high price. Harvesting of flowers is done by hand in the morning before sunrise and material is distilled the same day.
There are three main methods of extracting the oil from the plant material:
- Steam distillation, which produces an oil called rose otto or attar of roses.
- Solvent extraction, which results in an oil called rose absolute.
- Supercritical carbon dioxide extraction, yielding an essential oil that may be marketed as either an absolute or as a CO2 extract.
## Distillation
In the process of distillation, large stills, traditionally of copper, are filled with roses and water. The still is fired for 60-105 minutes. The vaporized water and rose oil exit the still and enter a condensing apparatus and are then collected in a flask. This distillation yields a very concentrated oil, direct oil, which makes up ahout 20% of the final product. The water which condenses along with the oil is drained off and redistilled, cohobation, in order to obtain the water-soluble fractions of the rose oil such as phenyl ethyl alcohol which are a vital component of the aroma and which make up the large bulk, 80%, of the oil.
The two oils are combined and make the final rose otto.
Rose otto is usually dark olive-green in color and will form white crystals at normal room temperature which disappear when the oil is gently warmed. It will tend to become more viscous at lower temperatures due to this crystallization of some of its components.
The essence has a very strong odor, but is pleasant when diluted and used for perfume. Attar of roses was once made in India, Persia, Syria, and the Ottoman Empire. The Rose Valley in Bulgaria, near the town of Kazanlak, is among the major producers of attar of roses in the world.
Due to the heat required for distillation, some of the compounds extracted from the rose undergo denaturing or chemical breakdown. As such, rose otto does not smell very similar to "fresh" roses.
The hydrosol portion of the distillate is known as rosewater. This inexpensive by-product is used widely as a food flavoring as well as in skin care.
## Solvent extraction
In the solvent extraction method, the flowers are agitated in a vat with a solvent such as hexane, which draws out the aromatic compounds as well as other soluble substances such as wax and pigments. The extract is subjected to vacuum processing which removes the solvent for re-use. The remaining waxy mass is known as a concrete. The concrete is then mixed with alcohol which dissolves the aromatic constituents, leaving behind the wax and other substances. The alcohol is low-pressure evaporated, leaving behind the finished absolute. The absolute may be further processed to remove any impurities that are still present from the solvent extraction.
Rose absolute is a deep reddish brown with no crystals. Due to the low temperatures in this process, the absolute may be more faithful to the scent of the fresh rose than the otto, which is subjected to high heat during the distillation process.
## CO2 extraction
A third process, supercritical carbon dioxide extraction, combines the best aspects of the other two methods. When carbon dioxide is put under high pressure, it becomes a liquid. (Under normal pressure CO2 changes directly from a solid to a gas in a process known as sublimation.) The liquid CO2 extracts the aromatics from the plant material.
Like solvent extraction, the CO2 extraction takes place at a low temperature, extracts a wide range of compounds rendering an essence more faithful to the original, and leaves the aromatics unaltered by heat. Because CO2 is gas at normal atmospheric pressure, it leaves no trace of itself in the final product. The equipment for CO2 extraction is expensive, which is reflected in the price of the essential oils obtained from the process.
# Adulteration
It takes many pounds of rose petals to distill one ounce of essential oil. To mitigate the cost, some dishonest dealers will dilute rose oil with Geranium (Pelargonium graveolens) or Palmarosa (Cymbopogon martinii) EO's, both of which are rich in geraniol, the main constituent of rose oil. Some of these 'rose oils' are up to 90% geranium or palmarosa to 10% rose. This is referred to as extending the Rose fragrance. Sometimes rose oil is adulterated with other chemicals such as phenylethanol, which, although a natural component of rose oil, is usually artificially produced. This may be done to compensate for chemotype, e.g. Bulgarian distilled Rose oil is naturally low in phenylethanol, and Ukrainian or Russian Rose oil is naturally high in phenylethanol. | Rose oil
Rose oil, meaning either rose otto (attar of rose, attar of roses) or rose absolute, is the essential oil extracted from the petals of various types of rose. Rose ottos are extracted through steam distillation, while rose absolutes are obtained through solvent extraction or supercritical carbon dioxide extraction, with the absolute being used more commonly in perfumery. Even with their prohibitive price and the advent of organic synthesis, rose oils are still perhaps the most widely used essential oil in perfumery.
# Components
Two major species of rose are cultivated for the production of rose oil:
- Rosa damascena, the damask rose, which is widely grown in Bulgaria, Turkey, Russia, India, Iran and China
- Rosa centifolia, the cabbage rose, which is more commonly grown in Morocco, France and Egypt
Most rose oil is produced in Bulgaria, Morocco, Iran and Turkey. Recently, China has begun producing Rose oil as well.
More than 300 compounds have been identified in rose oil. The most common are:
The key compounds that contribute to the distinctive scent of rose oil, however, are beta-damascenone, beta-damascone, beta-ionone, and rose oxide. Even though these compounds exist in less than 1% quantity of rose oil, they make up for slightly more than 90% of the odor content due to their low odor detection thresholds.[1]
# Production
Due to the labor-intensive production process and the low content of oil in the rose blooms, rose oil commands a very high price. Harvesting of flowers is done by hand in the morning before sunrise and material is distilled the same day.
There are three main methods of extracting the oil from the plant material:
- Steam distillation, which produces an oil called rose otto or attar of roses.
- Solvent extraction, which results in an oil called rose absolute.
- Supercritical carbon dioxide extraction, yielding an essential oil that may be marketed as either an absolute or as a CO2 extract.
## Distillation
In the process of distillation, large stills, traditionally of copper, are filled with roses and water. The still is fired for 60-105 minutes. The vaporized water and rose oil exit the still and enter a condensing apparatus and are then collected in a flask. This distillation yields a very concentrated oil, direct oil, which makes up ahout 20% of the final product. The water which condenses along with the oil is drained off and redistilled, cohobation, in order to obtain the water-soluble fractions of the rose oil such as phenyl ethyl alcohol which are a vital component of the aroma and which make up the large bulk, 80%, of the oil.
The two oils are combined and make the final rose otto.
Rose otto is usually dark olive-green in color and will form white crystals at normal room temperature which disappear when the oil is gently warmed. It will tend to become more viscous at lower temperatures due to this crystallization of some of its components.
The essence has a very strong odor, but is pleasant when diluted and used for perfume. Attar of roses was once made in India, Persia, Syria, and the Ottoman Empire. The Rose Valley in Bulgaria, near the town of Kazanlak, is among the major producers of attar of roses in the world.[2]
Due to the heat required for distillation, some of the compounds extracted from the rose undergo denaturing or chemical breakdown. As such, rose otto does not smell very similar to "fresh" roses.
The hydrosol portion of the distillate is known as rosewater. This inexpensive by-product is used widely as a food flavoring as well as in skin care.
## Solvent extraction
In the solvent extraction method, the flowers are agitated in a vat with a solvent such as hexane, which draws out the aromatic compounds as well as other soluble substances such as wax and pigments. The extract is subjected to vacuum processing which removes the solvent for re-use. The remaining waxy mass is known as a concrete. The concrete is then mixed with alcohol which dissolves the aromatic constituents, leaving behind the wax and other substances. The alcohol is low-pressure evaporated, leaving behind the finished absolute. The absolute may be further processed to remove any impurities that are still present from the solvent extraction.
Rose absolute is a deep reddish brown with no crystals. Due to the low temperatures in this process, the absolute may be more faithful to the scent of the fresh rose than the otto, which is subjected to high heat during the distillation process.
## CO2 extraction
A third process, supercritical carbon dioxide extraction, combines the best aspects of the other two methods. When carbon dioxide is put under high pressure, it becomes a liquid. (Under normal pressure CO2 changes directly from a solid to a gas in a process known as sublimation.) The liquid CO2 extracts the aromatics from the plant material.
Like solvent extraction, the CO2 extraction takes place at a low temperature, extracts a wide range of compounds rendering an essence more faithful to the original, and leaves the aromatics unaltered by heat. Because CO2 is gas at normal atmospheric pressure, it leaves no trace of itself in the final product. The equipment for CO2 extraction is expensive, which is reflected in the price of the essential oils obtained from the process.
# Adulteration
It takes many pounds of rose petals to distill one ounce of essential oil. To mitigate the cost, some dishonest dealers will dilute rose oil with Geranium (Pelargonium graveolens) or Palmarosa (Cymbopogon martinii) EO's, both of which are rich in geraniol, the main constituent of rose oil. Some of these 'rose oils' are up to 90% geranium or palmarosa to 10% rose. This is referred to as extending the Rose fragrance. Sometimes rose oil is adulterated with other chemicals such as phenylethanol, which, although a natural component of rose oil, is usually artificially produced. This may be done to compensate for chemotype, e.g. Bulgarian distilled Rose oil is naturally low in phenylethanol, and Ukrainian or Russian Rose oil is naturally high in phenylethanol. | https://www.wikidoc.org/index.php/Rose_oil | |
5e55091c7f47c4f6462d82d1a52e334c73695e52 | wikidoc | Rosemary | Rosemary
Rosemary (Rosmarinus officinalis) is a woody, perennial herb with fragrant evergreen needle-like leaves. It is native to the Mediterranean region. It is a member of the mint family Lamiaceae, which also includes many other herbs. Forms range from upright to trailing; the upright forms can reach 1.5 m tall, rarely 2 m. The leaves are evergreen, 2-4 cm long and 2-5 mm broad, green above, and white below with dense short woolly hairs. The flowers are variable in color, being white, pink, purple, or blue.
The name rosemary has nothing to do with the rose or the name Mary, but derives from the Latin name rosmarinus, which literally means "dew of the sea", though some think this too may be derived from an earlier name.
# Cultivation and uses
The fresh and dried leaves are used frequently in traditional Mediterranean cuisine as a herb; they have a bitter, astringent taste, which complements oily foods, such as lamb and oily fish. A tisane can also be made from them. They are extensively used in cooking, and when burned give off a distinct mustard smell, as well as a smell similar to that of burning which can be used to flavor foods while barbecueing.
Rosemary, in the dried form, is extremely high in iron, calcium, and Vitamin B6. It is in fact more nutrient rich in its dry form than fresh rosemary across the board.
Since it is attractive and tolerates some degree of drought, it is also used in landscaping, especially in areas having a Mediterranean climate. It can in fact die in over-watered soil, but is otherwise quite easy to grow for beginner gardeners. It is very pest-resistant.
Rosemary is easily pruned into shapes and has been used for topiary. When grown in pots, it is best kept trimmed to stop it getting too straggly and unsightly, though when grown in a garden, rosemary can grow quite large and still be attractive. It can be propagated from an existing plant by clipping a shoot 10-15 cm long, stripping a few leaves from the bottom, and planting it directly into soil.
Numerous cultivars have been selected for garden use. The following are frequently sold:
- Albus — white flowers
- Arp — leaves light green, lemon-scented
- Aureus — leaves speckled yellow
- Benenden Blue — leaves narrow, dark green
- Blue Boy — dwarf, small leaves
- Golden Rain — leaves green, with yellow streaks
- Irene — lax, trailing
- Lockwood de Forest — procumbent selection from Tuscan Blue
- Ken Taylor — shrubby
- Majorica Pink — pink flowers
- Miss Jessop's Upright — tall, erect
- Pinkie — pink flowers
- Prostratus
- Pyramidalis (a.k.a Erectus) — pale blue flowers
- Roseus — pink flowers
- Salem — pale blue flowers, cold hardy similar to Arp
- Severn Sea — spreading, low-growing, with arching branches; flowers deep violet
- Tuscan Blue — upright
Rosemary is a useful food preservative, according to research published in 1987 by Rutgers University, New Jersey. Researchers at Rutgers patented a chemical derived from rosemary that compares favorably with BHA and BHT in its preservative properties.
Rosemary can be added as an unusual extra flavoring in lemonade.
# Medicinal uses
Hungary water was first invented for a Queen of Hungary to "renovate vitality of paralysed limbs". It was used externally and prepared by mixing 180g of fresh rosemary tops in full flower into a liter of spirits of wine. Leave to stand for four days then distill. It is also supposed to work as a remedy against gout if rubbed vigorously on hands and feet.
Rosemary has a very old reputation for improving memory, and has been used as a symbol for remembrance (during weddings, war commemorations and funerals) in Europe, probably as a result of this reputation. Mourners would throw it into graves as a symbol of remembrance for the dead. In Shakespeare's Hamlet, Ophelia says, "There's rosemary, that's for remembrance". One modern study lends some credence to this reputation. When the smell of rosemary was pumped into cubicles where people were working, those people showed improved memory, though with slower recall.
Don Quixote (Chapter XVII, 1st volume) mixes it in his recipe of the miraculous balm of Fierabras with revolting results.
Health Precautions: In some cases, rosemary can cause autoimmune diseases. Rosemary in culinary or therapeutic doses is generally safe, however precaution is necessary for those displaying allergic reaction, or those prone to epileptic seizure.
Rosemary essential oil is a powerful convulsant; if applied to the skin, it may cause seizures in otherwise healthy adults or children.
Rosemary essential oil is potentially toxic if ingested. Large quantities of rosemary leaves can cause adverse reactions, such as coma, spasm, vomiting, and pulmonary edema (fluid in the lungs) that can be fatal. Avoid consuming large quantities of rosemary if pregnant or breastfeeding.
# Trivia
Along with Parsley, Sage, and Thyme Rosemary is named in the song Scarborough Fair | Rosemary
Template:Nutritionalvalue
Template:Wikispecies
Template:Cookbook
Rosemary (Rosmarinus officinalis) is a woody, perennial herb with fragrant evergreen needle-like leaves. It is native to the Mediterranean region. It is a member of the mint family Lamiaceae, which also includes many other herbs. Forms range from upright to trailing; the upright forms can reach 1.5 m tall, rarely 2 m. The leaves are evergreen, 2-4 cm long and 2-5 mm broad, green above, and white below with dense short woolly hairs. The flowers are variable in color, being white, pink, purple, or blue.
The name rosemary has nothing to do with the rose or the name Mary, but derives from the Latin name rosmarinus, which literally means "dew of the sea", though some think this too may be derived from an earlier name.
# Cultivation and uses
The fresh and dried leaves are used frequently in traditional Mediterranean cuisine as a herb; they have a bitter, astringent taste, which complements oily foods, such as lamb and oily fish. A tisane can also be made from them. They are extensively used in cooking, and when burned give off a distinct mustard smell, as well as a smell similar to that of burning which can be used to flavor foods while barbecueing.
Rosemary, in the dried form, is extremely high in iron, calcium, and Vitamin B6. It is in fact more nutrient rich in its dry form than fresh rosemary across the board.[1]
Since it is attractive and tolerates some degree of drought, it is also used in landscaping, especially in areas having a Mediterranean climate. It can in fact die in over-watered soil, but is otherwise quite easy to grow for beginner gardeners. It is very pest-resistant.
Rosemary is easily pruned into shapes and has been used for topiary. When grown in pots, it is best kept trimmed to stop it getting too straggly and unsightly, though when grown in a garden, rosemary can grow quite large and still be attractive. It can be propagated from an existing plant by clipping a shoot 10-15 cm long, stripping a few leaves from the bottom, and planting it directly into soil.
Numerous cultivars have been selected for garden use. The following are frequently sold:
- Albus — white flowers
- Arp — leaves light green, lemon-scented
- Aureus — leaves speckled yellow
- Benenden Blue — leaves narrow, dark green
- Blue Boy — dwarf, small leaves
- Golden Rain — leaves green, with yellow streaks
- Irene — lax, trailing
- Lockwood de Forest — procumbent selection from Tuscan Blue
- Ken Taylor — shrubby
- Majorica Pink — pink flowers
- Miss Jessop's Upright — tall, erect
- Pinkie — pink flowers
- Prostratus
- Pyramidalis (a.k.a Erectus) — pale blue flowers
- Roseus — pink flowers
- Salem — pale blue flowers, cold hardy similar to Arp
- Severn Sea — spreading, low-growing, with arching branches; flowers deep violet
- Tuscan Blue — upright
Rosemary is a useful food preservative, according to research published in 1987 by Rutgers University, New Jersey[citation needed]. Researchers at Rutgers patented a chemical derived from rosemary that compares favorably with BHA and BHT in its preservative properties.
Rosemary can be added as an unusual extra flavoring in lemonade.
# Medicinal uses
Hungary water was first invented for a Queen of Hungary to "renovate vitality of paralysed limbs". It was used externally and prepared by mixing 180g of fresh rosemary tops in full flower into a liter of spirits of wine. Leave to stand for four days then distill. It is also supposed to work as a remedy against gout if rubbed vigorously on hands and feet.[2]
Rosemary has a very old reputation for improving memory, and has been used as a symbol for remembrance (during weddings, war commemorations and funerals) in Europe, probably as a result of this reputation. Mourners would throw it into graves as a symbol of remembrance for the dead. In Shakespeare's Hamlet, Ophelia says, "There's rosemary, that's for remembrance". One modern study lends some credence to this reputation. When the smell of rosemary was pumped into cubicles where people were working, those people showed improved memory, though with slower recall.[3]
Don Quixote (Chapter XVII, 1st volume) mixes it in his recipe of the miraculous balm of Fierabras with revolting results.
Health Precautions: In some cases, rosemary can cause autoimmune diseases. Rosemary in culinary or therapeutic doses is generally safe, however precaution is necessary for those displaying allergic reaction, or those prone to epileptic seizure.
Rosemary essential oil is a powerful convulsant; if applied to the skin, it may cause seizures in otherwise healthy adults or children.[4]
Rosemary essential oil is potentially toxic if ingested. Large quantities of rosemary leaves can cause adverse reactions, such as coma, spasm, vomiting, and pulmonary edema (fluid in the lungs) that can be fatal. Avoid consuming large quantities of rosemary if pregnant or breastfeeding.[5]
# Trivia
Along with Parsley, Sage, and Thyme Rosemary is named in the song Scarborough Fair | https://www.wikidoc.org/index.php/Rosemary | |
604c6570d374bb0f6e0551a2e9ddb96c9d642f6f | wikidoc | Rotaxane | Rotaxane
A rotaxane is a mechanically-interlocked molecular architecture consisting of a "dumbbell shaped molecule" which is threaded through a "macrocycle" (see graphical representation). The name is derived from the Latin for wheel (rota) and axle (axis). The two components of a rotaxane are kinetically trapped since the ends of the dumbbell (often called stoppers) are larger than the internal diameter of the ring and prevent disassociation (unthreading) of the components since this would require significant distortion of the covalent bonds.
Much of the research concerning rotaxanes and other mechanically-interlocked molecular architectures, such as catenanes, has been focused on their efficient synthesis. However, examples of rotaxane have been found in biological systems including: cystine knots, cyclotides or lasso-peptides such as microcin J25 are protein, and a variety of peptides with rotaxane substructure.
# Synthesis
The earliest reported synthesis of a rotaxane in 1967 relied on the statistical probability that if two halves of a dumbbell shaped molecule were reacted in the presence of a macrocycle that some small percentage would connect through the ring. To obtain a reasonable quantity of rotaxane the macrocycle was attached to a solid phase support and treated with both halves of the dumbbell 70 time and then severed from the support to give a 6% yield. However, the synthesis of rotaxanes has advanced significantly and efficient yields can be obtained by preorganizing the components utilizing hydrogen bonding, metal coordination, hydrophobic forces, covalent bonds, or coulombic interactions. The three most common strategies to synthesize rotaxane are "capping", "clipping", and "slipping", though others do exist.
## Capping
Synthesis via the capping method relies strongly upon a thermodynamically driven template effect; that is the "thread" is held within the "macrocycle" by non-covalent interactions. This dynamic complex or pseudorotaxane is then converted to the rotaxane by reacting the ends of the threaded guest with large groups preventing disassociation.
## Clipping
The clipping method is similar to the capping reaction except that in this case the dumbbell shaped molecule is complete and is bound to a partial macrocyle. The partial macrocyle then undergoes a ring closing reaction around the dumbbell shaped molecule forming the rotaxane.
## Slipping
The method of slipping is one which exploits the kinetic stability of the rotaxane. If the end groups of the dumbbell are an appropriate size it will be able to reversibly thread through the macrocycle at higher temperatures. By cooling the dynamic complex it becomes kinetically trapped as a rotaxane at the lower temperature.
# Potential applications
## Molecular machines
Rotaxane-based molecular machines have been of initial interest for their potential use in molecular electronics as logic molecular switching elements and as molecular shuttles. These molecular machines are usually based on the movement of macrocycle on the dumbbell. The macrocycle can rotate around the axis of the dumbbell like a wheel and axle or it can slide along its axis from one site to another. Controlling the position of the macrocycle allows the rotaxane to function as molecular switch with each possible location of the macrocycle corresponding to a different state. These rotaxane machines can be manipulated both by chemical and photochemical inputs. Rotaxane based systems have also been demonstrated as molecular muscles.
## Ultrastable dyes
Potential application as long lasting dyes is based on the enhanced stability of the inner portion of the dumbbell shaped molecule. Studies with cyclodextrin protected rotaxane azo dyes established this characteristic. More reactive squaraine dyes have also been shown to have enhanced stability by preventing nucleophilic attack of the inner squaraine moiety. The enhanced stabilities of rotaxane dyes is attributed to the insulating effect of the macrocycle which is able to block interactions with other molecules.
## Nanorecording
In a nanorecording application a certain rotaxane is deposited as a Langmuir-Blodgett film on ITO coated glass. When a positive voltage is applied with the tip of a scanning tunneling microscope probe, the rotaxane rings in the tip area switch to a different part of the dumbbell and the resulting new conformation makes the molecules stick out from the surface by 0.3 nanometer and this height difference turns out to be sufficient for a memory dot. It is not yet possible to erase such a nanorecording film.
# Nomenclature
Accepted nomenclature is to designate the number of components of the rotaxane in brackets as a prefix. Therefore the graphical representation of rotaxane displayed above would be a rotaxane as it consists of a single dumbbell and a single macrocycle. | Rotaxane
A rotaxane is a mechanically-interlocked molecular architecture consisting of a "dumbbell shaped molecule" which is threaded through a "macrocycle" (see graphical representation). The name is derived from the Latin for wheel (rota) and axle (axis). The two components of a rotaxane are kinetically trapped since the ends of the dumbbell (often called stoppers) are larger than the internal diameter of the ring and prevent disassociation (unthreading) of the components since this would require significant distortion of the covalent bonds.
Much of the research concerning rotaxanes and other mechanically-interlocked molecular architectures, such as catenanes, has been focused on their efficient synthesis. However, examples of rotaxane have been found in biological systems including: cystine knots, cyclotides or lasso-peptides such as microcin J25 are protein, and a variety of peptides with rotaxane substructure.
# Synthesis
The earliest reported synthesis of a rotaxane in 1967 relied on the statistical probability that if two halves of a dumbbell shaped molecule were reacted in the presence of a macrocycle that some small percentage would connect through the ring.[2] To obtain a reasonable quantity of rotaxane the macrocycle was attached to a solid phase support and treated with both halves of the dumbbell 70 time and then severed from the support to give a 6% yield. However, the synthesis of rotaxanes has advanced significantly and efficient yields can be obtained by preorganizing the components utilizing hydrogen bonding, metal coordination, hydrophobic forces, covalent bonds, or coulombic interactions. The three most common strategies to synthesize rotaxane are "capping", "clipping", and "slipping",[3] though others do exist.[4][5]
## Capping
Synthesis via the capping method relies strongly upon a thermodynamically driven template effect; that is the "thread" is held within the "macrocycle" by non-covalent interactions. This dynamic complex or pseudorotaxane is then converted to the rotaxane by reacting the ends of the threaded guest with large groups preventing disassociation.
## Clipping
The clipping method is similar to the capping reaction except that in this case the dumbbell shaped molecule is complete and is bound to a partial macrocyle. The partial macrocyle then undergoes a ring closing reaction around the dumbbell shaped molecule forming the rotaxane.
## Slipping
The method of slipping is one which exploits the kinetic stability of the rotaxane. If the end groups of the dumbbell are an appropriate size it will be able to reversibly thread through the macrocycle at higher temperatures. By cooling the dynamic complex it becomes kinetically trapped as a rotaxane at the lower temperature.
# Potential applications
## Molecular machines
Rotaxane-based molecular machines have been of initial interest for their potential use in molecular electronics as logic molecular switching elements and as molecular shuttles.[7][8] These molecular machines are usually based on the movement of macrocycle on the dumbbell. The macrocycle can rotate around the axis of the dumbbell like a wheel and axle or it can slide along its axis from one site to another. Controlling the position of the macrocycle allows the rotaxane to function as molecular switch with each possible location of the macrocycle corresponding to a different state. These rotaxane machines can be manipulated both by chemical and photochemical inputs.[9] Rotaxane based systems have also been demonstrated as molecular muscles.
## Ultrastable dyes
Potential application as long lasting dyes is based on the enhanced stability of the inner portion of the dumbbell shaped molecule.[10][11] Studies with cyclodextrin protected rotaxane azo dyes established this characteristic. More reactive squaraine dyes have also been shown to have enhanced stability by preventing nucleophilic attack of the inner squaraine moiety.[12] The enhanced stabilities of rotaxane dyes is attributed to the insulating effect of the macrocycle which is able to block interactions with other molecules.
## Nanorecording
In a nanorecording application[13] a certain rotaxane is deposited as a Langmuir-Blodgett film on ITO coated glass. When a positive voltage is applied with the tip of a scanning tunneling microscope probe, the rotaxane rings in the tip area switch to a different part of the dumbbell and the resulting new conformation makes the molecules stick out from the surface by 0.3 nanometer and this height difference turns out to be sufficient for a memory dot. It is not yet possible to erase such a nanorecording film.
# Nomenclature
Accepted nomenclature is to designate the number of components of the rotaxane in brackets as a prefix.[14] Therefore the graphical representation of rotaxane displayed above would be a [2]rotaxane as it consists of a single dumbbell and a single macrocycle. | https://www.wikidoc.org/index.php/Rotaxane | |
86eb5c3fe00c08792c6af4f6943c18948f66d4b4 | wikidoc | Rotenone | Rotenone
Synonyms and keywords: Tubatoxin, paraderil
# Overview
Rotenone is a colorless-to-red, odorless solid. In solution it is used as a broad-spectrum insecticide and piscicide that works by inhibiting the transfer of electrons from Fe-S centers in Complex I to ubiquinone (see electron transfer chain). This prevents NADH from being converted into usable cellular energy (ATP).
Rotenone is commonly used in powdered or emulsified liquid form in fisheries management to remove unwanted fish species (such as to eradicate exotic fish from their non-native habitats). Rotenone is also used in powdered form to reduce parasitic mites on chickens and other fowl.
Rotenone is classified by the World Health Organization as a moderately hazardous and is mildly toxic to humans and other mammals. The lowest lethal dose for a child is 143 mg/kg. However, human deaths attributed to Rotenone are rare because its irritating action causes vomiting in cases where it could be fatal. The compound breaks down when exposed to sunlight and usually has a short lifetime (two weeks or less) in the environment. In water rotenone may last six months.
Rotenone is classified by the USDA National Organic Program as a nonsynthetic and is allowed to be used to grow "organic" produce.
Rotenone is produced by extraction from the roots and stems of several tropical and subtropical plant species belonging to the genus Lonchocarpus or Derris. People have been known to catch fish by extracting rotenone from plants and releasing it into water. The initial such usage was by various indigenous tribes who simply smashed the roots.
# Plants containing rotenone
Some of the plants containing rotenone :
- Hoary Pea or Goat’s Rue (Tephrosia virginiana) - North America
- Cubé Plant or Lancepod (Lonchocarpus utilis) - South America
The root extract is referred to as Cubé resin
- The root extract is referred to as Cubé resin
- Barbasco (Lonchocarpus urucu) - South America
The root extract is referred to as Cubé resin
- The root extract is referred to as Cubé resin
- Tuba Plant (Derris elliptica) - southeast Asia & southwest Pacific islands
The root extract is referred to as Derris or Derris root
- The root extract is referred to as Derris or Derris root
- Jewel Vine (Derris involuta) - southeast Asia & southwest Pacific islands
- Among the Mizo tribes of India (Derris walchii/D. thyrsiflora) the tender root is eaten as vegetable
The root extract is referred to as Derris or Derris root
- The root extract is referred to as Derris or Derris root
- Duboisia - This shrub grows in Australia and bears white clusters of flowers and berry like fruit. The crushed plants were used by the Aboriginals for poisoning fish for food.
# Rotenone and Parkinson's disease
Research has shown a correlation between intravenous rotenone and Parkinson's disease in rats.
The study does not directly suggest that rotenone exposure is responsible for Parkinson's disease in humans but is consistent with the belief that chronic exposure to environmental toxins can increase the likelihood of the disease.
In addition, studies with primary cultures of rat neurons and microglia have shown low doses of rotenone (below 10 nM) to induce oxidative damage and death of dopaminergic neurons. | Rotenone
Template:Chembox new
Synonyms and keywords: Tubatoxin, paraderil
# Overview
Rotenone is a colorless-to-red, odorless solid. In solution it is used as a broad-spectrum insecticide and piscicide that works by inhibiting the transfer of electrons from Fe-S centers in Complex I to ubiquinone (see electron transfer chain). This prevents NADH from being converted into usable cellular energy (ATP).
Rotenone is commonly used in powdered or emulsified liquid form in fisheries management to remove unwanted fish species[1] (such as to eradicate exotic fish from their non-native habitats). Rotenone is also used in powdered form to reduce parasitic mites on chickens and other fowl.
Rotenone is classified by the World Health Organization as a moderately hazardous and is mildly toxic to humans and other mammals. The lowest lethal dose for a child is 143 mg/kg. However, human deaths attributed to Rotenone are rare because its irritating action causes vomiting in cases where it could be fatal.[2] The compound breaks down when exposed to sunlight and usually has a short lifetime (two weeks or less) in the environment. In water rotenone may last six months.[citation needed]
Rotenone is classified by the USDA National Organic Program as a nonsynthetic and is allowed to be used to grow "organic" produce.[3]
Rotenone is produced by extraction from the roots and stems of several tropical and subtropical plant species belonging to the genus Lonchocarpus or Derris. People have been known to catch fish by extracting rotenone from plants and releasing it into water. The initial such usage was by various indigenous tribes[4] who simply smashed the roots.
# Plants containing rotenone
Some of the plants containing rotenone [Order Fabales; Family Fabaceae (or Leguminosae) – Pea family]:
- Hoary Pea or Goat’s Rue (Tephrosia virginiana) - North America
- Cubé Plant or Lancepod (Lonchocarpus utilis) - South America[5]
The root extract is referred to as Cubé resin
- The root extract is referred to as Cubé resin
- Barbasco (Lonchocarpus urucu) - South America[5]
The root extract is referred to as Cubé resin
- The root extract is referred to as Cubé resin
- Tuba Plant (Derris elliptica) - southeast Asia & southwest Pacific islands
The root extract is referred to as Derris or Derris root
- The root extract is referred to as Derris or Derris root
- Jewel Vine (Derris involuta) - southeast Asia & southwest Pacific islands
- Among the Mizo tribes of India (Derris walchii/D. thyrsiflora) the tender root is eaten as vegetable
The root extract is referred to as Derris or Derris root
- The root extract is referred to as Derris or Derris root
- Duboisia - This shrub grows in Australia and bears white clusters of flowers and berry like fruit. The crushed plants were used by the Aboriginals for poisoning fish for food.
# Rotenone and Parkinson's disease
Research has shown a correlation between intravenous rotenone and Parkinson's disease in rats.[6]
The study does not directly suggest that rotenone exposure is responsible for Parkinson's disease in humans but is consistent with the belief that chronic exposure to environmental toxins can increase the likelihood of the disease.[7]
In addition, studies with primary cultures of rat neurons and microglia have shown low doses of rotenone (below 10 nM) to induce oxidative damage and death of dopaminergic neurons.[8] | https://www.wikidoc.org/index.php/Rotenone | |
7f4daa000413377ec67a45ff8b7ce8b9b0c71d6b | wikidoc | Rouleaux | Rouleaux
# Overview
Rouleaux (singular is rouleau) are stacks of red blood cells formed because of the unique discoid shape of these cells in vertebrate body. The flat surface of the discoid RBCs give them a large surface area to make contact and stick to each other forming rouleux. They occur when the plasma protein concentration is high, and because of them the ESR (erythrocyte sedimentation rate) is also increased. Conditions which do this include infections, inflammatory and connective tissue disorders, and cancers. It also occurs in diabetics and is one of the causative factors for microvascular occlusion in diabetic retinopathy.
1. Rouleaux refers to the stacking of RBC
2. The presence of acute phase proteins particularly fibrinogen interacts with sialic acid on the surface of RBC and allows the formation of rouleaux
3. Anaemia by altering the ratio of RBC to plasma increases rouleaux formation and accelerates sedimentation
4. Rouleaux formation is retarded by albumin proteins
# Kinetics of Linear Rouleaux Formation
According to Smoluchowski, the kinetics of aggregation of colloids is based on the assumption that each particle is surrounded by a "sphere influence”. Single spherical particles, which undergo Brownian motion collide and sticking of particles. As aggregation proceeds, the average diffusion constant of the aggregate population decreases. The aggregation of red blood cells prgresses in the same manner except that cells are biconcave rather than spherical. | Rouleaux
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rouleaux (singular is rouleau) are stacks of red blood cells formed because of the unique discoid shape of these cells in vertebrate body. The flat surface of the discoid RBCs give them a large surface area to make contact and stick to each other forming rouleux. They occur when the plasma protein concentration is high, and because of them the ESR (erythrocyte sedimentation rate) is also increased. Conditions which do this include infections, inflammatory and connective tissue disorders, and cancers. It also occurs in diabetics and is one of the causative factors for microvascular occlusion in diabetic retinopathy.
1. Rouleaux refers to the stacking of RBC
2. The presence of acute phase proteins particularly fibrinogen interacts with sialic acid on the surface of RBC and allows the formation of rouleaux
3. Anaemia by altering the ratio of RBC to plasma increases rouleaux formation and accelerates sedimentation
4. Rouleaux formation is retarded by albumin proteins
# Kinetics of Linear Rouleaux Formation
According to Smoluchowski, the kinetics of aggregation of colloids is based on the assumption that each particle is surrounded by a "sphere influence”. Single spherical particles, which undergo Brownian motion collide and sticking of particles. As aggregation proceeds, the average diffusion constant of the aggregate population decreases. The aggregation of red blood cells prgresses in the same manner except that cells are biconcave rather than spherical.
# External links
- Rouleaux: Presented by the University of Virginia | https://www.wikidoc.org/index.php/Rouleaux | |
6d0c4734f6d5e2d9f8001695e4b9b853249821c8 | wikidoc | Ryegrass | Ryegrass
# Overview
Ryegrass (Lolium) is a genus of nine species of tufted grasses in the Pooideae subfamily of the Poaceae family. They are characterized by bunch-like growth habits. Also called tares (even though there is no firm evidence that this is the same as the plant given that name in English language translations of the Bible (as in the "Parable of the Tares") - vetches are another candidate), these plants are native to Europe, Asia and northern Africa, but are widely cultivated and naturalized elsewhere. Ryegrasses are naturally diploid, with 2n = 14, and are closely related to the fescues Festuca.
Ryegrass should not be confused with rye, which is a grain crop.
# Species
The following are accepted as distinct species:
- Lolium canariense Steud. - Canary Islands ryegrass
- Lolium edwardii H.Scholz, Stierst. & Gaisberg
- Lolium multiflorum Lam. - Italian ryegrass
- Lolium perenne L. - Perennial ryegrass
- Lolium persicum - Persian ryegrass or Persian darnel
- Lolium remotum Schrank
- Lolium rigidum Gaudin - Stiff darnel, Wimmera ryegrass
- Lolium temulentum L. - Darnel, poison darnel
# Cultivation and uses
Ryegrasses contain some species which are important grasses for both lawns, and as pasture and for grazing and hay for livestock, being a highly nutritious stock feed. Ryegrasses are also used in soil erosion control programs. It is the principal grazing grass in New Zealand where some 10 million kilograms of certified seed are produced every year. There is a large range of cultivars. The primary species found worldwide and used for both lawns and as a forage crop is perennial ryegrass (Lolium perenne). Like many cool-season grasses of the family Poaceae, it harbors a symbiotic fungal endophyte, either Epichloë or its close relative Neotyphodium, of which both are of the fungal family Clavicipitaceae
Some species, particularly L. temulentum, are weeds which can have a severe impact on the production of wheat and other crops. Ryegrass pollen is also one of the major causes of hay fever.
Many grass tennis courts including Wimbledon are planted in ryegrass in different compositions, depending on the tournament.
# Synonyms
- L. ambiguum = Lolium multiflorum
- L. annuum = Lolium temulentum
- L. arundinaceum = Festuca arundinacea
- L. berteronianum = Lolium temulentum
- L. brasilianum = Lolium perenne
- L. canadense = Lolium perenne
- L. crassiculme = Lolium rigidum
- L. cuneatum = Lolium temulentum
- L. dorei = Lolium persicum
- L. giganteum = Festuca gigantea
- L. gracile = Lolium temulentum
- L. lepturoides = Lolium rigidum subsp. lepturoides
- L. marschallii = Lolium perenne
- L. parabolicae = Lolium rigidum
- L. pratense = Festuca pratensis
- L. remotum = Lolium temulentum subsp. remotum
- L. romanum = Lolium multiflorum
- L. scabrum = Lolium multiflorum
- L. siculum = Lolium multiflorum
- L. subulatum = Lolium rigidum subsp. lepturoides
- L. teres = Lolium rigidum subsp. lepturoides
- L. trabutii = Lolium rigidum | Ryegrass
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ryegrass (Lolium) is a genus of nine species of tufted grasses in the Pooideae subfamily of the Poaceae family. They are characterized by bunch-like growth habits. Also called tares (even though there is no firm evidence that this is the same as the plant given that name in English language translations of the Bible (as in the "Parable of the Tares") - vetches are another candidate), these plants are native to Europe, Asia and northern Africa, but are widely cultivated and naturalized elsewhere. Ryegrasses are naturally diploid, with 2n = 14, and are closely related to the fescues Festuca.
Ryegrass should not be confused with rye, which is a grain crop.
# Species
The following are accepted as distinct species:
- Lolium canariense Steud. - Canary Islands ryegrass
- Lolium edwardii H.Scholz, Stierst. & Gaisberg
- Lolium multiflorum Lam. - Italian ryegrass
- Lolium perenne L. - Perennial ryegrass
- Lolium persicum - Persian ryegrass or Persian darnel
- Lolium remotum Schrank
- Lolium rigidum Gaudin - Stiff darnel, Wimmera ryegrass
- Lolium temulentum L. - Darnel, poison darnel
# Cultivation and uses
Ryegrasses contain some species which are important grasses for both lawns, and as pasture and for grazing and hay for livestock, being a highly nutritious stock feed. Ryegrasses are also used in soil erosion control programs. It is the principal grazing grass in New Zealand where some 10 million kilograms of certified seed are produced every year. There is a large range of cultivars. The primary species found worldwide and used for both lawns and as a forage crop is perennial ryegrass (Lolium perenne). Like many cool-season grasses of the family Poaceae, it harbors a symbiotic fungal endophyte, either Epichloë or its close relative Neotyphodium, of which both are of the fungal family Clavicipitaceae[1][2]
Some species, particularly L. temulentum, are weeds which can have a severe impact on the production of wheat and other crops. Ryegrass pollen is also one of the major causes of hay fever.
Many grass tennis courts including Wimbledon are planted in ryegrass in different compositions, depending on the tournament.
# Synonyms
- L. ambiguum = Lolium multiflorum
- L. annuum = Lolium temulentum
- L. arundinaceum = Festuca arundinacea
- L. berteronianum = Lolium temulentum
- L. brasilianum = Lolium perenne
- L. canadense = Lolium perenne
- L. crassiculme = Lolium rigidum
- L. cuneatum = Lolium temulentum
- L. dorei = Lolium persicum
- L. giganteum = Festuca gigantea
- L. gracile = Lolium temulentum
- L. lepturoides = Lolium rigidum subsp. lepturoides
- L. marschallii = Lolium perenne
- L. parabolicae = Lolium rigidum
- L. pratense = Festuca pratensis
- L. remotum = Lolium temulentum subsp. remotum
- L. romanum = Lolium multiflorum
- L. scabrum = Lolium multiflorum
- L. siculum = Lolium multiflorum
- L. subulatum = Lolium rigidum subsp. lepturoides
- L. teres = Lolium rigidum subsp. lepturoides
- L. trabutii = Lolium rigidum | https://www.wikidoc.org/index.php/Ryegrass | |
64b9d2426e71de603b11730059bde6689bc643bf | wikidoc | Serratia | Serratia
# Overview
Serratia is a short, facultatively anaerobic, Gram-negative, rod-shaped bacteria of the Enterobacteriaceae family. Serratia species are ubiquitous opportunistic pathogens that are frequently present under damp conditions in food, plants, animals, soil, and household items.
# Microbiological Characteristics
- Serratia is a ubiquitous opportunistic pathogen that is frequently present under damp conditions in food, plants, animals, soil, and household items (e.g. bathroom tiles).
- Serratia is a short, facultatively anaerobic, Gram-negative, rod-shaped bacteria of the Enterobacteriaceae family.
- It is often associated with hospital-acquired infections.
- Serratia contains enzymes that facilitate its survival under oxygenated conditions against reactive oxygen species. Enzymes include superoxide dismutase, catalase, and peroxidase.
- Serratia has a unique thin cell wall that contains lipopolysaccharides (LPS) that does not resemble the LPS-containing cell walls of other Gram-negative bacteria.
- Out of a total of 12 Serratia species (see Scientific Classification Table), 8 have been reported to be infectious in humans. To view the list of infectiuous Serratia species, click here.
- Serratia is notoriously known for its antimicrobial resistance due to the presence of R-factor and efflux pumps.
- R-factors are genes on plasmids that code for antibiotic resistance and may be transferred from one strain to another.
- Efflux pumps, such as the SdeXY, SdeY, and ABC-type efflux pumps, may eliminate toxins. These pumps may reduce susceptibility to antimicrobial agents, such as erythromycin, tetracycline, norfloxacin, benzalkonium chloride, ethidium bromide, acriflavine, and rhodamine.
# Taxonomy
Serratia belongs to the following higher order taxa:
- Bacteria (Domain); Proteobacteria (Phylum); Gamma Proteobacteria (Class); Enterobacteriales (Order); Enterobacteriaceae (Family); Serratia (Genus).
## Species
The following is the list of Serratia species:
- S. entomophila
- S. ficaria
- S. fonticola
- S. grimesii
- S. liquefaciens
- S. marcescens
- S. odoriferae
- S. plymuthica
- S. proteamaculans
- S. quinivorans
- S. rubidaea
- S. ureilytica
# Serratia marcescens
- S. marcescens is a thin, motile (flagellated), non-septated, Gram-negative, facultatively anaerobic rod-shaped bacteria that can grow in temperatures ranging from 5–40 °C and in pH levels ranging from 5 to 9.
- S. marcescens is able to perform casein hydrolysis, which facilitates the production of extracellular metalloproteases thought to function in cell-to-extracellular matrix interactions.
- S. marcescens also exhibits tryptophan- and citrate-degradation. Pyruvic acid, an end-product of tryptophan degradation, and carbon, an end-product of citrate degradation, are then incorporated into metabolic processes.
- S. marcescens produces a reddish-orange (bloody) pigment called prodigiosin. Not all strains, however, are able to produce prodigiosin. It is thought that prodigiosin is an antigen, and during an infection, the production of prodigiosin is limited to avoid the triggering of human immune responses.
- Identification of the organism is commonly done via the following tests:
- Methyl red test, which determines if a microorganism performs mixed-acid fermentation. Typically, S. marcescens results in a negative test due to the production of 2, 3-butanediol and ethanol.
- Voges-Proskauer test, which determines the organism's ability to convert pyruvatet to acetonin. Typically, S. marcescens results in a positive test.
- Nitrate test, which determines the organism's ability to produce nitrate products. Typically, S. marcescens results in a positive test.
## Identification
The following table demonstrates the microbiological characteristics and a comprehensive list of techniques to identify S. marcescens:
# Clinical Association
Clinically, Serratia may infect multiple organ systems. It may be responsible for urinary tract infection, pneumonia , osteomyelitis, meningitis, cerebral abscess formation, endocarditis, intra-abdominal infections, eye and tear duct infections (conjunctivitis, keratitis, endophthalmitis), otitis media, and rarely parotitis. To learn more about the clinical infection of Serratia, click here.
# Gallery
- Blood agar base plate cultivated colonial growth of Gram-negative, rod-shaped and facultatively anaerobic Serratia marcescens bacteria. From Public Health Image Library (PHIL).
- Antibiogram of Serratia marcescens. From WikiMedia.org.
- Serratia marcescens on bread. From WikiMedia.org.
- Serratia marcescens appears as bloody red spots on culture medium. From WikiMedia.org.
- Serratia marcescens appears as bloody red spots on culture medium. From WikiMedia.org.
- Serratia marcescens on slates of bread shelves. From WikiMedia.org. | Serratia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Serratia is a short, facultatively anaerobic, Gram-negative, rod-shaped bacteria of the Enterobacteriaceae family. Serratia species are ubiquitous opportunistic pathogens that are frequently present under damp conditions in food, plants, animals, soil, and household items.
# Microbiological Characteristics
- Serratia is a ubiquitous opportunistic pathogen that is frequently present under damp conditions in food, plants, animals, soil, and household items (e.g. bathroom tiles).
- Serratia is a short, facultatively anaerobic, Gram-negative, rod-shaped bacteria of the Enterobacteriaceae family.
- It is often associated with hospital-acquired infections.
- Serratia contains enzymes that facilitate its survival under oxygenated conditions against reactive oxygen species. Enzymes include superoxide dismutase, catalase, and peroxidase.
- Serratia has a unique thin cell wall that contains lipopolysaccharides (LPS) that does not resemble the LPS-containing cell walls of other Gram-negative bacteria.
- Out of a total of 12 Serratia species (see Scientific Classification Table), 8 have been reported to be infectious in humans. To view the list of infectiuous Serratia species, click here.
- Serratia is notoriously known for its antimicrobial resistance due to the presence of R-factor and efflux pumps.
- R-factors are genes on plasmids that code for antibiotic resistance and may be transferred from one strain to another.
- Efflux pumps, such as the SdeXY, SdeY, and ABC-type efflux pumps, may eliminate toxins. These pumps may reduce susceptibility to antimicrobial agents, such as erythromycin, tetracycline, norfloxacin, benzalkonium chloride, ethidium bromide, acriflavine, and rhodamine.
# Taxonomy
Serratia belongs to the following higher order taxa:
- Bacteria (Domain); Proteobacteria (Phylum); Gamma Proteobacteria (Class); Enterobacteriales (Order); Enterobacteriaceae (Family); Serratia (Genus).
## Species
The following is the list of Serratia species:
- S. entomophila
- S. ficaria
- S. fonticola
- S. grimesii
- S. liquefaciens
- S. marcescens
- S. odoriferae
- S. plymuthica
- S. proteamaculans
- S. quinivorans
- S. rubidaea
- S. ureilytica
# Serratia marcescens
- S. marcescens is a thin, motile (flagellated), non-septated, Gram-negative, facultatively anaerobic rod-shaped bacteria that can grow in temperatures ranging from 5–40 °C and in pH levels ranging from 5 to 9.
- S. marcescens is able to perform casein hydrolysis, which facilitates the production of extracellular metalloproteases thought to function in cell-to-extracellular matrix interactions.
- S. marcescens also exhibits tryptophan- and citrate-degradation. Pyruvic acid, an end-product of tryptophan degradation, and carbon, an end-product of citrate degradation, are then incorporated into metabolic processes.
- S. marcescens produces a reddish-orange (bloody) pigment called prodigiosin. Not all strains, however, are able to produce prodigiosin. It is thought that prodigiosin is an antigen, and during an infection, the production of prodigiosin is limited to avoid the triggering of human immune responses.
- Identification of the organism is commonly done via the following tests:
- Methyl red test, which determines if a microorganism performs mixed-acid fermentation. Typically, S. marcescens results in a negative test due to the production of 2, 3-butanediol and ethanol.
- Voges-Proskauer test, which determines the organism's ability to convert pyruvatet to acetonin. Typically, S. marcescens results in a positive test.
- Nitrate test, which determines the organism's ability to produce nitrate products. Typically, S. marcescens results in a positive test.
## Identification
The following table demonstrates the microbiological characteristics and a comprehensive list of techniques to identify S. marcescens:
# Clinical Association
Clinically, Serratia may infect multiple organ systems. It may be responsible for urinary tract infection, pneumonia , osteomyelitis, meningitis, cerebral abscess formation, endocarditis, intra-abdominal infections, eye and tear duct infections (conjunctivitis, keratitis, endophthalmitis), otitis media, and rarely parotitis. To learn more about the clinical infection of Serratia, click here.
# Gallery
- Blood agar base plate cultivated colonial growth of Gram-negative, rod-shaped and facultatively anaerobic Serratia marcescens bacteria. From Public Health Image Library (PHIL). [2]
- Antibiogram of Serratia marcescens. From WikiMedia.org. [3]
- Serratia marcescens on bread. From WikiMedia.org. [4]
- Serratia marcescens appears as bloody red spots on culture medium. From WikiMedia.org. [5]
- Serratia marcescens appears as bloody red spots on culture medium. From WikiMedia.org. [6]
- Serratia marcescens on slates of bread shelves. From WikiMedia.org. [6] | https://www.wikidoc.org/index.php/S._entomophila | |
2997b3e4fe04a148b62e4f2d7ecab6f25f095946 | wikidoc | SAPS III | SAPS III
# Overview
SAPS III is a system for predicting mortality, one of several ICU scoring systems. Its name stands for "Simplified Acute Physiology Score" and is a supplement to the SAPS II scoring system. It has been designed to provide a real-life predicted mortality for a patient by following a well defined procedure, based on a mathematical model that needs calibration. Predicted mortalities are good when comparing groups of patients, and having near-real-life mortalities means, that this scoring system can answer questions like "if the patients from hospital A had been in hospital B, what would their mortality have been?".
However, in order to achieve this great functionality, you must calibrate the system, which is additional effort, and it is difficult to compare two groups of patients if they weren't scored using the same calibration. SAPS III is therefore not suitable for publishing data about the morbidity of a single group of patients.
The SAPS III project is conducted by the SAPS III Outcomes Research Group (SORG). | SAPS III
# Overview
SAPS III is a system for predicting mortality, one of several ICU scoring systems. Its name stands for "Simplified Acute Physiology Score" and is a supplement to the SAPS II scoring system. It has been designed to provide a real-life predicted mortality for a patient by following a well defined procedure, based on a mathematical model that needs calibration. Predicted mortalities are good when comparing groups of patients, and having near-real-life mortalities means, that this scoring system can answer questions like "if the patients from hospital A had been in hospital B, what would their mortality have been?".
However, in order to achieve this great functionality, you must calibrate the system, which is additional effort, and it is difficult to compare two groups of patients if they weren't scored using the same calibration. SAPS III is therefore not suitable for publishing data about the morbidity of a single group of patients.
The SAPS III project is conducted by the SAPS III Outcomes Research Group (SORG).
# External links
- The SAPS III Outcome Research Group
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/SAPS_III | |
ff053d41b7564ee1abf899ff5c929962e840140e | wikidoc | SDS-PAGE | SDS-PAGE
# Overview
SDS-PAGE, officially sodium dodecyl sulfate polyacrylamide gel electrophoresis, is a technique used in biochemistry, genetics and molecular biology to separate proteins according to their electrophoretic mobility (a function of length of polypeptide chain or molecular weight as well as higher order protein folding, posttranslational modifications and other factors).
# Procedure
The solution of proteins to be analyzed is first mixed with SDS, an anionic detergent which denatures secondary and non–disulfide–linked tertiary structures, and applies a negative charge to each protein in proportion to its mass. Without SDS, different proteins with similar molecular weights would migrate differently due to differences in folding, as differences in folding patterns would cause some proteins to better fit through the gel matrix than others. Adding SDS solves this problem, as it linearizes the proteins so that they may be separated strictly by molecular weight (primary structure, or number (and size) of amino acids). The SDS binds to the protein in a ratio of approximately 1.4 g SDS per 1.0 g protein (although binding ratios can vary from 1.1-2.2 g SDS/g protein), giving an approximately uniform mass:charge ratio for most proteins, so that the distance of migration through the gel can be assumed to be directly related to only the size of the protein. A tracking dye may be added to the protein solution to allow the experimenter to track the progress of the protein solution through the gel during the electrophoretic run.
# SDS PAGE chemical ingredients and roles
''Poly acrylamide gel (PAG)'' had been known as a potential embedding medium for sectioning tissues as early as 1954. Two independent groups Davis and Raymond employed PAG in electrophoresis in 1959. It possesses several electrophoretically desirable features that made it a versatile medium. Poly acrylamide gel separates protein molecules according to both size and charge. It is a synthetic gel, thermo-stable, transparent, strong, relatively chemically inert, can be prepared with a wide range of average pore sizes, can withstand high voltage gradients, feasible to various staining and destaining procedures and can be digested to extract separated fractions or dried for autoradiography and permanent recording. DISC electrophoresis utilizes gels of different pore sizes. The name DISC was derived from the discontinuities in the electrophoretic matrix and coincidentally from the discoid shape of the separated zones of ions (Anbalagan, 1999). There are two layers of gel namely staking gel or spacer gel and resolving gel or separating gel.
Staking gel or spacer gel: It is a large pore poly acrylamide gel (4%). This gel is prepared with Tris buffer pH 6.8 of about 2 pH units lower than that of electrophoresis buffer. These conditions provide an environment for Kohlrausch reactions, as a result, proteins are concentrated to several fold and a thin starting zone of the order of 19 micrometres is achieved in a few minutes. This gel is cast over the resolving gel. The height of the staking gel region was always maintained more than double the height and the volume of the sample to be applied.
Resolving gel or Separating Gel: This is a small pore polyacryl amide gel (3 - 30%). The Tris buffer used is of pH 8.8. In this gel, macro molecules separate according to their size. In the present experiment, 8%, 10% and 12% Resolving gel were used for separating different range of proteins. 8% gel for 24 – 205 kD proteins, 10% gel for 14-205 kD proteins and 12% gel for 14-66 kD proteins
The chemical ingredients of the gel are the following
Tris (tris (hydroxy methyl) aminomethane) (C4H11NO3; mw: 121.14). It has been used as a buffer because it is an innocuous substance to most proteins. Its pKa is 8.3 at 20 °C and reasonably a very satisfactory buffer in the pH range 7.0 – 9.0.
Glycine (Amino Acetic Acid) (C2H5NO2; mw: 75.07). Glycine has been used as the source of trailing ion or slow ion because its pKa is 9.69 and mobility of glycinate are such that the effective mobility can be set at a value below that of the slowest known proteins of net negative charge in the pH range. The minimum pH of this range is somewhere around 8.0.
Acrylamide (C3H5NO; mw: 71.08). It is a white crystalline powder. While dissolving in water, autopolymerisation of acrylamide takes place. It is a slow spontaneous process by which acrylamide molecules join together by head on tail fashion. But in presence of free radicals generating system, acrylamide monomers are activated into a free-radical state. These activated monomers polymerise quickly and form long chain polymers. This kind of reaction is known as Vinyl addition polymerisation. A solution of these polymer chains becomes viscous but does not form a gel, because the chains simply slide over one another. Gel formation requires hooking various chains together. Acrylamide is a neuro toxin. It is also essential to store acrylamide in a cool dark and dry place to reduce autopolymerisation and hydrolysis.
Bisacrylamide (N,N’-Methylenebisacrylamide) (C7H10N2O2; mw: 154.17). Bisacrylamide is the most frequently used cross linking agent for poly acryl- amide gels. Chemically it is thought of having two-acrylamide molecules coupled head to head at their non-reactive ends. Bisacrylamide was preserved at 4 °C.
Sodium Dodecyl Sulphate (SDS) (C12H25NaO4S; mw: 288.38). SDS is the most common dissociating agent used to denature native proteins to individual polypeptides. When a protein mixture is heated to 100 °C in presence of SDS, the detergent wraps around the polypeptide backbone. It binds to polypeptides in a constant weight ratio of 1.4 g/g of polypeptide. In this process, the intrinsic charges of polypeptides becomes negligible when compared to the negative charges contributed by SDS. Thus polypeptides after treatment becomes a rod like structure possessing a uniform charge density, that is same net negative charge per unit length. Mobilities of these proteins will be a linear function of the logarithms of their molecular weights.
Ammonium per sulphate (APS) (N2H8S2O8; mw: 228.2). APS is an initiator for gel formation. APS was stored at 4 °C.
TEMED (N, N, N’, N’-tetramethylethylenediamine) (C6H16N2; mw: 116.21). Chemical polymerisation of acrylamide gel is used for SDS-PAGE. It can be initiated by ammonium per sulphate and the quarternary amine, N, N, N’, N’-tetramethylethylenediamine (TEMED). The rate of polymerisation and the properties of the resulting gel depends on the concentration of APS and TEMED. Increasing the amount of APS and TEMED results in a decrease in the average polymer chain length, an increase in gel turbidity and a decrease in gel elasticity. Decreasing the amount of initiators shows the reverse effect. It is recommended that lowest catalysts concentrations that will allow polymerisation in the optimal period of time should be used. APS and TEMED are used, approximately in equimoloar concentrations in the range of 1 to 10 mM. TEMED was stored at 4 °C.
The following chemicals are used for processing of the gel and the protein samples visualized in it.
Bromo Phenol Blue (BPB) (3’, 3’’, 5’, 5’’-Tetrabromophenolsulph- onephthalein) (C19H10Br4O5S; mw: 669.99). BPB is the universal marker dye. Proteins and nucleic acids are mostly colourless. When they are subjected to electrophoresis, it is important to stop the run before they run off the gel. BPB is the most commonly employed tracking dye, because it is viable in alkali and neutral pH, it is a small molecule, it is ionisable and it is negatively charged above pH 4.6 and hence moves towards anode. Being a small molecule it moves ahead of most proteins and nucleic acids. As it reaches the anodic end of the electrophoresis medium electrophoresis is stopped. It can bind with proteins weakly and give blue colour.
Glycerol (C3H8O3; mw: 92.09). It is a preservative and a weighing agent. Additon of glycerol (20-30 or 50%) is often recommended for the storage of enzymes. Glycerol maintains the protein solution at very low temperature, without freezing. It also helps to weigh down the sample into the wells without being spread while loading.
Coomassie Brilliant Blue (CBB) (C45H44N3NaO7S2; mw: 825.97). CBB is the most popular protein stain. It is an anionic dye, which binds with proteins non-specifically. The structure of CBB is predominantly non-polar. So is usually used (0.025%) in methanolic solution (40%) and Acetic Acid (7%). Proteins in the gel are fixed by acetic acid and simultaneously stained. The excess dye incorporated in the gel can be removed by destaining with the same solution containing no dye. The proteins are detected as blue bands on a clear background. As SDS is also anionic in nature, it is reported to interfere with staining process. Therefore, large volume of staining solution is recommended. Approximately 10 times the volume of the gel.
Butanol (C4H10O; mw: 74.12). Water saturated butanol is used as an overlay solution on the resolving gel.
Beta Mercapto Ethanol (HS-CH2CH2OH; mw: 78.13). BME was procured from LKB, Bromma, Sweden and was stored at 4 °C.
## Reducing SDS-PAGE
Besides the addition of SDS, proteins may optionally be briefly heated to near boiling in the presence of a reducing agent, such as dithiothreitol (DTT) or 2-mercaptoethanol (beta-Mercaptoethanol/BME), which further denatures the proteins by reducing disulfide linkages, thus overcoming some forms of tertiary protein folding, and breaking up quaternary protein structure (oligomeric subunits). This is known as reducing SDS-PAGE, and is most commonly used. Non-reducing SDS-PAGE (no boiling and no reducing agent) may be used when native structure is important in further analysis (e.g. enzyme activity, shown by the use of zymograms). For example, quantitative preparative native continuous polyacrylamide gel electrophoresis (QPNC-PAGE) is a new method for separating native metalloproteins in complex biological matrices.
## Electrophoresis and staining
The denatured proteins are subsequently applied to one end of a layer of polyacrylamide gel submerged in a suitable buffer. An electric current is applied across the gel, causing the negatively-charged proteins to migrate across the gel towards the anode. Depending on their size, each protein will move differently through the gel matrix: short proteins will more easily fit through the pores in the gel, while larger ones will have more difficulty (they encounter more resistance). After a set amount of time (usually a few hours- though this depends on the voltage applied across the gel; higher voltages run faster but tend to produce somewhat poorer resolution), the proteins will have differentially migrated based on their size; smaller proteins will have traveled farther down the gel, while larger ones will have remained closer to the point of origin. Thus proteins may be separated roughly according to size (and therefore, molecular weight). Following electrophoresis, the gel may be stained (most commonly with Coomassie Brilliant Blue or silver stain), allowing visualisation of the separated proteins, or processed further (e.g. Western blot). After staining, different proteins will appear as distinct bands within the gel. It is common to run "marker proteins" of known molecular weight in a separate lane in the gel, in order to calibrate the gel and determine the weight of unknown proteins by comparing the distance traveled relative to the marker. The gel is actually formed because the acrylamide solution contains a small amount, generally about 1 part in 35 of bisacrylamide, which can form cross-links between two polyacrylamide molecules. The ratio of acrylamide to bisacrylamide can be varied for special purposes. The acrylamide concentration of the gel can also be varied, generally in the range from 5% to 25%. Lower percentage gels are better for resolving very high molecular weight proteins, while much higher percentages are needed to resolve smaller proteins. Determining how much of the various solutions to mix together to make gels of particular acrylamide concentration can be done on line
Gel electrophoresis is usually the first choice as an assay of protein purity due to its reliability and ease. The presence of SDS and the denaturing step causes proteins to be separated solely based on size. False negatives and positives are possible. A co migrating contaminant can appear as the same band as the desired protein. This comigration could also cause a protein to run at a different position or to not be able to penetrate the gel. This is why it is important to stain the entire gel including the stacking section. Coomassie Brilliant Blue will also bind with less affinity to glycoproteins and fibrous proteins, which interferes with quantification (Deutscher 1990).
## Buffer systems
Most protein separations are performed using a "discontinuous" buffer system that significantly enhances the sharpness of the bands within the gel. During electrophoresis in a discontinuous gel system, an ion gradient is formed in the early stage of electrophoresis that causes all of the proteins to focus into a single sharp band. This occurs in a region of the gel that has larger pores so that the gel matrix does not retard the migration during the focusing or "stacking" event. Negative ions from the buffer in the tank then "outrun" the SDS-covered protein "stack" and eliminate the ion gradient so that the proteins subsequently separate by the sieving action in the lower, "resolving" region of the gel.
Many people continue to use a tris-glycine or "Laemmli" buffering system that stacks and resolves at a pH of ~8.3-9.0. These pHs promote disulfide bond formation between cysteine residues in the proteins, especially when they are present at high concentrations because the pKa of cysteine ranges from 8-9 and because reducing agent present in the loading buffer doesn't co-migrate with the proteins. Recent advances in buffering technology alleviate this problem by resolving the proteins at a pH well below the pKa of cysteine (e.g., bis-tris, pH 6.5) and include reducing agents (e.g. sodium bisulfite) that move into the gel ahead of the proteins to maintain a reducing environment. An additional benefit of using buffers with lower pHs is that the acrylamide gel is more stable so the gels can be stored for long periods of time before use. | SDS-PAGE
# Overview
SDS-PAGE, officially sodium dodecyl sulfate polyacrylamide gel electrophoresis, is a technique used in biochemistry, genetics and molecular biology to separate proteins according to their electrophoretic mobility (a function of length of polypeptide chain or molecular weight as well as higher order protein folding, posttranslational modifications and other factors).
# Procedure
The solution of proteins to be analyzed is first mixed with SDS, an anionic detergent which denatures secondary and non–disulfide–linked tertiary structures, and applies a negative charge to each protein in proportion to its mass. Without SDS, different proteins with similar molecular weights would migrate differently due to differences in folding, as differences in folding patterns would cause some proteins to better fit through the gel matrix than others. Adding SDS solves this problem, as it linearizes the proteins so that they may be separated strictly by molecular weight (primary structure, or number (and size) of amino acids). The SDS binds to the protein in a ratio of approximately 1.4 g SDS per 1.0 g protein (although binding ratios can vary from 1.1-2.2 g SDS/g protein), giving an approximately uniform mass:charge ratio for most proteins, so that the distance of migration through the gel can be assumed to be directly related to only the size of the protein. A tracking dye may be added to the protein solution to allow the experimenter to track the progress of the protein solution through the gel during the electrophoretic run.
# SDS PAGE chemical ingredients and roles
''Poly acrylamide gel (PAG)'' had been known as a potential embedding medium for sectioning tissues as early as 1954. Two independent groups Davis and Raymond employed PAG in electrophoresis in 1959. It possesses several electrophoretically desirable features that made it a versatile medium. Poly acrylamide gel separates protein molecules according to both size and charge. It is a synthetic gel, thermo-stable, transparent, strong, relatively chemically inert, can be prepared with a wide range of average pore sizes, can withstand high voltage gradients, feasible to various staining and destaining procedures and can be digested to extract separated fractions or dried for autoradiography and permanent recording. DISC electrophoresis utilizes gels of different pore sizes. The name DISC was derived from the discontinuities in the electrophoretic matrix and coincidentally from the discoid shape of the separated zones of ions (Anbalagan, 1999). There are two layers of gel namely staking gel or spacer gel and resolving gel or separating gel.
Staking gel or spacer gel: It is a large pore poly acrylamide gel (4%). This gel is prepared with Tris buffer pH 6.8 of about 2 pH units lower than that of electrophoresis buffer. These conditions provide an environment for Kohlrausch reactions, as a result, proteins are concentrated to several fold and a thin starting zone of the order of 19 micrometres is achieved in a few minutes. This gel is cast over the resolving gel. The height of the staking gel region was always maintained more than double the height and the volume of the sample to be applied.
Resolving gel or Separating Gel: This is a small pore polyacryl amide gel (3 - 30%). The Tris buffer used is of pH 8.8. In this gel, macro molecules separate according to their size. In the present experiment, 8%, 10% and 12% Resolving gel were used for separating different range of proteins. 8% gel for 24 – 205 kD proteins, 10% gel for 14-205 kD proteins and 12% gel for 14-66 kD proteins
The chemical ingredients of the gel are the following
Tris (tris (hydroxy methyl) aminomethane) (C4H11NO3; mw: 121.14). It has been used as a buffer because it is an innocuous substance to most proteins. Its pKa is 8.3 at 20 °C and reasonably a very satisfactory buffer in the pH range 7.0 – 9.0.
Glycine (Amino Acetic Acid) (C2H5NO2; mw: 75.07). Glycine has been used as the source of trailing ion or slow ion because its pKa is 9.69 and mobility of glycinate are such that the effective mobility can be set at a value below that of the slowest known proteins of net negative charge in the pH range. The minimum pH of this range is somewhere around 8.0.
Acrylamide (C3H5NO; mw: 71.08). It is a white crystalline powder. While dissolving in water, autopolymerisation of acrylamide takes place. It is a slow spontaneous process by which acrylamide molecules join together by head on tail fashion. But in presence of free radicals generating system, acrylamide monomers are activated into a free-radical state. These activated monomers polymerise quickly and form long chain polymers. This kind of reaction is known as Vinyl addition polymerisation. A solution of these polymer chains becomes viscous but does not form a gel, because the chains simply slide over one another. Gel formation requires hooking various chains together. Acrylamide is a neuro toxin. It is also essential to store acrylamide in a cool dark and dry place to reduce autopolymerisation and hydrolysis.
Bisacrylamide (N,N’-Methylenebisacrylamide) (C7H10N2O2; mw: 154.17). Bisacrylamide is the most frequently used cross linking agent for poly acryl- amide gels. Chemically it is thought of having two-acrylamide molecules coupled head to head at their non-reactive ends. Bisacrylamide was preserved at 4 °C.
Sodium Dodecyl Sulphate (SDS) (C12H25NaO4S; mw: 288.38). SDS is the most common dissociating agent used to denature native proteins to individual polypeptides. When a protein mixture is heated to 100 °C in presence of SDS, the detergent wraps around the polypeptide backbone. It binds to polypeptides in a constant weight ratio of 1.4 g/g of polypeptide. In this process, the intrinsic charges of polypeptides becomes negligible when compared to the negative charges contributed by SDS. Thus polypeptides after treatment becomes a rod like structure possessing a uniform charge density, that is same net negative charge per unit length. Mobilities of these proteins will be a linear function of the logarithms of their molecular weights.
Ammonium per sulphate (APS) (N2H8S2O8; mw: 228.2). APS is an initiator for gel formation. APS was stored at 4 °C.
TEMED (N, N, N’, N’-tetramethylethylenediamine) (C6H16N2; mw: 116.21). Chemical polymerisation of acrylamide gel is used for SDS-PAGE. It can be initiated by ammonium per sulphate and the quarternary amine, N, N, N’, N’-tetramethylethylenediamine (TEMED). The rate of polymerisation and the properties of the resulting gel depends on the concentration of APS and TEMED. Increasing the amount of APS and TEMED results in a decrease in the average polymer chain length, an increase in gel turbidity and a decrease in gel elasticity. Decreasing the amount of initiators shows the reverse effect. It is recommended that lowest catalysts concentrations that will allow polymerisation in the optimal period of time should be used. APS and TEMED are used, approximately in equimoloar concentrations in the range of 1 to 10 mM. TEMED was stored at 4 °C.
The following chemicals are used for processing of the gel and the protein samples visualized in it.
Bromo Phenol Blue (BPB) (3’, 3’’, 5’, 5’’-Tetrabromophenolsulph- onephthalein) (C19H10Br4O5S; mw: 669.99). BPB is the universal marker dye. Proteins and nucleic acids are mostly colourless. When they are subjected to electrophoresis, it is important to stop the run before they run off the gel. BPB is the most commonly employed tracking dye, because it is viable in alkali and neutral pH, it is a small molecule, it is ionisable and it is negatively charged above pH 4.6 and hence moves towards anode. Being a small molecule it moves ahead of most proteins and nucleic acids. As it reaches the anodic end of the electrophoresis medium electrophoresis is stopped. It can bind with proteins weakly and give blue colour.
Glycerol (C3H8O3; mw: 92.09). It is a preservative and a weighing agent. Additon of glycerol (20-30 or 50%) is often recommended for the storage of enzymes. Glycerol maintains the protein solution at very low temperature, without freezing. It also helps to weigh down the sample into the wells without being spread while loading.
Coomassie Brilliant Blue (CBB) (C45H44N3NaO7S2; mw: 825.97). CBB is the most popular protein stain. It is an anionic dye, which binds with proteins non-specifically. The structure of CBB is predominantly non-polar. So is usually used (0.025%) in methanolic solution (40%) and Acetic Acid (7%). Proteins in the gel are fixed by acetic acid and simultaneously stained. The excess dye incorporated in the gel can be removed by destaining with the same solution containing no dye. The proteins are detected as blue bands on a clear background. As SDS is also anionic in nature, it is reported to interfere with staining process. Therefore, large volume of staining solution is recommended. Approximately 10 times the volume of the gel.
Butanol (C4H10O; mw: 74.12). Water saturated butanol is used as an overlay solution on the resolving gel.
Beta Mercapto Ethanol (HS-CH2CH2OH; mw: 78.13). BME was procured from LKB, Bromma, Sweden and was stored at 4 °C.
## Reducing SDS-PAGE
Besides the addition of SDS, proteins may optionally be briefly heated to near boiling in the presence of a reducing agent, such as dithiothreitol (DTT) or 2-mercaptoethanol (beta-Mercaptoethanol/BME), which further denatures the proteins by reducing disulfide linkages, thus overcoming some forms of tertiary protein folding, and breaking up quaternary protein structure (oligomeric subunits). This is known as reducing SDS-PAGE, and is most commonly used. Non-reducing SDS-PAGE (no boiling and no reducing agent) may be used when native structure is important in further analysis (e.g. enzyme activity, shown by the use of zymograms). For example, quantitative preparative native continuous polyacrylamide gel electrophoresis (QPNC-PAGE) is a new method for separating native metalloproteins in complex biological matrices.
## Electrophoresis and staining
The denatured proteins are subsequently applied to one end of a layer of polyacrylamide gel submerged in a suitable buffer. An electric current is applied across the gel, causing the negatively-charged proteins to migrate across the gel towards the anode. Depending on their size, each protein will move differently through the gel matrix: short proteins will more easily fit through the pores in the gel, while larger ones will have more difficulty (they encounter more resistance). After a set amount of time (usually a few hours- though this depends on the voltage applied across the gel; higher voltages run faster but tend to produce somewhat poorer resolution), the proteins will have differentially migrated based on their size; smaller proteins will have traveled farther down the gel, while larger ones will have remained closer to the point of origin. Thus proteins may be separated roughly according to size (and therefore, molecular weight). Following electrophoresis, the gel may be stained (most commonly with Coomassie Brilliant Blue or silver stain), allowing visualisation of the separated proteins, or processed further (e.g. Western blot). After staining, different proteins will appear as distinct bands within the gel. It is common to run "marker proteins" of known molecular weight in a separate lane in the gel, in order to calibrate the gel and determine the weight of unknown proteins by comparing the distance traveled relative to the marker. The gel is actually formed because the acrylamide solution contains a small amount, generally about 1 part in 35 of bisacrylamide, which can form cross-links between two polyacrylamide molecules. The ratio of acrylamide to bisacrylamide can be varied for special purposes. The acrylamide concentration of the gel can also be varied, generally in the range from 5% to 25%. Lower percentage gels are better for resolving very high molecular weight proteins, while much higher percentages are needed to resolve smaller proteins. Determining how much of the various solutions to mix together to make gels of particular acrylamide concentration can be done on line
Gel electrophoresis is usually the first choice as an assay of protein purity due to its reliability and ease. The presence of SDS and the denaturing step causes proteins to be separated solely based on size. False negatives and positives are possible. A co migrating contaminant can appear as the same band as the desired protein. This comigration could also cause a protein to run at a different position or to not be able to penetrate the gel. This is why it is important to stain the entire gel including the stacking section. Coomassie Brilliant Blue will also bind with less affinity to glycoproteins and fibrous proteins, which interferes with quantification (Deutscher 1990).
## Buffer systems
Most protein separations are performed using a "discontinuous" buffer system that significantly enhances the sharpness of the bands within the gel. During electrophoresis in a discontinuous gel system, an ion gradient is formed in the early stage of electrophoresis that causes all of the proteins to focus into a single sharp band. This occurs in a region of the gel that has larger pores so that the gel matrix does not retard the migration during the focusing or "stacking" event. Negative ions from the buffer in the tank then "outrun" the SDS-covered protein "stack" and eliminate the ion gradient so that the proteins subsequently separate by the sieving action in the lower, "resolving" region of the gel.
Many people continue to use a tris-glycine or "Laemmli" buffering system that stacks and resolves at a pH of ~8.3-9.0. These pHs promote disulfide bond formation between cysteine residues in the proteins, especially when they are present at high concentrations because the pKa of cysteine ranges from 8-9 and because reducing agent present in the loading buffer doesn't co-migrate with the proteins. Recent advances in buffering technology alleviate this problem by resolving the proteins at a pH well below the pKa of cysteine (e.g., bis-tris, pH 6.5) and include reducing agents (e.g. sodium bisulfite) that move into the gel ahead of the proteins to maintain a reducing environment. An additional benefit of using buffers with lower pHs is that the acrylamide gel is more stable so the gels can be stored for long periods of time before use. | https://www.wikidoc.org/index.php/SDS-PAGE | |
4a16c593709beeeb2c592e770b21dc3569b67f49 | wikidoc | SECISBP2 | SECISBP2
SECIS-binding protein 2 (commonly referred to as SBP2) is a protein that in humans is encoded by the SECISBP2 gene.
# Function
The incorporation of selenocysteine into a protein requires the concerted action of an mRNA element called a sec insertion sequence (SECIS), a selenocysteine-specific translation elongation factor and a SECIS binding protein. With these elements in place, a UGA codon can be decoded as selenocysteine. SBP2 is a nuclear protein that functions as a SECIS binding protein, but experimental evidence indicates that SBP2 is cytoplasmic.
# Clinical significance
Mutations in this gene have been associated with a reduction in activity of a specific thyroxine deiodinase, a selenocysteine-containing enzyme, and abnormal thyroid hormone metabolism. | SECISBP2
SECIS-binding protein 2 (commonly referred to as SBP2) is a protein that in humans is encoded by the SECISBP2 gene.[1][2]
# Function
The incorporation of selenocysteine into a protein requires the concerted action of an mRNA element called a sec insertion sequence (SECIS), a selenocysteine-specific translation elongation factor and a SECIS binding protein. With these elements in place, a UGA codon can be decoded as selenocysteine. SBP2 is a nuclear protein that functions as a SECIS binding protein, but experimental evidence indicates that SBP2 is cytoplasmic.[2]
# Clinical significance
Mutations in this gene have been associated with a reduction in activity of a specific thyroxine deiodinase, a selenocysteine-containing enzyme, and abnormal thyroid hormone metabolism.[2] | https://www.wikidoc.org/index.php/SECISBP2 | |
61def9435a3cf7d54b891efb643a94caba45744b | wikidoc | SERPINA2 | SERPINA2
Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2 is a protein that in humans is encoded by the SERPINA2 gene. Serine peptidase inhibitor, clade A member 2 belongs to the member of serine family of proteins which have a functional activity of inhibiting serine proteases.
# Discovery
SERPINA2 was known as pseudogenes as it had a very similar structure and function to SERPINA1. During the cloning characterisation of alpha 1- antitrypsin like gene, it was discovered that SERPINA2 did not have any promoter but did contain substantial homology to SERPINA1 gene sequence.
# Gene location
SERPINA2 is located at 14q32.13.
# Gene expression and localisation
Extracellular predictions of SERPINs and common domain clades show that ER localisation of SERPINA2 are most likely be more, these common ER motifs indicates their localisation are most likely to be in the ER.
# Structure
Population studies indicate that this gene is polymorphic. Deletions, frameshift mutations, and a critical start codon mutation (ATG to ATA) have been found in some populations, as well as an allele that can encode a functional protein. This gene may be an evolving pseudogene. The reference genome contains the start codon mutation and has a coding region deletion. A three-dimensional model of SERPINA2 was created using the non-deleted form of crystal structure, which is homologous with the SERPINA1 protein. The model was created using swissmodel in EXPASY, and has shown that SERPINA2 preserves a SERPIN reactive centre loop which is most compatible with protease inhibitory activity. The consensus sequence surrounding the reactive centre loop have diverged considerably so that now it contains tryptophan sarin motifs instead of the methionine serine motif.
# Function
SERPINA2 was previously identified as pseudogene; however, recently there have been new evidence which specifies that SERPINA2 produces an active transcript that is responsible for encoding protein located in the endoplasmic reticulum. A detailed study of the SERPINA2 gene across multiple ethnic groups have relieved that with the addition of SERPINA2 gene therein a haplotype characterisation by partial deletion which has patterns suggesting positive selection of loss of function of SERPINA2 protein.
SERPINA2 studies have shown different results regarding the extent of sequence degeneration it can undergo. Bao et al. (1988) describes in his studies that sequence with RNA splice sites are preserved in SERPINA2, and when expressed, it encodes a new secretory protein (SERPIN) with different substrate specificity. These studies with SERPINA2 in humans have concluded that recent positive selection is favoured by the loss of SERPINA2 function and pseudogenization. SERPINA2 genes are mostly expressed in leukocytes and testes which gives a residual expression in liver. SERPINA2 have been linked with on going adaptive process linked with advantages in the role of fertility and host pathogen interactions.
# Mutations
A critical mutation present in the start codon and an 2kb deletion over exon IV and part of exon V. This deletion in the start codon occurs at a frequency of 30%. Studies with SERPINA2 in vitro and in vivo have shown that it expresses stable proteins with n-linked glycosylation with a molecular weight of 52kDa and compatible with regular SERPINs
# Disease associated
SERPINA2 is a member of SERPIN family, which are known as protein coding genes. A disease associated with this gene is emphysema, due to aat protein deficiency. SERPINA2 has similar function to SERPINA1 and is related to the function of serine type peptidase inhibitor activity. | SERPINA2
Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2 is a protein that in humans is encoded by the SERPINA2 gene. Serine peptidase inhibitor, clade A member 2 belongs to the member of serine family of proteins which have a functional activity of inhibiting serine proteases.[1]
# Discovery
SERPINA2 was known as pseudogenes as it had a very similar structure and function to SERPINA1. During the cloning characterisation of alpha 1- antitrypsin like gene, it was discovered that SERPINA2 did not have any promoter but did contain substantial homology to SERPINA1 gene sequence.[2]
# Gene location
SERPINA2 is located at 14q32.13.[3]
# Gene expression and localisation
Extracellular predictions of SERPINs and common domain clades show that ER localisation of SERPINA2 are most likely be more, these common ER motifs indicates their localisation are most likely to be in the ER.[4]
# Structure
Population studies indicate that this gene is polymorphic. Deletions, frameshift mutations, and a critical start codon mutation (ATG to ATA) have been found in some populations, as well as an allele that can encode a functional protein. This gene may be an evolving pseudogene.[5] The reference genome contains the start codon mutation and has a coding region deletion. A three-dimensional model of SERPINA2 was created using the non-deleted form of crystal structure, which is homologous with the SERPINA1 protein. The model was created using swissmodel in EXPASY, and has shown that SERPINA2 preserves a SERPIN reactive centre loop which is most compatible with protease inhibitory activity. The consensus sequence surrounding the reactive centre loop have diverged considerably so that now it contains tryptophan sarin motifs instead of the methionine serine motif.[6]
# Function
SERPINA2 was previously identified as pseudogene; however, recently there have been new evidence which specifies that SERPINA2 produces an active transcript that is responsible for encoding protein located in the endoplasmic reticulum. A detailed study of the SERPINA2 gene across multiple ethnic groups have relieved that with the addition of SERPINA2 gene therein a haplotype characterisation by partial deletion which has patterns suggesting positive selection of loss of function of SERPINA2 protein.[3]
SERPINA2 studies have shown different results regarding the extent of sequence degeneration it can undergo.[5] Bao et al. (1988) describes in his studies that sequence with RNA splice sites are preserved in SERPINA2, and when expressed, it encodes a new secretory protein (SERPIN) with different substrate specificity. These studies with SERPINA2 in humans have concluded that recent positive selection is favoured by the loss of SERPINA2 function and pseudogenization.[7] SERPINA2 genes are mostly expressed in leukocytes and testes which gives a residual expression in liver. SERPINA2 have been linked with on going adaptive process linked with advantages in the role of fertility and host pathogen interactions.[6]
# Mutations
A critical mutation present in the start codon and an 2kb deletion over exon IV and part of exon V. This deletion in the start codon occurs at a frequency of 30%.[2] Studies with SERPINA2 in vitro and in vivo have shown that it expresses stable proteins with n-linked glycosylation with a molecular weight of 52kDa and compatible with regular SERPINs [6]
# Disease associated
SERPINA2 is a member of SERPIN family, which are known as protein coding genes. A disease associated with this gene is emphysema, due to aat protein deficiency. SERPINA2 has similar function to SERPINA1 and is related to the function of serine type peptidase inhibitor activity.[8] | https://www.wikidoc.org/index.php/SERPINA2 | |
317b403b829b55f642b18ab0f298d7903926abf1 | wikidoc | SERPINB1 | SERPINB1
Leukocyte elastase inhibitor (LEI) also known as serpin B1 is a protein that in humans is encoded by the SERPINB1 gene. It is a member of the clade B serpins or ov-serpins (ovalbumin related serpins) founded by ovalbumin.
MNEI (monocyte/neutrophil elastase inhibitor) is the mouse orthologue of human SerpinB1.
# Function
SerpinB1 is a cytoplasmic serine protease inhibitor of polymorphonuclear neutrophils. Among other serine proteases, it specifically inhibits neutrophil elastase, PR3 and cathepsin G, all found in neutrophil granules, by a suicide inhibition mechanism. SerpinB1 was found to reduce tissue damage caused by the mentioned proteases during inflammation and has a role in neutrophil homeostasis in mice. In various infection models (e.g. pneumonia) correlation of SerpinB1 absence and lack of microbial clearance have been shown. Different knockout strains serve as model to investigate the role of SerpinB1 in vivo. | SERPINB1
Leukocyte elastase inhibitor (LEI) also known as serpin B1 is a protein that in humans is encoded by the SERPINB1 gene. It is a member of the clade B serpins or ov-serpins (ovalbumin related serpins) founded by ovalbumin.[1][2][3]
MNEI (monocyte/neutrophil elastase inhibitor) is the mouse orthologue of human SerpinB1.[3]
# Function
SerpinB1 is a cytoplasmic serine protease inhibitor of polymorphonuclear neutrophils. Among other serine proteases, it specifically inhibits neutrophil elastase, PR3 and cathepsin G, all found in neutrophil granules, by a suicide inhibition mechanism. SerpinB1 was found to reduce tissue damage caused by the mentioned proteases during inflammation and has a role in neutrophil homeostasis in mice. In various infection models (e.g. pneumonia) correlation of SerpinB1 absence and lack of microbial clearance have been shown. Different knockout strains serve as model to investigate the role of SerpinB1 in vivo.[4][5][6] | https://www.wikidoc.org/index.php/SERPINB1 | |
dfeedb9e48f3b6c902b430ccd53e1d7c0aa52976 | wikidoc | SH3BGRL3 | SH3BGRL3
SH3 domain-binding glutamic acid-rich-like protein 3 is a protein that in humans is encoded by the SH3BGRL3 gene.
The 10.5kDa protein SH3 binding glutamic acid-rich protein-like 3 has an isoelectric point of 5.0. SH3 binding glutamic acid-rich (SH3BGR) gene is located to human chromosome 21. Two homologous genes, SH3BGRL and SH3BGRL3 are located to chromosome Xq13.3 and 1p34.3-35, respectively and code for small proteins similar to the N-terminal region of the SH3BGR protein. SH3BGRL3 protein shows a significant similarity to glutaredoxin 1 of E. coli, and all the three proteins are predicted to belong to thioredoxin-like protein family. Glutaredoxins (GRXs) are ubiquitous oxidoreductases, which catalyze the reduction of many intra-cellular protein disulfides and play an important role in many redox pathways. However, the SH3BGRL3 protein lacks the enzymatic function of glutaredoxins and may have a role as a regulator of redox activity.
# Role in cancer
Proteins such as glutaredoxin and thioredoxin are reported as up-regulated in many cancers such as lung and pancreatic; they have been implicated in increased resistance of cancer cells to free-radicals. There is little current evidence which directly links SH3GRPL3 with survival in cancer cells, however the protein has recently been identified as up-regulated in glioblastoma multiforme compared to normal cerebral tissue on proteomic analysis. Studies of acute promyelocytic leukemia cell line NB4 have also reported up-regulation of the protein. Conversely, the related protein SH3BGRL is reported to be downregulated in fibroblasts, lymphoid cells, and splenic tumor cells transformed by the viral oncogene v-Rel. Co-expression of SH3BGRL with v-Rel in primary splenic lymphocytes reduced the number of colonies formed by 76%. Xu et al. reported SH3BGRPL3 protein as a post-translational modification of the 27kDa tumor necrosis factor alpha (TNF-α) inhibitory protein, TIP-B1. This protein is potentially involved in resistance of cells to the apoptosis-inducing affect of TNF-α. | SH3BGRL3
SH3 domain-binding glutamic acid-rich-like protein 3 is a protein that in humans is encoded by the SH3BGRL3 gene.[1]
The 10.5kDa protein SH3 binding glutamic acid-rich protein-like 3 has an isoelectric point of 5.0. SH3 binding glutamic acid-rich (SH3BGR) gene is located to human chromosome 21. Two homologous genes, SH3BGRL and SH3BGRL3 are located to chromosome Xq13.3 and 1p34.3-35, respectively and code for small proteins similar to the N-terminal region of the SH3BGR protein.[2] SH3BGRL3 protein shows a significant similarity to glutaredoxin 1 of E. coli, and all the three proteins are predicted to belong to thioredoxin-like protein family. Glutaredoxins (GRXs) are ubiquitous oxidoreductases, which catalyze the reduction of many intra-cellular protein disulfides and play an important role in many redox pathways. However, the SH3BGRL3 protein lacks the enzymatic function of glutaredoxins and may have a role as a regulator of redox activity.[3]
# Role in cancer
Proteins such as glutaredoxin and thioredoxin are reported as up-regulated in many cancers such as lung and pancreatic; they have been implicated in increased resistance of cancer cells to free-radicals. There is little current evidence which directly links SH3GRPL3 with survival in cancer cells, however the protein has recently been identified as up-regulated in glioblastoma multiforme compared to normal cerebral tissue on proteomic analysis.[4] Studies of acute promyelocytic leukemia cell line NB4 have also reported up-regulation of the protein. Conversely, the related protein SH3BGRL is reported to be downregulated in fibroblasts, lymphoid cells, and splenic tumor cells transformed by the viral oncogene v-Rel.[5] Co-expression of SH3BGRL with v-Rel in primary splenic lymphocytes reduced the number of colonies formed by 76%. Xu et al. reported SH3BGRPL3 protein as a post-translational modification of the 27kDa tumor necrosis factor alpha (TNF-α) inhibitory protein, TIP-B1. This protein is potentially involved in resistance of cells to the apoptosis-inducing affect of TNF-α.[6] | https://www.wikidoc.org/index.php/SH3BGRL3 | |
9b1ab499fccb34284de46702e0e933c097a0ead5 | wikidoc | SIGLEC10 | SIGLEC10
Sialic acid-binding Ig-like lectin 10 is a protein that in humans is encoded by the SIGLEC10 gene. The mouse orthologue is Siglec G.
# Structure and Function
Like most but not all other Siglecs, Siglec-10 bears an ITIM (Immunoreceptor tyrosine-based inhibitory motif) within its cytoplasmic domain. Siglec-10 is a ligand for CD52, the target of the therapeutic monoclonal antibody Alemtuzumab. It is also reported to bind to Vascular adhesion protein 1 (VAP-1) and to the co-stimulatory molecule CD24 also known as HSA (Heat-stable antigen).
# Gene Family summary
SIGLECs are members of the immunoglobulin superfamily that are expressed on the cell surface. Most SIGLECs have 1 or more cytoplasmic immune receptor tyrosine-based inhibitory motifs, or ITIMs. SIGLECs are typically expressed on cells of the innate immune system, with the exception of the B-cell expressed SIGLEC6 (MIM 604405). | SIGLEC10
Sialic acid-binding Ig-like lectin 10 is a protein that in humans is encoded by the SIGLEC10 gene.[1][2] The mouse orthologue is Siglec G.
# Structure and Function
Like most but not all other Siglecs, Siglec-10 bears an ITIM (Immunoreceptor tyrosine-based inhibitory motif) within its cytoplasmic domain. Siglec-10 is a ligand for CD52, the target of the therapeutic monoclonal antibody Alemtuzumab.[3] It is also reported to bind to Vascular adhesion protein 1 (VAP-1) and to the co-stimulatory molecule CD24 also known as HSA (Heat-stable antigen).
# Gene Family summary
SIGLECs are members of the immunoglobulin superfamily that are expressed on the cell surface. Most SIGLECs have 1 or more cytoplasmic immune receptor tyrosine-based inhibitory motifs, or ITIMs. SIGLECs are typically expressed on cells of the innate immune system, with the exception of the B-cell expressed SIGLEC6 (MIM 604405).[supplied by OMIM][2] | https://www.wikidoc.org/index.php/SIGLEC10 | |
400d524cb01a649b33c63f7c98211c3a48233fdc | wikidoc | SLC22A12 | SLC22A12
Solute carrier family 22 (organic anion/cation transporter), member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.
# Function
The protein encoded by this gene is a urate transporter and urate-anion exchanger which regulates the level of urate in the blood. This protein is an integral membrane protein primarily found in kidney. Two transcript variants encoding different isoforms have been found for this gene.
# Clinical significance
Numerous single nucleotide polymorphisms of this gene are significantly associated with altered (increased or decreased) reabsorption of uric acid by the kidneys. Respectively, these altered rates of reabsorption contribute to hyperuricemia and hypouricemia.
# Interactions
SLC22A12 has been shown to interact with PDZK1.
# Inhibition
Lesinurad is a urate transporter inhibitor that has been approved to treat gout. Lesinurad enhances urate excretion by inhibition the tubular re-absorption. Probenecid also facilitates uric acid secretion. | SLC22A12
Solute carrier family 22 (organic anion/cation transporter), member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.[1][2]
# Function
The protein encoded by this gene is a urate transporter and urate-anion exchanger which regulates the level of urate in the blood. This protein is an integral membrane protein primarily found in kidney. Two transcript variants encoding different isoforms have been found for this gene.[1]
# Clinical significance
Numerous single nucleotide polymorphisms of this gene are significantly associated with altered (increased or decreased) reabsorption of uric acid by the kidneys.[3][4] Respectively, these altered rates of reabsorption contribute to hyperuricemia and hypouricemia.
# Interactions
SLC22A12 has been shown to interact with PDZK1.[5]
# Inhibition
Lesinurad is a urate transporter inhibitor that has been approved to treat gout.[6] Lesinurad enhances urate excretion by inhibition the tubular re-absorption. Probenecid also facilitates uric acid secretion.[7][8] | https://www.wikidoc.org/index.php/SLC22A12 | |
8a32240770955e112c5ac75e7f560e27137e980a | wikidoc | SLC25A10 | SLC25A10
The mitochondrial dicarboxylate carrier (DIC) is an integral membrane protein encoded by the SLC25A10 gene in humans that catalyzes the transport of dicarboxylates such as malonate, malate, and succinate across the inner mitochondrial membrane in exchange for phosphate, sulfate, and thiosulfate by a simultaneous antiport mechanism, thus supplying substrates for the Krebs cycle, gluconeogenesis, urea synthesis, fatty acid synthesis, and sulfur metabolism.
# Structure
The SLC25A10 gene is located on the q arm of chromosome 17 in position 25.3 and spans 8,781 base pairs. The gene has 11 exons and produces a 31.3 kDa protein composed of 287 amino acids. Intron 1 of this gene has five short Alu sequences. Mitochondrial dicarboxylate carriers are dimers, each consisting of six transmembrane domains with both the N- and C- terminus exposed to the cytoplasm. Like all mitochondrial carriers, dicarboxylate carriers features a tripartite structure with three repeats of about 100 amino acid residues, each of which contains a conserved sequence motif. These three tandem sequences fold into two anti-parallel transmembrane α-helices linked by hydrophilic sequences.
# Function
A crucial function of dicarboxylate carriers is to export malate from the mitochondria in exchange for inorganic phosphate. Dicarboxylate carriers are highly abundant in the adipose tissue and play a central role in supplying cytosolic malate for the citrate transporter, which then exchanges cytosolic malate for mitochondrial citrate to begin fatty acid synthesis. Abundant levels of DIC are also detected in the kidneys and liver, whereas lower levels are found in the lung, spleen, heart, and brain. Dicarboxylate carriers are involved in glucose-stimulated insulin secretion through pyruvate cycling, which mediates NADPH production, and by providing cytosolic malate as a counter-substrate for citrate export. It is also involved in reactive oxygen species (ROS) production through hyperpolarization of mitochondria and increases ROS levels when overexpressed. Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairs complex I activity in mitochondria.
# Regulation
Insulin causes a dramatic (approximately 80%) reduction of DIC expression in mice, whereas free fatty acids induces DIC expression. Cold exposure, which increases energy expenditure and decreases fatty acid biosynthesis, resulted in a significant (approximately 50%) reduction of DIC expression. DIC is inhibited by some dicarboxylate analogues, such as butylmalonate, as well as bathophenanthroline and thiol reagents such as Mersalyl and p-hydroxymercuribenzoate. The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress. The rate of malonate uptake is inhibited by 2-oxoglutarate and unaffected by citrate, whereas the rates of succinate and malate uptake are inhibited by both 2-oxoglutarate and citrate.
# Disease relevance
Suppression of SLC25A10 down-regulated fatty acid synthesis in mice, resulting in decreased lipid accumulation in adipocytes. Additionally, knockout of SLC25A10 inhibited insulin-stimulated lipogenesis in adipocytes. These findings presents a possible target for anti-obesity treatments. It is also upregulated in tumors, which is likely because it regulates energy metabolism and redox homeostasis, both of which are frequently altered in tumor cells. In non-small cell lung cancer (NSCLC) cells, inhibition of SLC25A10 was found to increase the sensitivity to traditional anticancer drugs, and thus may present a potential target for anti-cancer strategies. Furthermore, overexpression of dicarboxylate carriers in renal proximal tubular cells has been found to cause a reversion to a non-diabetic state and protect cells from oxidative injury. This finding supports the dicarboxylate carriers as a potential therapeutic target to correct underlying metabolic disturbances in diabetic nephropathy.
# Interactions
This protein has binary interactions with NOTCH2NL, KRTAP5-9, KRTAP4-2, KRTAP10-8, MDFI, and KRT40. | SLC25A10
The mitochondrial dicarboxylate carrier (DIC) is an integral membrane protein encoded by the SLC25A10 gene in humans that catalyzes the transport of dicarboxylates such as malonate, malate, and succinate across the inner mitochondrial membrane in exchange for phosphate, sulfate, and thiosulfate by a simultaneous antiport mechanism, thus supplying substrates for the Krebs cycle, gluconeogenesis, urea synthesis, fatty acid synthesis, and sulfur metabolism.[1][2][3][4]
# Structure
The SLC25A10 gene is located on the q arm of chromosome 17 in position 25.3 and spans 8,781 base pairs.[3] The gene has 11 exons and produces a 31.3 kDa protein composed of 287 amino acids.[5][6] Intron 1 of this gene has five short Alu sequences.[7][8] Mitochondrial dicarboxylate carriers are dimers, each consisting of six transmembrane domains with both the N- and C- terminus exposed to the cytoplasm.[9] Like all mitochondrial carriers, dicarboxylate carriers features a tripartite structure with three repeats of about 100 amino acid residues, each of which contains a conserved sequence motif.[10] These three tandem sequences fold into two anti-parallel transmembrane α-helices linked by hydrophilic sequences.[1]
# Function
A crucial function of dicarboxylate carriers is to export malate from the mitochondria in exchange for inorganic phosphate. Dicarboxylate carriers are highly abundant in the adipose tissue and play a central role in supplying cytosolic malate for the citrate transporter, which then exchanges cytosolic malate for mitochondrial citrate to begin fatty acid synthesis.[11] Abundant levels of DIC are also detected in the kidneys and liver, whereas lower levels are found in the lung, spleen, heart, and brain.[12] Dicarboxylate carriers are involved in glucose-stimulated insulin secretion through pyruvate cycling, which mediates NADPH production, and by providing cytosolic malate as a counter-substrate for citrate export.[13][13] It is also involved in reactive oxygen species (ROS) production through hyperpolarization of mitochondria and increases ROS levels when overexpressed.[14] Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairs complex I activity in mitochondria.[15]
# Regulation
Insulin causes a dramatic (approximately 80%) reduction of DIC expression in mice, whereas free fatty acids induces DIC expression. Cold exposure, which increases energy expenditure and decreases fatty acid biosynthesis, resulted in a significant (approximately 50%) reduction of DIC expression.[9] DIC is inhibited by some dicarboxylate analogues, such as butylmalonate, as well as bathophenanthroline and thiol reagents such as Mersalyl and p-hydroxymercuribenzoate.[16][17][18] The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress.[19] The rate of malonate uptake is inhibited by 2-oxoglutarate and unaffected by citrate, whereas the rates of succinate and malate uptake are inhibited by both 2-oxoglutarate and citrate.
# Disease relevance
Suppression of SLC25A10 down-regulated fatty acid synthesis in mice, resulting in decreased lipid accumulation in adipocytes. Additionally, knockout of SLC25A10 inhibited insulin-stimulated lipogenesis in adipocytes. These findings presents a possible target for anti-obesity treatments.[11][20] It is also upregulated in tumors, which is likely because it regulates energy metabolism and redox homeostasis, both of which are frequently altered in tumor cells. In non-small cell lung cancer (NSCLC) cells, inhibition of SLC25A10 was found to increase the sensitivity to traditional anticancer drugs, and thus may present a potential target for anti-cancer strategies.[21] Furthermore, overexpression of dicarboxylate carriers in renal proximal tubular cells has been found to cause a reversion to a non-diabetic state and protect cells from oxidative injury. This finding supports the dicarboxylate carriers as a potential therapeutic target to correct underlying metabolic disturbances in diabetic nephropathy.[22]
# Interactions
This protein has binary interactions with NOTCH2NL, KRTAP5-9, KRTAP4-2, KRTAP10-8, MDFI, and KRT40.[23][24] | https://www.wikidoc.org/index.php/SLC25A10 | |
b24f0b7af54e58bf7ebded3e2f17a81e5721afdd | wikidoc | SLC25A12 | SLC25A12
Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene. Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment. This gene has connections to autism.
# Structure
The SLC25A12 gene is located on the q arm of chromosome 2 in position 31.1 and spans 110,902 base pairs. The gene produces a 74.8 kDa protein composed of 678 amino acids. The encoded protein, Aralar1, is a multi-pass membrane protein located in the inner mitochondrial membrane. The N-terminal half of this protein contains 2 imperfect EF-hand domains along with 3 canonical EF-hand calcium-binding domains; this part of the protein binds calcium in vitro. Aralar's C-terminal half shares 28-29% identity with other members of the mitochondrial solute carrier family, including SLC25A11, SLC25A5, SLC25A1, and has 6 putative transmembrane domains like the other members of mitochondrial solute carrier family.
# Function
The protein encoded by SLC25A12, Aralar1, is a mitochondrial calcium-binding carrier that facilitates the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane. Aralar binds to one calcium ion with high affinity. Upon calcium binding, the EF-hand-containing regulatory N-terminal domain binds to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain. In the absence of calcium, the linker loop domain may close the vestibule, which may prevent substrates from entering the carrier domain. As a member of the malate-aspartate NADH shuttle, Aralar is also involved in the transfer of cytosolic reducing equivalents from the cytosol to the mitochondrial matrix. Aralar, along with the protein encoded by SLC25A13, are both calcium-binding aspartate/glutamate carriers which are substrates in the TIMM8A/TIMM13 complex.
# Clinical Significance
Overexpression of Aralar1 augments mitochondrial metabolism and increases insulin secretion in pancreatic cells. Aralar is expressed as both a 3.2 kb and 2.9 kb mRNA transcript in heart and skeletal muscle cells, and in lesser amounts in brain and kidney cells.
## Epileptic Encephalopathy
Mutations in the SLC25A12 gene cause early infantile epileptic encephalopathy 39(EIEE39), characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive.
## Autism
2 SNPs in introns 3 and 16 of the SLC25A12 gene may be associated with autism. In Brodmann's Area (BA) 46 of the prefrontal cortex, SLC25A12 is expressed more strongly in the neurons of those suffering from autism. SLC25A12 overexpression may modify neuronal networks in certain subregions of the brain during the fetal development of autistic patients.
# Interactions
Aralar has interactions with SCO1, ATF2, COX14, COA3, in addition to 36 other proteins. | SLC25A12
Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene.[1][2][3][4] Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment.[5][6] This gene has connections to autism.[7][8]
# Structure
The SLC25A12 gene is located on the q arm of chromosome 2 in position 31.1 and spans 110,902 base pairs.[4] The gene produces a 74.8 kDa protein composed of 678 amino acids.[9][10] The encoded protein, Aralar1, is a multi-pass membrane protein located in the inner mitochondrial membrane.[5][6] The N-terminal half of this protein contains 2 imperfect EF-hand domains along with 3 canonical EF-hand calcium-binding domains; this part of the protein binds calcium in vitro. Aralar's C-terminal half shares 28-29% identity with other members of the mitochondrial solute carrier family, including SLC25A11, SLC25A5, SLC25A1, and has 6 putative transmembrane domains like the other members of mitochondrial solute carrier family.[11][12]
# Function
The protein encoded by SLC25A12, Aralar1, is a mitochondrial calcium-binding carrier that facilitates the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane. Aralar binds to one calcium ion with high affinity. Upon calcium binding, the EF-hand-containing regulatory N-terminal domain binds to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain. In the absence of calcium, the linker loop domain may close the vestibule, which may prevent substrates from entering the carrier domain.[13] As a member of the malate-aspartate NADH shuttle, Aralar is also involved in the transfer of cytosolic reducing equivalents from the cytosol to the mitochondrial matrix.[14] Aralar, along with the protein encoded by SLC25A13, are both calcium-binding aspartate/glutamate carriers which are substrates in the TIMM8A/TIMM13 complex.
# Clinical Significance
Overexpression of Aralar1 augments mitochondrial metabolism and increases insulin secretion in pancreatic cells.[15] Aralar is expressed as both a 3.2 kb and 2.9 kb mRNA transcript in heart and skeletal muscle cells, and in lesser amounts in brain and kidney cells.[11][12]
## Epileptic Encephalopathy
Mutations in the SLC25A12 gene cause early infantile epileptic encephalopathy 39(EIEE39), characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive.[5][6]
## Autism
2 SNPs in introns 3 and 16 of the SLC25A12 gene may be associated with autism.[7] In Brodmann's Area (BA) 46 of the prefrontal cortex, SLC25A12 is expressed more strongly in the neurons of those suffering from autism. SLC25A12 overexpression may modify neuronal networks in certain subregions of the brain during the fetal development of autistic patients.[8]
# Interactions
Aralar has interactions with SCO1, ATF2, COX14, COA3, in addition to 36 other proteins.[16] | https://www.wikidoc.org/index.php/SLC25A12 | |
cd58015f8dd5c2615580c41163d6511cac459dee | wikidoc | SLC25A21 | SLC25A21
Mitochondrial 2-oxodicarboxylate carrier also known as solute carrier family 25 member 21 (SLC25A21) is a protein that in humans is encoded by the SLC25A21 gene.
It is a homolog of the S. cerevisiae ODC proteins, mitochondrial carriers that transport C5-C7 oxodicarboxylates across inner mitochondrial membranes. One of the species transported by ODC is 2-oxoadipate, a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine in mammals. Within mitochondria, 2-oxoadipate is converted into acetyl-CoA.
# Model organisms
Model organisms have been used in the study of SLC25A21 function. A conditional knockout mouse line, called Slc25a21tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty one tests were carried out on homozygous mutant mice and ten significant abnormalities were observed, including sub-viability at weaning, decreased body weight, absent pinna reflex, abnormal snout, skull, spine and tooth morphology, atypical indirect calorimetry, body composition and plasma chemistry data, increased mean platelet volume and moderate elevations in auditory thresholds. | SLC25A21
Mitochondrial 2-oxodicarboxylate carrier also known as solute carrier family 25 member 21 (SLC25A21) is a protein that in humans is encoded by the SLC25A21 gene.[1]
It is a homolog of the S. cerevisiae ODC proteins, mitochondrial carriers that transport C5-C7 oxodicarboxylates across inner mitochondrial membranes. One of the species transported by ODC is 2-oxoadipate, a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine in mammals. Within mitochondria, 2-oxoadipate is converted into acetyl-CoA.[1]
# Model organisms
Model organisms have been used in the study of SLC25A21 function. A conditional knockout mouse line, called Slc25a21tm1a(KOMP)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty one tests were carried out on homozygous mutant mice and ten significant abnormalities were observed, including sub-viability at weaning, decreased body weight, absent pinna reflex, abnormal snout, skull, spine and tooth morphology, atypical indirect calorimetry, body composition and plasma chemistry data, increased mean platelet volume and moderate elevations in auditory thresholds.[9] | https://www.wikidoc.org/index.php/SLC25A21 | |
d663209e74d557328602525c5b2b14601976c313 | wikidoc | SLC25A31 | SLC25A31
ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.
# Structure
The ANT4 protein contains six transmembrane helices, and a homodimer functional unit, which serves as an ADP/ATP channel protein. Unlike the other three ANT isoforms, ANT4 has additional amino acids at its N- and C-terminals. These amino acid sequences may interact with different factors for specialized functions such as localization to sperm flagella. The SLC25A31 gene is composed of 6 exons over a stretch of 44 kbp of DNA.
# Function
The ANT4 protein is a mitochondrial ADP/ATP carrier that catalyzes the exchange of ADP and ATP between the mitochondrial matrix and cytoplasm during ATP synthesis. In addition, ANT4 stabilizes the mitochondrial membrane potential and decreases the permeability transition pore complex (PTPC) opening in order to prevent nuclear chromatin fragmentation and resulting cell death. In humans, the protein localizes to the liver, brain and testis, though in adult males, it is expressed primarily in the testis. Studies on Ant4-deficient mice reveal increased apoptosis in the testis leading to infertility, thus indicating that Ant4 is required as for spermatogenesis. In this case, the anti-apoptotic function for ANT4 is attributed to its importing of cytosolic ATP into the mitochondria. In other cells, the isoform ANT2 carries out this role; however, since sperm lack the X chromosome on which the ANT2 gene resides, survival of the sperm is dependent on ANT4.
# Clinical significance
The SLC25A31 enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling. Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The SLC25A31 gene is important for the coding of the most abundant mitochondrial protein Ancp which represents 10% of the proteins of the inner membrane of bovine heart mitochondria. Ancp is encoded by four different genes: SLC25A4 (also known as ANC1 or ANT1), SLC25A5 (ANC3 or ANT2), SLC25A6 (ANC2 or ANT3) and SLC25A31 (ANC4 or ANT4). Their expression is tissue specific and highly regulated and adapted to particular cellular energetic demand. Indeed, human ANC expression patterns depend on the tissue and cell types, the developmental stage and the status of cell proliferation. Furthermore, expression of the genes is modulated by different transcriptional elements in the promoter regions. Therefore, Ancp emerges as a logical candidate to regulate the cellular dependence on oxidative energy metabolism.
To date, there is no evidence of SLC25A31 gene mutations associated with human disease, though they have been associated with male infertility in mice. In addition, ANT4 overexpression has been observed to protect cancer cells from induced apoptosis by anti-cancer drugs such as lonidamine and staurosporine.
# Interactions
- OPA1 | SLC25A31
ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4.[1][2] This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential.[2][3] In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival.[3][4] Outside this role, the SLC25AC31 gene has not been implicated in any human disease.[5][6]
# Structure
The ANT4 protein contains six transmembrane helices, and a homodimer functional unit, which serves as an ADP/ATP channel protein.[5][7] Unlike the other three ANT isoforms, ANT4 has additional amino acids at its N- and C-terminals. These amino acid sequences may interact with different factors for specialized functions such as localization to sperm flagella.[3][4] The SLC25A31 gene is composed of 6 exons over a stretch of 44 kbp of DNA.[6]
# Function
The ANT4 protein is a mitochondrial ADP/ATP carrier that catalyzes the exchange of ADP and ATP between the mitochondrial matrix and cytoplasm during ATP synthesis.[2] In addition, ANT4 stabilizes the mitochondrial membrane potential and decreases the permeability transition pore complex (PTPC) opening in order to prevent nuclear chromatin fragmentation and resulting cell death.[3] In humans, the protein localizes to the liver, brain and testis, though in adult males, it is expressed primarily in the testis.[3][5][6] Studies on Ant4-deficient mice reveal increased apoptosis in the testis leading to infertility, thus indicating that Ant4 is required as for spermatogenesis.[3] In this case, the anti-apoptotic function for ANT4 is attributed to its importing of cytosolic ATP into the mitochondria. In other cells, the isoform ANT2 carries out this role; however, since sperm lack the X chromosome on which the ANT2 gene resides, survival of the sperm is dependent on ANT4.[3][4]
# Clinical significance
The SLC25A31 enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling.[8] Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[9] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The SLC25A31 gene is important for the coding of the most abundant mitochondrial protein Ancp which represents 10% of the proteins of the inner membrane of bovine heart mitochondria.[6][10] Ancp is encoded by four different genes: SLC25A4 (also known as ANC1 or ANT1), SLC25A5 (ANC3 or ANT2), SLC25A6 (ANC2 or ANT3) and SLC25A31 (ANC4 or ANT4). Their expression is tissue specific and highly regulated and adapted to particular cellular energetic demand. Indeed, human ANC expression patterns depend on the tissue and cell types, the developmental stage and the status of cell proliferation. Furthermore, expression of the genes is modulated by different transcriptional elements in the promoter regions. Therefore, Ancp emerges as a logical candidate to regulate the cellular dependence on oxidative energy metabolism.[6]
To date, there is no evidence of SLC25A31 gene mutations associated with human disease, though they have been associated with male infertility in mice.[5][6] In addition, ANT4 overexpression has been observed to protect cancer cells from induced apoptosis by anti-cancer drugs such as lonidamine and staurosporine.[3]
# Interactions
- OPA1[11] | https://www.wikidoc.org/index.php/SLC25A31 | |
894ef13a74bbcd45f27f57c5f6faf1897c2d6069 | wikidoc | SLC25A46 | SLC25A46
Solute carrier family 25 member 46 is a protein that in humans is encoded by the SLC25A46 gene. This protein is a member of the SLC25 mitochondrial solute carrier family. It is a transmembrane protein located in the mitochondrial outer membrane involved in lipid transfer from the endoplasmic reticulum (ER) to mitochondria. Mutations in this gene result in neuropathy and optic atrophy.
# Structure
The SLC25A46 gene is located on the q arm of chromosome 5 in position 22.1 and spans 27,039 base pairs. The gene produces a 46.2 kDa protein composed of 418 amino acids. This gene has 8 exons and encodes a multi-pass integral membrane protein localized to the mitochondrial outer membrane.
# Function
The encoded protein is an orphan transporter involved in lipid transfer from the endoplasmic reticulum to mitochondria. It promotes mitochondrial fission and prevents the formation of hyperfilamentous mitochondria. This protein forms a complex with mitofilin (IMMT) on the inner mitochondrial membrane, independent of MFN2.
# Clinical Significance
Mutations in the SLC25A46 gene, inherited in an autosomal recessive manner, cause type 6B hereditary motor and sensory neuropathy. Symptoms include early-onset optic atrophy, progressive visual loss, and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease, with variable age at onset and severity.
Overexpression of this protein causes mitochondrial fragmentation while knockdown of this protein causes mitochondrial hyperfusion and hyperfilamentous mitochondria due to decreased mitochondrial fission. Loss of this gene also has many other effects: premature cellular senescence, impaired cellular respiration, destabilization of the MICOS (mitochondrial contact site and cristae organizing system) complex, loss of and shortened cristae, altered ER morphology, impaired cell migration, and changes in mitochondrial phospholipid composition.
# Interactions
This protein interacts with IMMT, a component of the MICOS complex, along with other components of this complex and components of an ER membrane protein complex involved in transferring lipids to mitochondria. Additionally, this protein interacts with SLC7A8, SLC10A1, SLC10A6, FHL3, FUNDC1, linc01142, LEPROTL1, ODF4, VMA21, MFSD14B, PQLC1, HSD17B11, REEP2, REEP4, and TOMM22. This protein possibly interacts with OPA1 and MFN2. | SLC25A46
Solute carrier family 25 member 46 is a protein that in humans is encoded by the SLC25A46 gene. This protein is a member of the SLC25 mitochondrial solute carrier family. It is a transmembrane protein located in the mitochondrial outer membrane involved in lipid transfer from the endoplasmic reticulum (ER) to mitochondria.[1][2] Mutations in this gene result in neuropathy and optic atrophy.[3]
# Structure
The SLC25A46 gene is located on the q arm of chromosome 5 in position 22.1 and spans 27,039 base pairs.[3] The gene produces a 46.2 kDa protein composed of 418 amino acids.[4][5] This gene has 8 exons and encodes a multi-pass integral membrane protein localized to the mitochondrial outer membrane.[6][7][8]
# Function
The encoded protein is an orphan transporter involved in lipid transfer from the endoplasmic reticulum to mitochondria.[9][2] It promotes mitochondrial fission and prevents the formation of hyperfilamentous mitochondria. This protein forms a complex with mitofilin (IMMT) on the inner mitochondrial membrane, independent of MFN2.[1]
# Clinical Significance
Mutations in the SLC25A46 gene, inherited in an autosomal recessive manner, cause type 6B hereditary motor and sensory neuropathy. Symptoms include early-onset optic atrophy, progressive visual loss, and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease, with variable age at onset and severity.[7][8]
Overexpression of this protein causes mitochondrial fragmentation while knockdown of this protein causes mitochondrial hyperfusion and hyperfilamentous mitochondria due to decreased mitochondrial fission.[1] Loss of this gene also has many other effects: premature cellular senescence, impaired cellular respiration, destabilization of the MICOS (mitochondrial contact site and cristae organizing system) complex, loss of and shortened cristae, altered ER morphology, impaired cell migration, and changes in mitochondrial phospholipid composition.[2]
# Interactions
This protein interacts with IMMT, a component of the MICOS complex, along with other components of this complex and components of an ER membrane protein complex involved in transferring lipids to mitochondria.[7][8][2] Additionally, this protein interacts with SLC7A8, SLC10A1, SLC10A6, FHL3, FUNDC1, linc01142, LEPROTL1, ODF4, VMA21, MFSD14B, PQLC1, HSD17B11, REEP2, REEP4, and TOMM22.[10] This protein possibly interacts with OPA1 and MFN2.[2] | https://www.wikidoc.org/index.php/SLC25A46 | |
701df78789148fe1b433abd3ab032e03c3c863c7 | wikidoc | SLC38A10 | SLC38A10
Sodium-coupled neutral amino acid transporter 10 also known as solute carrier family 38, member 10 is a protein that in humans is encoded by the SLC38A10 gene.
# Model organisms
Model organisms have been used in the study of SLC38A10 function. A conditional knockout mouse line, called Slc38a10tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and four significant abnormalities were observed. Homozygous animals of both sex had decreased body weights, and DEXA analysis showed that this correlated with decreased bone mineral content and decreased body length. Indirect calorimetry analysis showed that males displayed increased oxygen consumption and energy expenditure, while clinical chemistry tests found that females had decreased circulating amylase levels and males had hypoalbuminemia and increased circulating creatinine levels. | SLC38A10
Sodium-coupled neutral amino acid transporter 10 also known as solute carrier family 38, member 10 is a protein that in humans is encoded by the SLC38A10 gene.[1]
# Model organisms
Model organisms have been used in the study of SLC38A10 function. A conditional knockout mouse line, called Slc38a10tm1a(EUCOMM)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on mutant mice and four significant abnormalities were observed.[8] Homozygous animals of both sex had decreased body weights, and DEXA analysis showed that this correlated with decreased bone mineral content and decreased body length. Indirect calorimetry analysis showed that males displayed increased oxygen consumption and energy expenditure, while clinical chemistry tests found that females had decreased circulating amylase levels and males had hypoalbuminemia and increased circulating creatinine levels.[8] | https://www.wikidoc.org/index.php/SLC38A10 | |
e920c1314e3bbafc27ccf622a6f3cd538b3ba826 | wikidoc | SMARCAL1 | SMARCAL1
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 is a protein that in humans is encoded by the SMARCAL1 gene.
# Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The SMARCAL1 protein convert RPA-bound, single stranded DNA into double-stranded DNA, an enzyme activity termed "annealing helicase".
The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency.
# Model organisms
Model organisms have been used in the study of SMARCAL1 function. A conditional knockout mouse line, called Smarcal1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty tests were carried out and one significant phenotype was observed: homozygous mutant mice had abnormal brain histopathology, including an enlarged hippocampus and a thickened hippocampus stratum oriens. | SMARCAL1
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 is a protein that in humans is encoded by the SMARCAL1 gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The SMARCAL1 protein convert RPA-bound, single stranded DNA into double-stranded DNA, an enzyme activity termed "annealing helicase".[4]
The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency.[3]
# Model organisms
Model organisms have been used in the study of SMARCAL1 function. A conditional knockout mouse line, called Smarcal1tm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty tests were carried out and one significant phenotype was observed: homozygous mutant mice had abnormal brain histopathology, including an enlarged hippocampus and a thickened hippocampus stratum oriens.[5] | https://www.wikidoc.org/index.php/SMARCAL1 | |
91a3ce370f2aa47351968ae5e16118c704abf207 | wikidoc | Safe sex | Safe sex
# Overview
Safe sex (also called safer sex or protected sex) is a set of practices that are designed to reduce the risk of infection during sexual intercourse to avoid developing sexually transmitted diseases (STDs). Conversely, unsafe sex refers to engaging in sexual intercourse without the use of any barrier contraception or other preventive measures against STDs.
Safe sex practices became prominent in the late 1980s as a result of the AIDS epidemic. Promoting safe sex is now a principal aim of sex education. From the viewpoint of society, safer sex can be regarded as a harm reduction strategy. Safe sex is about risk reduction, not complete risk elimination.
Although safe sex practices can be used as a form of family planning, the term refers to efforts made to prevent infection rather than conception. Many effective forms of contraception do not offer protection against STDs.
# Terminology
Recently, and mostly within Canada and the United States, the use of the term safer sex rather than safe sex has gained greater use by health workers, with the realization the grounds that risk of transmission of sexually transmitted infections in various sexual activities is a continuum rather than a simple dichotomy between risky and safe. However, in most other countries, including the United Kingdom and Australia, the term safe sex is still mainly used by sex educators. Because these terms are virtually synonymous with each other, they are used interchangeably throughout this article.
# Focus on HIV/AIDS
Much attention has focused on controlling HIV, the virus that causes AIDS, through the use of condoms, but each STD presents a different problem. However, sex educators recommend that some form of barrier protection as a harm reduction measure should be used for all sexual activities which might potentially result in the exchange of body fluids.
# Safe sex precautions
## Sex by yourself
Known as Autoeroticism, solitary sexual activity (including "phone sex" and "cybersex") is relatively safe. However, some practices, such as self-bondage and autoerotic asphyxia, are made considerably more dangerous by the absence of people who can intervene if something goes wrong. Masturbation is safe, so long as contact is not made with other people's discharged bodily fluids.
## Non-penetrative Sex
A range of sex acts, sometimes called outercourse can be enjoyed by lovers with significantly reduced risks of infection and no risk of pregnancy. U.S. President Bill Clinton's surgeon general, Dr. Joycelyn Elders, tried to encourage the use of these practices in the U.S.A. but criticism by the religious right forced her to resign.
## Limiting fluid exchange
Various devices are used to avoid contact with blood, vaginal fluid, and semen during sexual activity:
- Condoms cover the penis during sexual activity. They are most frequently made of latex, but can also be made out of polyurethane. Polyurethane is thought to be a safe material for use in condoms, since it is nonporous and viruses cannot pass through it. However, there is less research on its effectiveness than there is on latex.
- Female condoms are inserted into the vagina prior to intercourse. They may also be used for anal sex, although they are less effective.
- A dental dam (originally used in dentistry) is a sheet of latex used for protection when engaging in oral sex. It is typically used as a barrier between the mouth and the vulva during cunnilingus or between the mouth and the anus during anilingus.
- Medical gloves made out of latex, vinyl, nitrile, or polyurethane may be used as an ersatz dental dam during oral sex, or to protect the hands during mutual masturbation. Hands may have invisible cuts on them that may admit pathogens that are found in the semen or the vaginal fluids of STD infectees. Although the risk of infection in this manner is thought to be low, gloves can be used as an extra precaution.
- Another way to avoid contact with blood and semen is penetration, but not by the penis, such as using (properly cleaned) dildos or other sex toys. If a sex toy is to be used in more than one orifice, a condom can be used over it and changed when the toy is moved. Fisting (penetration by the hand), has its own risks, but the risk of HIV transfer can be reduced by latex gloves or a condom. Pegging, female-to-male anal sex with a strap-on dildo, as promoted by sex educator Carol Queen does not involve fluid transfer.
If a latex barrier is being used, any lubrication must not be oil based, as this can break down the structure of the latex and undo the protection it gives.
## Other Precautions
Acknowledging that it is usually impossible to have entirely risk-free sex with another person, proponents of safer sex recommend that some of the following methods be used to minimize the risks of STD transmission and unwanted pregnancy.
- Monogamy or polyfidelity, practiced faithfully, is very safe (as far as STDs are concerned) when all partners are non-infected. However, many monogamous people have been infected with sexually transmitted diseases by partners who are sexually unfaithful, have used injection drugs, or were infected by previous sexual partners; the same risks apply to polyfidelitous people, who face slightly higher risks depending on how many people are in the polyfidelitous group.
- For those who are not monogamous, reducing the number of one's sexual partners, particularly anonymous sexual partners, may also reduce one's potential exposure to STDs. Similarly, one may restrict one's sexual contact to a community of trusted individuals - this is the approach taken by some pornographic actors and other non-monogamous people.
- Communication with one's sexual partner(s) makes for greater safety. Before initiating sexual activities, partners may discuss what activities they will and will not engage in, and what precautions they will take. This can reduce the chance of risky decisions being made "in the heat of passion".
- Refraining from the use of recreational drugs, including alcohol, before and during sexual activity can protect against associated risks such as lowered inhibitions, decreased immune response, impaired judgment, and loss of consciousness.
- If a person is sexually active with a number of partners, it is important that they get regular check-ups from a doctor. Anyone noticing unusual symptoms should get medical advice quickly. Unfortunately HIV is almost symptom free until AIDS develops.
# Ineffective methods
Note that most methods of contraception other than the barrier methods mentioned above are not effective at preventing the spread of STDs. This includes the "rhythm method", which is also commonly known as Natural Family Planning.
The spermicide Nonoxynol-9 has been claimed to reduce the likelihood of STD transmission. However a recent study by the World Health Organization has shown that Nonoxynol-9 is an irritant and can produce tiny tears in mucous membranes, which may increase the risk of transmission by offering pathogens more easy points of entry into the system. As a result condoms with a Nonoxynol-9 lubricant are not to be promoted.
Coitus interruptus (or "pulling out"), in which the penis is removed from the vagina, anus, or mouth before ejaculation, is not safe sex and can result in STD transmission. This is because of the formation of pre-ejaculate, a fluid that oozes from the urethra before actual ejaculation. In opposition to conventional wisdom, some recent studies awaiting confirmation suggest that pre-ejaculate may not contain sperm; it can, however, contain pathogens such as HIV. In addition, open sores on either partner can permit transmission, as can microscopic breaks in the skin which arise due to friction, or other irregularities in the skin of either partners genitalia or other body parts.
# Dangers of anal sex
Unprotected anal sex is a high risk activity regardless of sexual orientation. Research suggests that although gay men are more likely to engage in anal sex, heterosexual couples are more likely not to use condoms when doing so.
Anal sex is more risky than vaginal, since being very thin tissues of anus and rectum can be easily damaged during such sex activities as anal intercourse or use of anal toys. Even slight injuries can become "open gates" for various bacteria and viruses, including HIV. This implies that anal sex does require some certain safety measures. First of all, any partners who practice anal sex should be aware of the necessity of using a condom. The condom must be put on properly, otherwise it does not provide reliable protection. Users should keep in mind that oil-based lubricants damage latex. For this reason water-based lubricants should be used for anal sex. Those who have allergy to latex should consider use of non-latex condoms, for instance polyurethane condoms that are compatible with both oil-based and water-based lubricants.
Condoms should also be used with sex toys. Through putting a condom on the sex toy a user provides better hygiene and prevents transmission of infections if the sex toy is shared. Cleaning of anal sex toys is also a very important matter as many anal sex toys are made of porous materials. Pores retain viruses and bacteria. For this reason users should clean anal toys (plugs, anal vibrators) thoroughly, preferably with use of special sex toy cleaners. Glass sex toys are more preferred for sexual uses because of their non-porus nature and ability to be sterilized between uses.
# Abstinence as an alternative to safe sex
One way to avoid the risks associated with sexual contact is to abstain from sexual activity entirely, which nearly eliminates the chances of contracting STDs (the only alternative methods of infection being non-sexual as described below).
Some groups, notably some American evangelical Christians and the Roman Catholic Church oppose sex outside marriage, and object to safe-sex education programs because they believe that providing such education promotes promiscuity. Virginity pledges and sexual abstinence education programs are often promoted in lieu of contraceptives and safe-sex education programs. This can place some teenagers at higher risk of unintended pregnancy and STDs, because up to 60 percent of teenagers who pledge virginity until marriage do engage in pre-marital sex and are then one-third less likely to use contraceptives than their peers who have received more traditional sex education.
STDs may also be transmitted through non-sexual means. Thus, abstinence from sexual behavior does not guarantee complete protection against STDs. For example, HIV may be transmitted through contaminated needles used in tattooing, body piercing, or injections. Medical or dental procedures using contaminated instruments can also spread HIV, while some health-care workers have acquired HIV through occupational exposure to accidental injuries with needles. | Safe sex
# Overview
Safe sex (also called safer sex or protected sex) is a set of practices that are designed to reduce the risk of infection during sexual intercourse to avoid developing sexually transmitted diseases (STDs). Conversely, unsafe sex refers to engaging in sexual intercourse without the use of any barrier contraception or other preventive measures against STDs.
Safe sex practices became prominent in the late 1980s as a result of the AIDS epidemic. Promoting safe sex is now a principal aim of sex education. From the viewpoint of society, safer sex can be regarded as a harm reduction strategy. Safe sex is about risk reduction, not complete risk elimination.
Although safe sex practices can be used as a form of family planning, the term refers to efforts made to prevent infection rather than conception. Many effective forms of contraception do not offer protection against STDs.
# Terminology
Recently, and mostly within Canada and the United States, the use of the term safer sex rather than safe sex has gained greater use by health workers, with the realization the grounds that risk of transmission of sexually transmitted infections in various sexual activities is a continuum rather than a simple dichotomy between risky and safe. However, in most other countries, including the United Kingdom and Australia, the term safe sex is still mainly used by sex educators. Because these terms are virtually synonymous with each other, they are used interchangeably throughout this article.
# Focus on HIV/AIDS
Much attention has focused on controlling HIV, the virus that causes AIDS, through the use of condoms, but each STD presents a different problem. However, sex educators recommend that some form of barrier protection as a harm reduction measure should be used for all sexual activities which might potentially result in the exchange of body fluids.
# Safe sex precautions
## Sex by yourself
Known as Autoeroticism, solitary sexual activity (including "phone sex" and "cybersex") is relatively safe. However, some practices, such as self-bondage and autoerotic asphyxia, are made considerably more dangerous by the absence of people who can intervene if something goes wrong. Masturbation is safe, so long as contact is not made with other people's discharged bodily fluids.
## Non-penetrative Sex
A range of sex acts, sometimes called outercourse can be enjoyed by lovers with significantly reduced risks of infection and no risk of pregnancy. U.S. President Bill Clinton's surgeon general, Dr. Joycelyn Elders, tried to encourage the use of these practices in the U.S.A. but criticism by the religious right forced her to resign.
## Limiting fluid exchange
Various devices are used to avoid contact with blood, vaginal fluid, and semen during sexual activity:
- Condoms cover the penis during sexual activity. They are most frequently made of latex, but can also be made out of polyurethane. Polyurethane is thought to be a safe material for use in condoms, since it is nonporous and viruses cannot pass through it. However, there is less research on its effectiveness than there is on latex.
- Female condoms are inserted into the vagina prior to intercourse. They may also be used for anal sex, although they are less effective.
- A dental dam (originally used in dentistry) is a sheet of latex used for protection when engaging in oral sex. It is typically used as a barrier between the mouth and the vulva during cunnilingus or between the mouth and the anus during anilingus.
- Medical gloves made out of latex, vinyl, nitrile, or polyurethane may be used as an ersatz dental dam during oral sex, or to protect the hands during mutual masturbation. Hands may have invisible cuts on them that may admit pathogens that are found in the semen or the vaginal fluids of STD infectees. Although the risk of infection in this manner is thought to be low, gloves can be used as an extra precaution.
- Another way to avoid contact with blood and semen is penetration, but not by the penis, such as using (properly cleaned) dildos or other sex toys. If a sex toy is to be used in more than one orifice, a condom can be used over it and changed when the toy is moved. Fisting (penetration by the hand), has its own risks, but the risk of HIV transfer can be reduced by latex gloves or a condom. Pegging, female-to-male anal sex with a strap-on dildo, as promoted by sex educator Carol Queen does not involve fluid transfer.
If a latex barrier is being used, any lubrication must not be oil based, as this can break down the structure of the latex and undo the protection it gives.
## Other Precautions
Acknowledging that it is usually impossible to have entirely risk-free sex with another person, proponents of safer sex recommend that some of the following methods be used to minimize the risks of STD transmission and unwanted pregnancy.
- Monogamy or polyfidelity, practiced faithfully, is very safe (as far as STDs are concerned) when all partners are non-infected. However, many monogamous people have been infected with sexually transmitted diseases by partners who are sexually unfaithful, have used injection drugs, or were infected by previous sexual partners; the same risks apply to polyfidelitous people, who face slightly higher risks depending on how many people are in the polyfidelitous group.
- For those who are not monogamous, reducing the number of one's sexual partners, particularly anonymous sexual partners, may also reduce one's potential exposure to STDs. Similarly, one may restrict one's sexual contact to a community of trusted individuals - this is the approach taken by some pornographic actors and other non-monogamous people.
- Communication with one's sexual partner(s) makes for greater safety. Before initiating sexual activities, partners may discuss what activities they will and will not engage in, and what precautions they will take. This can reduce the chance of risky decisions being made "in the heat of passion".
- Refraining from the use of recreational drugs, including alcohol, before and during sexual activity can protect against associated risks such as lowered inhibitions, decreased immune response, impaired judgment, and loss of consciousness.
- If a person is sexually active with a number of partners, it is important that they get regular check-ups from a doctor. Anyone noticing unusual symptoms should get medical advice quickly. Unfortunately HIV is almost symptom free until AIDS develops.
# Ineffective methods
Note that most methods of contraception other than the barrier methods mentioned above are not effective at preventing the spread of STDs. This includes the "rhythm method", which is also commonly known as Natural Family Planning.
The spermicide Nonoxynol-9 has been claimed to reduce the likelihood of STD transmission. However a recent study by the World Health Organization [1] has shown that Nonoxynol-9 is an irritant and can produce tiny tears in mucous membranes, which may increase the risk of transmission by offering pathogens more easy points of entry into the system. As a result condoms with a Nonoxynol-9 lubricant are not to be promoted.
Coitus interruptus (or "pulling out"), in which the penis is removed from the vagina, anus, or mouth before ejaculation, is not safe sex and can result in STD transmission. This is because of the formation of pre-ejaculate, a fluid that oozes from the urethra before actual ejaculation. In opposition to conventional wisdom, some recent studies awaiting confirmation suggest that pre-ejaculate may not contain sperm; it can, however, contain pathogens such as HIV.[1][2] In addition, open sores on either partner can permit transmission, as can microscopic breaks in the skin which arise due to friction, or other irregularities in the skin of either partners genitalia or other body parts.
# Dangers of anal sex
Unprotected anal sex is a high risk activity regardless of sexual orientation. Research suggests that although gay men are more likely to engage in anal sex, heterosexual couples are more likely not to use condoms when doing so.[3]
Anal sex is more risky than vaginal, since being very thin tissues of anus and rectum can be easily damaged during such sex activities as anal intercourse or use of anal toys. Even slight injuries can become "open gates" for various bacteria and viruses, including HIV. This implies that anal sex does require some certain safety measures. First of all, any partners who practice anal sex should be aware of the necessity of using a condom. The condom must be put on properly, otherwise it does not provide reliable protection. Users should keep in mind that oil-based lubricants damage latex. For this reason water-based lubricants should be used for anal sex. Those who have allergy to latex should consider use of non-latex condoms, for instance polyurethane condoms that are compatible with both oil-based and water-based lubricants.
Condoms should also be used with sex toys. Through putting a condom on the sex toy a user provides better hygiene and prevents transmission of infections if the sex toy is shared. Cleaning of anal sex toys is also a very important matter as many anal sex toys are made of porous materials. Pores retain viruses and bacteria. For this reason users should clean anal toys (plugs, anal vibrators) thoroughly, preferably with use of special sex toy cleaners. Glass sex toys are more preferred for sexual uses because of their non-porus nature and ability to be sterilized between uses.
# Abstinence as an alternative to safe sex
One way to avoid the risks associated with sexual contact is to abstain from sexual activity entirely, which nearly eliminates the chances of contracting STDs (the only alternative methods of infection being non-sexual as described below).
Some groups, notably some American evangelical Christians and the Roman Catholic Church oppose sex outside marriage, and object to safe-sex education programs because they believe that providing such education promotes promiscuity. Virginity pledges and sexual abstinence education programs are often promoted in lieu of contraceptives and safe-sex education programs. This can place some teenagers at higher risk of unintended pregnancy and STDs, because up to 60 percent of teenagers who pledge virginity until marriage do engage in pre-marital sex and are then one-third less likely to use contraceptives than their peers who have received more traditional sex education.[4]
STDs may also be transmitted through non-sexual means. Thus, abstinence from sexual behavior does not guarantee complete protection against STDs. For example, HIV may be transmitted through contaminated needles used in tattooing, body piercing, or injections. Medical or dental procedures using contaminated instruments can also spread HIV, while some health-care workers have acquired HIV through occupational exposure to accidental injuries with needles.[5] | https://www.wikidoc.org/index.php/Safe_sex | |
f59e4eac327cd179aab94c569c3d27d0e4e5a27b | wikidoc | Salinity | Salinity
Salinity is the saltiness or dissolved salt content of a body of water. Salinity in Australian English and North American English may also refer to the salt in soil (see soil salination).
# Definitions
The technical term for saltiness in the ocean is salinity, from the fact that halides - chloride specifically - are the most abundant anions in the mix of dissolved elements. In oceanography, it has been traditional to express salinity not as percent, but as parts per thousand (ppt or ‰), which is approximately grams of salt per liter of solution. Other disciplines use chemical analyses of solutions, and thus salinity is frequently reported in mg/L or ppm (parts per million). Prior to 1978, salinity or halinity was expressed as ‰ usually based on the electrical conductivity ratio of the sample to "Copenhagen water", an artificial sea water manufactured to serve as a world "standard". In 1978, oceanographers redefined salinity in the Practical Salinity Scale (PSS) as the conductivity ratio of a sea water sample to a standard KCl solution. Ratios have no units, so it is not the case that a salinity of 35 exactly equals 35 grams of salt per litre of solution.
These seemingly esoteric approaches to measuring and reporting salt concentrations may appear to obscure their practical use; but it must be remembered that salinity is the sum weight of many different elements within a given volume of water. It has always been the case that to get a precise salinity as a concentration and convert this to an amount of substance (sodium chloride, for instance) required knowing much more about the sample and the measurement than just the weight of the solids upon evaporation (one method of determining "salinity"). For example, volume is influenced by water temperature; and the composition of the salts is not a constant (although generally very much the same throughout the world ocean). Saline waters from inland seas can have a composition that differs from that of the ocean. For the latter reason, these waters are termed saline as differentiated from ocean waters, where the term haline applies (although is not universally used).
Contour lines of constant salinity are called isohales.
# Systems of classification of water bodies based upon salinity
Marine waters are those of the ocean, another term for which is euhaline seas. The salinity of euhaline seas is 30 to 35. Brackish seas or waters have salinity in the range of 0.5 to 29 and metahaline seas from 36 to 40. These waters are all regarded as thalassic because their salinity is derived from the ocean and defined as homoiohaline if salinity does not vary much over time (essentially invariant). The table on the right, modified from Por (1972), follows the "Venice system" (1959).
In contrast to homoiohaline environments are certain poikilohaline environments (which may also be thallassic) in which the salinity variation is biologically significant. Poikilohaline water salinities may range anywhere from 0.5 to greater than 300. The important characteristic is that these waters tend to vary in salinity over some biologically meaningful range seasonally or on some other roughly comparable time scale. Put simply, these are bodies of water with quite variable salinity.
Highly saline water, from which salts crystallize (or are about to), is referred to as brine.
# Environmental considerations
Salinity is an ecological factor of considerable importance, influencing the types of organisms that live in a body of water. As well, salinity influences the kinds of plants that will grow either in a water body, or on land fed by a water (or by a groundwater). A plant adapted to saline conditions is called a halophyte. Organisms (mostly bacteria) that can live in very salty conditions are classified as extremophiles, halophiles specifically. An organism that can withstand a wide range of salinities is euryhaline.
Salt is difficult to remove from water, and salt content is an important factor in water use (such as potability). | Salinity
Salinity is the saltiness or dissolved salt content of a body of water. Salinity in Australian English and North American English may also refer to the salt in soil (see soil salination).
# Definitions
The technical term for saltiness in the ocean is salinity, from the fact that halides - chloride specifically - are the most abundant anions in the mix of dissolved elements. In oceanography, it has been traditional to express salinity not as percent, but as parts per thousand (ppt or ‰), which is approximately grams of salt per liter of solution. Other disciplines use chemical analyses of solutions, and thus salinity is frequently reported in mg/L or ppm (parts per million). Prior to 1978, salinity or halinity was expressed as ‰ usually based on the electrical conductivity ratio of the sample to "Copenhagen water", an artificial sea water manufactured to serve as a world "standard"[1]. In 1978, oceanographers redefined salinity in the Practical Salinity Scale (PSS) as the conductivity ratio of a sea water sample to a standard KCl solution[2][3]. Ratios have no units, so it is not the case that a salinity of 35 exactly equals 35 grams of salt per litre of solution[4].
These seemingly esoteric approaches to measuring and reporting salt concentrations may appear to obscure their practical use; but it must be remembered that salinity is the sum weight of many different elements within a given volume of water. It has always been the case that to get a precise salinity as a concentration and convert this to an amount of substance (sodium chloride, for instance) required knowing much more about the sample and the measurement than just the weight of the solids upon evaporation (one method of determining "salinity"). For example, volume is influenced by water temperature; and the composition of the salts is not a constant (although generally very much the same throughout the world ocean). Saline waters from inland seas can have a composition that differs from that of the ocean. For the latter reason, these waters are termed saline as differentiated from ocean waters, where the term haline applies (although is not universally used).
Contour lines of constant salinity are called isohales.
# Systems of classification of water bodies based upon salinity
Marine waters are those of the ocean, another term for which is euhaline seas. The salinity of euhaline seas is 30 to 35. Brackish seas or waters have salinity in the range of 0.5 to 29 and metahaline seas from 36 to 40. These waters are all regarded as thalassic because their salinity is derived from the ocean and defined as homoiohaline if salinity does not vary much over time (essentially invariant). The table on the right, modified from Por (1972)[5], follows the "Venice system" (1959)[6].
In contrast to homoiohaline environments are certain poikilohaline environments (which may also be thallassic) in which the salinity variation is biologically significant[7]. Poikilohaline water salinities may range anywhere from 0.5 to greater than 300. The important characteristic is that these waters tend to vary in salinity over some biologically meaningful range seasonally or on some other roughly comparable time scale. Put simply, these are bodies of water with quite variable salinity.
Highly saline water, from which salts crystallize (or are about to), is referred to as brine.
# Environmental considerations
Salinity is an ecological factor of considerable importance, influencing the types of organisms that live in a body of water. As well, salinity influences the kinds of plants that will grow either in a water body, or on land fed by a water (or by a groundwater). A plant adapted to saline conditions is called a halophyte. Organisms (mostly bacteria) that can live in very salty conditions are classified as extremophiles, halophiles specifically. An organism that can withstand a wide range of salinities is euryhaline.
Salt is difficult to remove from water, and salt content is an important factor in water use (such as potability). | https://www.wikidoc.org/index.php/Salinity | |
3ac0bbdeea929916703a9c9ba4a3d15f4b49cb77 | wikidoc | Sandbox2 | Sandbox2
The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, ZOCOR can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of ZOCOR should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
Patients who are currently tolerating the 80-mg dose of ZOCOR who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.
Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of ZOCOR, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
Patients taking Verapamil, Diltiazem, or Dronedarone
The dose of ZOCOR should not exceed 10 mg/day.
Patients taking Amiodarone, Amlodipine or Ranolazine
The dose of ZOCOR should not exceed 20 mg/day.
The recommended dosage is 40 mg/day in the evening. ZOCOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ZOCOR should be reduced by 50% if initiating lomitapide. ZOCOR dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken ZOCOR 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.
Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when ZOCOR is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored.
Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.
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- The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
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- Developed by: (Organisation)
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- Concomitant administration of gemfibrozil, cyclosporine, or danazol.
- Hypersensitivity to any component of this medication.
- Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels.
- Women who are pregnant or may become pregnant
- Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZOCOR may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with ZOCOR during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. ZOCOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ZOCOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus.
- Nursing mothers
- It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with ZOCOR should not breastfeed their infants.
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with ZOCOR, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase >10 times upper limit of normal ) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of ZOCOR should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. If, however, a patient who is currently tolerating the 80-mg dose of ZOCOR needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with ZOCOR, or whose dose of ZOCOR is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ZOCOR. ZOCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with ZOCOR or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. ZOCOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. ZOCOR therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or grapefruit juice. Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated.
Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered.
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.
The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine.
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.
Prescribing recommendations for interacting agents are summarized in the table below.
Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
In the Scandinavian Simvastatin Survival Study (4S), the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 vs. 12 ). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.
It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ZOCOR, promptly interrupt therapy. If an alternate etiology is not found do not restart ZOCOR. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.
As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including ZOCOR.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and . The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).
Scandinavian Simvastatin Survival Study
In 4S involving 4,444 (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of ZOCOR (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.
Heart Protection Study
In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with ZOCOR 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with ZOCOR compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with ZOCOR.
Other Clinical Studies
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase >10 times upper limit of normal ) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.
Laboratory Tests
Marked persistent increases of hepatic transaminases have been noted. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK.
Adolescent Patients (ages 10-17 years)
In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or ZOCOR (10-40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use .
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated . If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated.
- Gemfibrozil: Contraindicated with simvastatin.
- Other fibrates: Caution should be used when prescribing with simvastatin.
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine.
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day Niacin) of Niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of Niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of Niacin-containing products.
# Digoxin
In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.
# Coumarin Anticoagulants
In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
# Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.
There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review3 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.
Women of childbearing potential, who require treatment with ZOCOR for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of ZOCOR should be considered. If pregnancy occurs, ZOCOR should be immediately discontinued.
A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and ZOCOR significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). he relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ZOCOR should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age.
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
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A few cases of overdosage with ZOCOR have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present
Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.
The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
In a study including 16 elderly patients between 70 and 78 years of age who received ZOCOR 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients.
Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.
In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.
CNS Toxicity
Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.
A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.
There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).
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- ↑ Jump up to: 1.0 1.1 1.2 1.3 "ZOCOR (SIMVASTATIN) TABLET, FILM COATED ". Retrieved 18 February 2014..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents". Pediatrics. 89 (3): 495–501. 1992. PMID 1741227. | Sandbox2
The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, ZOCOR can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of ZOCOR should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
Patients who are currently tolerating the 80-mg dose of ZOCOR who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.
Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of ZOCOR, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
Patients taking Verapamil, Diltiazem, or Dronedarone
The dose of ZOCOR should not exceed 10 mg/day.
Patients taking Amiodarone, Amlodipine or Ranolazine
The dose of ZOCOR should not exceed 20 mg/day.
The recommended dosage is 40 mg/day in the evening. ZOCOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ZOCOR should be reduced by 50% if initiating lomitapide. ZOCOR dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken ZOCOR 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.
Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when ZOCOR is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored.
Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.[1]
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- The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.[2]
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- Concomitant administration of gemfibrozil, cyclosporine, or danazol.
- Hypersensitivity to any component of this medication.
- Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels.
- Women who are pregnant or may become pregnant
- Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZOCOR may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with ZOCOR during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. ZOCOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ZOCOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus.
- Nursing mothers
- It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with ZOCOR should not breastfeed their infants.
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with ZOCOR, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of ZOCOR should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. If, however, a patient who is currently tolerating the 80-mg dose of ZOCOR needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with ZOCOR, or whose dose of ZOCOR is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ZOCOR. ZOCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with ZOCOR or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. ZOCOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. ZOCOR therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or grapefruit juice. Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated.
Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered.
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.
The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine.
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.
Prescribing recommendations for interacting agents are summarized in the table below.
Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
In the Scandinavian Simvastatin Survival Study (4S), the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.
It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ZOCOR, promptly interrupt therapy. If an alternate etiology is not found do not restart ZOCOR. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.
As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including ZOCOR.[1]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and [arthralgia ]](0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).
Scandinavian Simvastatin Survival Study
In 4S involving 4,444 (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of ZOCOR (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.
Heart Protection Study
In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with ZOCOR 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with ZOCOR compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with ZOCOR.
Other Clinical Studies
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.
Laboratory Tests
Marked persistent increases of hepatic transaminases have been noted. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK.
Adolescent Patients (ages 10-17 years)
In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or ZOCOR (10-40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).[1]
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [SeeWarnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated.
- Gemfibrozil: Contraindicated with simvastatin.
- Other fibrates: Caution should be used when prescribing with simvastatin.
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine.
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day Niacin) of Niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of Niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of Niacin-containing products.
## Digoxin
In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.
## Coumarin Anticoagulants
In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
## Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.[1]
There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review3 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.
Women of childbearing potential, who require treatment with ZOCOR for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of ZOCOR should be considered. If pregnancy occurs, ZOCOR should be immediately discontinued.
A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and ZOCOR significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). he relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ZOCOR should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age.
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
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A few cases of overdosage with ZOCOR have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present
Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.
The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
In a study including 16 elderly patients between 70 and 78 years of age who received ZOCOR 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients.
Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.
In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and [[carcinomas] (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.
CNS Toxicity
Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.
A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.
There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).
(Description)
(Description)
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- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
- ↑ Jump up to: 1.0 1.1 1.2 1.3 "ZOCOR (SIMVASTATIN) TABLET, FILM COATED [MERCK SHARP & DOHME CORP.]". Retrieved 18 February 2014..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents". Pediatrics. 89 (3): 495–501. 1992. PMID 1741227. | https://www.wikidoc.org/index.php/Sandbox2 | |
febb7bb99f4e1fd8d1d49720d2bce0ea5b139028 | wikidoc | Santonin | Santonin
Santonin is a drug which was widely used in the past as an anthelminthic, a drug that expels parasitic worms (helminths) from the body, by either killing or stunning them. Santonin was formerly listed in U.S. and British pharmacopoeia but has fallen out of use with the development of safer ascaricides and is no longer registered as a drug in most countries .
# Chemical composition and derivation
Santonin (C15H18O3) is the anhydride of santonic acid (C15H20O4), which is a chemical derivative of dimethylnaphtalene (C10H62). Santonin dissolves in alkalies with formation of salts of this carboxylic acid.
Santonin, in acetic acid solution, when exposed to sunlight for about a month, is converted into (colorless) photosantonic acid (C15H22O5) which is generally regarded as less toxic. The ethyl ester of the latter is obtained when an alcoholic solution of santonin is exposed to sunlight (Sestini). A yellow coloration is developed upon exposure of santonin to light. Santonin is optically levorotatory.
The full chemical name of santonin is (3S,3aS,5aS,9bS)-3a,5,5a,9b-tetrahydro-3,5a,9-trimethylnapthofuran-2,8(3H,4H)-dione. Its molecular weight is 246.30 daltons.
santonin is an organic chemical consisting of colorless flat prisms, turning slightly yellow from the action of light and soluble in alcohol, chloroform and boiling water. It is derived from santonica which is the unexpanded flower-heads of Artemisia maritima.
According to the US Pharmacopoeia Santonin occurs "in colorless, shining, flattened, prismatic crystals, odorless and nearly tasteless when first put in the mouth, but afterward developing a bitter taste; not altered by exposure to air, but turning yellow on exposure to light. Nearly insoluble in cold water; soluble in 40 parts of alcohol at 15°C. (59°F.), in 250 parts of boiling water, and in 8 parts of boiling alcohol; also soluble in 140 parts of ether, in 4 parts of chloroform, and in solutions of caustic alkalies. When heated to 170°C. (338°F.), santonin melts, and forms, if rapidly cooled, an amorphous mass, which instantly crystallizes oil coming in contact with a minute quantity of one of its solvents. At a higher temperature, it sublimes partly unchanged, and, when ignited, it is consumed, leaving no residue. Santonin is neutral to litmus paper moistened with alcohol. Santonin yields, with an alcoholic solution of potassium hydrate, a bright pinkish-red liquid, which gradually becomes colorless. From its solution in caustic alkalies, santonin is completely precipitated by supersaturation with an acid" .
# Historical pharmacological use
As noted above, santonin was formerly used as an anthelminthic, typically administered with a purgative. Santonin was used in treatment of infestation by the roundworm Ascaris lumbricoides and in ascarid parasitoses in general (including threadworm parasitosis). It is ineffective in treatment of tapeworm infestation.
The Encyclopedia Britannica (1911) notes that the typical dose was 2 to 5 grams. (It should be noted this was a total dose; many regimens called for 3 doses daily over 3 days, and the "3 teaspoons 3 times a day for 3 days" regimen was typical around the 50's when use of santonin was starting to wane; actual doses per dose were closer to 20-30 milligrams per adult dose in a typical "50's regimen", but "one-shot" doses of santonin (especially via suppository) were common in the late 1800s-early 1900s.) The only formerly registered British preparation (as of 1911) was the "trochiscus santonini" (santonin lozenge), but the preparation "sodii santoninas" (soda of santonin) was also formerly listed as an official preparation in the U.S. Pharmacopeia. Commercial preparations containing santonin (usually containing a purgative laxative as well) also appeared in US drug formularies as late as the 50's; the Modern Drug Encyclopedia and Therapeutic Index of 1955 listed Lumbricide (produced by Massengill) and a generic santonin prepraration made by Winthrop-Stearns (now Winthrop-Sanofi).
Santonin also was used in a lesser extent in treatment of atony of the bladder. This usage largely dropped off after the early 1900s.
Dosage forms varied for santonin; in the 1800s-1900s, santonin lozenges or suppositories designed for single-dosage treatment of ascarid infestation were the typical form of treatment, whilst in the 50's the two remaining santonin preparations on the market in the United States were liquid medications.
# Hazards and difficulty of use of santonin
Santonin was an agent which (compared to more modern anthelminthic drugs) was very complicated to use and entailed rather serious risk to the patient. Nearly every formulary and herbal which lists santonin or santonin-containing plants lists the real risk of yellow vision and of fatal reactions; even small doses of santonin cause disturbances of vision, usually yellow vision or perhaps green (xanthopsia or chromatopsia). Even the Encyclopedia Britannica noted:
...These effects usually pass off in a few days. Large doses, however, produce toxic effects, aphasia, muscular tremors and epileptiform convulsions, and the disturbances of vision may go on to total blindness.
More typical is the warning given regarding side effects of santonin in King's American Dispensatory:
Santonin is an active agent, and, in improper doses, is capable of producing serious symptoms, and even death. As small a dose as 2 grains is said to have killed a weakly child of 5 years, and 5 grains produced death in about 1/2 hour in a child of the same age. Among the toxic effects may be mentioned gastric pain, pallor and coldness of the surface, followed by heat and injection of the head, tremors, dizziness, pupillary dilatation, twitching of the eyes, stertor, copious sweating, hematuria, convulsive movements, tetanic cramps stupor, and insensibility. Occasionally symptoms resembling cholera morbus have been produced, and in all cases the urine presents a characteristic yellowish or greenish-yellow hue. We have observed convulsions caused by the administration of "worm lozenges." Death from santonin is due to respiratory paralysis, and post-mortem examination revealed in one instance a contracted and empty right ventricle, and about an ounce of liquid, black blood in the left heart, an inflamed duodenum, and inflamed patches in the stomach (Kilner).
Santonin often produces a singular effect upon the vision, causing surrounding objects to appear discolored, as if they were yellow or green, and occasionally blue or red; it also imparts a yellow or green color to the urine, and a reddish-purple color if that fluid be alkaline. Prof. Giovanni was led to believe that the apparent yellow color of objects observed by the eye, when under the influence of santonin, did not depend upon an elective action on the optic nerves, but rather to the yellow color which the drug itself takes when exposed to the air. Santonin colored by the air does not produce this effect, which only follows the white article. The air gives the yellow color to santonin, to passed urine containing it, and to the serum of the blood when drawn from a vein, and, according to Giovanni, it is owing to its direct action upon the aqueous humor, where it is carried by absorption, that objects present this color. The view now held, however, is that of Rose, that the alkaline serum dissolves the santonin, which then acts upon the perspective centers of the brain, producing the chromatopsia or xanthopsia.
At least one modern herbal has also noted these same severe side effects of santonin.
Even were it not for the fact that santonin is among the most toxic of herbal anthelminthic drugs, deworming using santonin is complicated in comparison to more modern anthelminthics. Typically, santonin must be taken whilst fasting completely (both before and after taking the drug) for "single dose" regimens or on a full stomach with all fats and oils in the diet being avoided for 2-3 days before treatment as well as during treatment and 2-3 days afterwards (due to santonin being fat soluble and having an increased risk of side effects); after a course of santonin, a purgative must be given to cleanse the body of the dead worms. (The two remaining registered santonin preparations in the United States as of 1955 were in fact santonin/purgative combinations; Lumbricide contained santonin and senna (among other ingredients) and the Winthrop-Stearns generic preparation was a santonin/cascara sagrada combination drug.)
Due to the severe side effects (even when used as directed), the need for a purgative, and the development of many safer deworming drugs, santonin has largely fallen out of use. Typically mebendazole and pyrantel pamoate are used in modern pharmacopoeia practice where santonin was formerly used; even guides on holistic medicine strongly recommend avoiding the use of santonin due to its severe and occasionally fatal side effects and the availability of far safer anthelminthics. The Council Directive 65/65 European Economic
Community (EEC) (in regards to pharmaceuticals and naturopathic preparations) has officially ruled santonin preparations to have an "unacceptable" risk-benefit ratio and preparations containing santonin are no longer eligible for registration in EU countries.
# Santonin and absinthe
Whilst absinthe is certainly more infamous for its content of thujone , the liquor does also contain small amounts of santonin . It has been speculated by some parties that Impressionist art--in particular, Van Gogh's artwork--may have been inspired not by thujone and its presumed psychotropic effects, but on the "yellow vision" or xanthopsia which is a known side effect of santonin. This has been disputed, however, most notably by Arnold and Loftus (1991) who have noted the santonin content would have been insufficient to cause xanthopsia. | Santonin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Santonin is a drug which was widely used in the past as an anthelminthic, a drug that expels parasitic worms (helminths) from the body, by either killing or stunning them. Santonin was formerly listed in U.S. and British pharmacopoeia but has fallen out of use with the development of safer ascaricides and is no longer registered as a drug in most countries [1].
# Chemical composition and derivation
Santonin (C15H18O3) is the anhydride of santonic acid (C15H20O4), which is a chemical derivative of dimethylnaphtalene (C10H6[CH3]2). Santonin dissolves in alkalies with formation of salts of this carboxylic acid.
Santonin, in acetic acid solution, when exposed to sunlight for about a month, is converted into (colorless) photosantonic acid (C15H22O5) which is generally regarded as less toxic. The ethyl ester of the latter is obtained when an alcoholic solution of santonin is exposed to sunlight (Sestini). A yellow coloration is developed upon exposure of santonin to light. Santonin is optically levorotatory.
The full chemical name of santonin is (3S,3aS,5aS,9bS)-3a,5,5a,9b-tetrahydro-3,5a,9-trimethylnaptho[1,2-b]furan-2,8(3H,4H)-dione. Its molecular weight is 246.30 daltons. [2] [3]
santonin is an organic chemical consisting of colorless flat prisms, turning slightly yellow from the action of light and soluble in alcohol, chloroform and boiling water. It is derived from santonica which is the unexpanded flower-heads of Artemisia maritima. [4] [5] [6] [7]
According to the US Pharmacopoeia Santonin occurs "in colorless, shining, flattened, prismatic crystals, odorless and nearly tasteless when first put in the mouth, but afterward developing a bitter taste; not altered by exposure to air, but turning yellow on exposure to light. Nearly insoluble in cold water; soluble in 40 parts of alcohol at 15°C. (59°F.), in 250 parts of boiling water, and in 8 parts of boiling alcohol; also soluble in 140 parts of ether, in 4 parts of chloroform, and in solutions of caustic alkalies. When heated to 170°C. (338°F.), santonin melts, and forms, if rapidly cooled, an amorphous mass, which instantly crystallizes oil coming in contact with a minute quantity of one of its solvents. At a higher temperature, it sublimes partly unchanged, and, when ignited, it is consumed, leaving no residue. Santonin is neutral to litmus paper moistened with alcohol. Santonin yields, with an alcoholic solution of potassium hydrate, a bright pinkish-red liquid, which gradually becomes colorless. From its solution in caustic alkalies, santonin is completely precipitated by supersaturation with an acid" [8].
# Historical pharmacological use
As noted above, santonin was formerly used as an anthelminthic, typically administered with a purgative. Santonin was used in treatment of infestation by the roundworm Ascaris lumbricoides and in ascarid parasitoses in general (including threadworm parasitosis). It is ineffective in treatment of tapeworm infestation.
The Encyclopedia Britannica (1911) notes that the typical dose was 2 to 5 grams. (It should be noted this was a total dose; many regimens called for 3 doses daily over 3 days, and the "3 teaspoons 3 times a day for 3 days" regimen was typical around the 50's when use of santonin was starting to wane; actual doses per dose were closer to 20-30 milligrams per adult dose in a typical "50's regimen", but "one-shot" doses of santonin (especially via suppository) were common in the late 1800s-early 1900s.) The only formerly registered British preparation (as of 1911) was the "trochiscus santonini" (santonin lozenge), but the preparation "sodii santoninas" (soda of santonin) was also formerly listed as an official preparation in the U.S. Pharmacopeia. Commercial preparations containing santonin (usually containing a purgative laxative as well) also appeared in US drug formularies as late as the 50's; the Modern Drug Encyclopedia and Therapeutic Index of 1955 listed Lumbricide (produced by Massengill) and a generic santonin prepraration made by Winthrop-Stearns (now Winthrop-Sanofi).
Santonin also was used in a lesser extent in treatment of atony of the bladder. This usage largely dropped off after the early 1900s.
Dosage forms varied for santonin; in the 1800s-1900s, santonin lozenges or suppositories designed for single-dosage treatment of ascarid infestation were the typical form of treatment, whilst in the 50's the two remaining santonin preparations on the market in the United States were liquid medications.
# Hazards and difficulty of use of santonin
Santonin was an agent which (compared to more modern anthelminthic drugs) was very complicated to use and entailed rather serious risk to the patient. Nearly every formulary and herbal which lists santonin or santonin-containing plants lists the real risk of yellow vision and of fatal reactions; even small doses of santonin cause disturbances of vision, usually yellow vision or perhaps green (xanthopsia or chromatopsia). Even the Encyclopedia Britannica noted:
...These effects usually pass off in a few days. Large doses, however, produce toxic effects, aphasia, muscular tremors and epileptiform convulsions, and the disturbances of vision may go on to total blindness.
More typical is the warning given regarding side effects of santonin in King's American Dispensatory:
Santonin is an active agent, and, in improper doses, is capable of producing serious symptoms, and even death. As small a dose as 2 grains is said to have killed a weakly child of 5 years, and 5 grains produced death in about 1/2 hour in a child of the same age. Among the toxic effects may be mentioned gastric pain, pallor and coldness of the surface, followed by heat and injection of the head, tremors, dizziness, pupillary dilatation, twitching of the eyes, stertor, copious sweating, hematuria, convulsive movements, tetanic cramps stupor, and insensibility. Occasionally symptoms resembling cholera morbus have been produced, and in all cases the urine presents a characteristic yellowish or greenish-yellow hue. We have observed convulsions caused by the administration of "worm lozenges." Death from santonin is due to respiratory paralysis, and post-mortem examination revealed in one instance a contracted and empty right ventricle, and about an ounce of liquid, black blood in the left heart, an inflamed duodenum, and inflamed patches in the stomach (Kilner).
. . .
Santonin often produces a singular effect upon the vision, causing surrounding objects to appear discolored, as if they were yellow or green, and occasionally blue or red; it also imparts a yellow or green color to the urine, and a reddish-purple color if that fluid be alkaline. Prof. Giovanni was led to believe that the apparent yellow color of objects observed by the eye, when under the influence of santonin, did not depend upon an elective action on the optic nerves, but rather to the yellow color which the drug itself takes when exposed to the air. Santonin colored by the air does not produce this effect, which only follows the white article. The air gives the yellow color to santonin, to passed urine containing it, and to the serum of the blood when drawn from a vein, and, according to Giovanni, it is owing to its direct action upon the aqueous humor, where it is carried by absorption, that objects present this color. The view now held, however, is that of Rose, that the alkaline serum dissolves the santonin, which then acts upon the perspective centers of the brain, producing the chromatopsia or xanthopsia.
At least one modern herbal has also noted these same severe side effects of santonin.
Even were it not for the fact that santonin is among the most toxic of herbal anthelminthic drugs, deworming using santonin is complicated in comparison to more modern anthelminthics. Typically, santonin must be taken whilst fasting completely (both before and after taking the drug) for "single dose" regimens or on a full stomach with all fats and oils in the diet being avoided for 2-3 days before treatment as well as during treatment and 2-3 days afterwards (due to santonin being fat soluble and having an increased risk of side effects); after a course of santonin, a purgative must be given to cleanse the body of the dead worms. (The two remaining registered santonin preparations in the United States as of 1955 were in fact santonin/purgative combinations; Lumbricide contained santonin and senna (among other ingredients) and the Winthrop-Stearns generic preparation was a santonin/cascara sagrada combination drug.)
Due to the severe side effects (even when used as directed), the need for a purgative, and the development of many safer deworming drugs, santonin has largely fallen out of use. Typically mebendazole and pyrantel pamoate are used in modern pharmacopoeia practice where santonin was formerly used; even guides on holistic medicine strongly recommend avoiding the use of santonin due to its severe and occasionally fatal side effects and the availability of far safer anthelminthics[2]. The Council Directive 65/65 European Economic
Community (EEC) (in regards to pharmaceuticals and naturopathic preparations) has officially ruled santonin preparations to have an "unacceptable" risk-benefit ratio and preparations containing santonin are no longer eligible for registration in EU countries[3].
# Santonin and absinthe
Whilst absinthe is certainly more infamous for its content of thujone [9], the liquor does also contain small amounts of santonin[citation needed] . It has been speculated by some parties that Impressionist art--in particular, Van Gogh's artwork--may have been inspired not by thujone and its presumed psychotropic effects, but on the "yellow vision" or xanthopsia which is a known side effect of santonin. This has been disputed, however, most notably by Arnold and Loftus (1991) who have noted the santonin content would have been insufficient to cause xanthopsia. | https://www.wikidoc.org/index.php/Santonin | |
7c41cd062a4d6017a25f9f3ccbba679565454f37 | wikidoc | Sapience | Sapience
# Overview
Sapience is often defined as wisdom, or the ability of an organism or entity to act with judgment. Judgment is a mental facility that is a particular form of intelligence or
may be considered an additional facility, above intelligence, with its own properties. Robert Sternberg has segregated the capacity for judgment from ordinary meanings of intelligence, which is closer to the sense of clever than to wisdom. Good judgment in making decisions about complex life or social decisions is a hallmark of being wise.
The word sapience is derived from the Latin word for wisdom, sapientia. Both are related to the Latin verb sapere, which means "to taste, to be wise, to know ;" the present participle of sapere forms part of Homo sapiens, the Latin binomial nomenclature created by Carolus Linnaeus to describe the human species. Linnaeus had originally given humans the species name of diurnus, meaning man of the day. But he later decided that the dominating feature of humans was wisdom, hence application of the name sapiens. His chosen biological name was intended to emphasize man's uniqueness and separation from the rest of the animal kingdom. | Sapience
# Overview
Sapience is often defined as wisdom, or the ability of an organism or entity to act with judgment. Judgment is a mental facility that is a particular form of intelligence or
may be considered an additional facility, above intelligence, with its own properties. Robert Sternberg [1] has segregated the capacity for judgment from ordinary meanings of intelligence, which is closer to the sense of clever than to wisdom. Good judgment in making decisions about complex life or social decisions is a hallmark of being wise.
The word sapience is derived from the Latin word for wisdom, sapientia.[2] Both are related to the Latin verb sapere, which means "to taste, to be wise, to know ;" the present participle of sapere forms part of Homo sapiens, the Latin binomial nomenclature created by Carolus Linnaeus to describe the human species. Linnaeus had originally given humans the species name of diurnus, meaning man of the day. But he later decided that the dominating feature of humans was wisdom, hence application of the name sapiens. His chosen biological name was intended to emphasize man's uniqueness and separation from the rest of the animal kingdom. | https://www.wikidoc.org/index.php/Sapience | |
102b3f1b6786715c627c60023ede669838ec89b3 | wikidoc | Secretin | Secretin
Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands. In humans, the secretin peptide is encoded by the SCT gene.
Secretin helps regulate the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate from the ductal cells of the pancreas. It also stimulates bile production by the liver; the bile emulsifies dietary fats in the duodenum so that pancreatic lipase can act upon them. Meanwhile, in concert with secretin's actions, the other main hormone simultaneously issued by the duodenum, cholecystokinin, is stimulating the gallbladder to contract, delivering its stored bile for the same reason.
Prosecretin is a precursor to secretin, which is present in digestion. Secretin is stored in this unusable form, and is activated by gastric acid in the lower intestine to neutralize the pH and ensure no damage is done to the small intestine by the aforementioned acid.
In 2007, secretin was discovered to play a role in osmoregulation by acting on the hypothalamus, pituitary gland, and kidney.
# Discovery
Secretin was the first hormone to be identified. In 1902, William Bayliss and Ernest Starling were studying how the nervous system controls the process of digestion. It was known that the pancreas secreted digestive juices in response to the passage of food (chyme) through the pyloric sphincter into the duodenum. They discovered (by cutting all the nerves to the pancreas in their experimental animals) that this process was not, in fact, governed by the nervous system. They determined that a substance secreted by the intestinal lining stimulates the pancreas after being transported via the bloodstream. They named this intestinal secretion secretin. Secretin was the first such "chemical messenger" identified. This type of substance is now called a hormone, a term coined by Bayliss in 1905.
# Structure
Secretin is initially synthesized as a 120 amino acid precursor protein known as prosecretin. This precursor contains an N-terminal signal peptide, spacer, secretin itself (residues 28–54), and a 72-amino acid C-terminal peptide.
The mature secretin peptide is a linear peptide hormone, which is composed of 27 amino acids and has a molecular weight of 3055. A helix is formed in the amino acids between positions 5 and 13. The amino acids sequences of secretin have some similarities to that of glucagon, vasoactive intestinal peptide (VIP), and gastric inhibitory peptide (GIP). Fourteen of 27 amino acids of secretin reside in the same positions as in glucagon, 7 the same as in VIP, and 10 the same as in GIP.
Secretin also has an amidated carboxyl-terminal amino acid which is valine. The sequence of amino acids in secretin is H–His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val–NH2.
# Physiology
## Production and secretion
Secretin is synthesized in cytoplasmic secretory granules of S-cells, which are found mainly in the mucosa of the duodenum, and in smaller numbers in the jejunum of the small intestine.
Secretin is released into circulation and/or intestinal lumen in response to low duodenal pH that ranges between 2 and 4.5 depending on species; the acidity is due to hydrochloric acid in the chyme that enters the duodenum from the stomach via the pyloric sphincter. Also, the secretion of secretin is increased by the products of protein digestion bathing the mucosa of the upper small intestine.
Secretin release is inhibited by H2 antagonists, which reduce gastric acid secretion. As a result, if the pH in the duodenum increases above 4.5, secretin cannot be released.
## Function
### pH regulation
Secretin primarily functions to neutralize the pH in the duodenum, allowing digestive enzymes from the pancreas (e.g., pancreatic amylase and pancreatic lipase) to function optimally.
Secretin targets the pancreas; pancreatic centroacinar cells have secretin receptors in their plasma membrane. As secretin binds to these receptors, it stimulates adenylate cyclase activity and converts ATP to cyclic AMP. Cyclic AMP acts as second messenger in intracellular signal transduction and causes the organ to secrete a bicarbonate-rich fluid that flows into the intestine. Bicarbonate is a base that neutralizes the acid, thus establishing a pH favorable to the action of other digestive enzymes in the small intestine.
Secretin also increases water and bicarbonate secretion from duodenal Brunner's glands to buffer the incoming protons of the acidic chyme, and also reduces acid secretion by parietal cells of the stomach. It does this through at least three mechanisms: 1) By stimulating release of somatostatin, 2) By inhibiting release of gastrin in the pyloric antrum, and 3) By direct downregulation of the parietal cell acid secretory mechanics.
It counteracts blood glucose concentration spikes by triggering increased insulin release from pancreas, following oral glucose intake.
### Osmoregulation
Secretin modulates water and electrolyte transport in pancreatic duct cells, liver cholangiocytes, and epididymis epithelial cells. It is found to play a role in the vasopressin-independent regulation of renal water reabsorption.
Secretin is found in the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus and along the neurohypophysial tract to neurohypophysis. During increased osmolality, it is released from the posterior pituitary. In the hypothalamus, it activates vasopressin release. It is also needed to carry out the central effects of angiotensin II. In the absence of secretin or its receptor in the gene knockout animals, central injection of angiotensin II was unable to stimulate water intake and vasopressin release.
It has been suggested that abnormalities in such secretin release could explain the abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). In these individuals, vasopressin release and response are normal, although abnormal renal expression, translocation of aquaporin 2, or both are found. It has been suggested that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades."
### Food intake
Secretin and its receptor are found in discrete nuclei of the hypothalamus, including the paraventricular nucleus and the arcuate nucleus, which are the primary brain sites for regulating body energy homeostasis. It was found that both central and peripheral injection of Sct reduce food intake in mouse, indicating an anorectic role of the peptide. This function of the peptide is mediated by the central melanocortin system.
# Uses
Secretin is used in a diagnostic tests for pancreatic function; secretin is injected and the pancreatic output can then be imaged with magnetic resonance imaging, a noninvasive procedure, or secretions generated as a result can gathered either through an endoscope or through tubes inserted through the mouth, down into the duodenum.
A recombinant human secretin has been available since 2004 for these diagnostic purposes. There were problems with the availability of this agent from 2012 to 2015.
# Research
A wave of enthusiasm for secretin as a possible treatment for autism arose in the 1990s based on a hypothetical gut-brain connection; as a result the NIH ran a series of clinical trials that showed that secretin was not effective, which brought an end to popular interest. | Secretin
Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands.[1] In humans, the secretin peptide is encoded by the SCT gene.[2]
Secretin helps regulate the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate from the ductal cells of the pancreas.[3][4] It also stimulates bile production by the liver; the bile emulsifies dietary fats in the duodenum so that pancreatic lipase can act upon them. Meanwhile, in concert with secretin's actions, the other main hormone simultaneously issued by the duodenum, cholecystokinin, is stimulating the gallbladder to contract, delivering its stored bile for the same reason.
Prosecretin is a precursor to secretin, which is present in digestion. Secretin is stored in this unusable form, and is activated by gastric acid in the lower intestine to neutralize the pH and ensure no damage is done to the small intestine by the aforementioned acid.[5]
In 2007, secretin was discovered to play a role in osmoregulation by acting on the hypothalamus, pituitary gland, and kidney.[6][7]
# Discovery
Secretin was the first hormone to be identified.[8] In 1902, William Bayliss and Ernest Starling were studying how the nervous system controls the process of digestion.[9] It was known that the pancreas secreted digestive juices in response to the passage of food (chyme) through the pyloric sphincter into the duodenum. They discovered (by cutting all the nerves to the pancreas in their experimental animals) that this process was not, in fact, governed by the nervous system. They determined that a substance secreted by the intestinal lining stimulates the pancreas after being transported via the bloodstream. They named this intestinal secretion secretin. Secretin was the first such "chemical messenger" identified. This type of substance is now called a hormone, a term coined by Bayliss in 1905.[10]
# Structure
Secretin is initially synthesized as a 120 amino acid precursor protein known as prosecretin. This precursor contains an N-terminal signal peptide, spacer, secretin itself (residues 28–54), and a 72-amino acid C-terminal peptide.[2]
The mature secretin peptide is a linear peptide hormone, which is composed of 27 amino acids and has a molecular weight of 3055. A helix is formed in the amino acids between positions 5 and 13. The amino acids sequences of secretin have some similarities to that of glucagon, vasoactive intestinal peptide (VIP), and gastric inhibitory peptide (GIP). Fourteen of 27 amino acids of secretin reside in the same positions as in glucagon, 7 the same as in VIP, and 10 the same as in GIP.[11]
Secretin also has an amidated carboxyl-terminal amino acid which is valine.[12] The sequence of amino acids in secretin is H–His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val–NH2.[12]
# Physiology
## Production and secretion
Secretin is synthesized in cytoplasmic secretory granules of S-cells, which are found mainly in the mucosa of the duodenum, and in smaller numbers in the jejunum of the small intestine.[13]
Secretin is released into circulation and/or intestinal lumen in response to low duodenal pH that ranges between 2 and 4.5 depending on species; the acidity is due to hydrochloric acid in the chyme that enters the duodenum from the stomach via the pyloric sphincter.[14] Also, the secretion of secretin is increased by the products of protein digestion bathing the mucosa of the upper small intestine.[15]
Secretin release is inhibited by H2 antagonists, which reduce gastric acid secretion. As a result, if the pH in the duodenum increases above 4.5, secretin cannot be released.[16]
## Function
### pH regulation
Secretin primarily functions to neutralize the pH in the duodenum, allowing digestive enzymes from the pancreas (e.g., pancreatic amylase and pancreatic lipase) to function optimally.[17]
Secretin targets the pancreas; pancreatic centroacinar cells have secretin receptors in their plasma membrane. As secretin binds to these receptors, it stimulates adenylate cyclase activity and converts ATP to cyclic AMP.[18] Cyclic AMP acts as second messenger in intracellular signal transduction and causes the organ to secrete a bicarbonate-rich fluid that flows into the intestine. Bicarbonate is a base that neutralizes the acid, thus establishing a pH favorable to the action of other digestive enzymes in the small intestine.[19]
Secretin also increases water and bicarbonate secretion from duodenal Brunner's glands to buffer the incoming protons of the acidic chyme,[17] and also reduces acid secretion by parietal cells of the stomach.[20] It does this through at least three mechanisms: 1) By stimulating release of somatostatin, 2) By inhibiting release of gastrin in the pyloric antrum, and 3) By direct downregulation of the parietal cell acid secretory mechanics.[21][14]
It counteracts blood glucose concentration spikes by triggering increased insulin release from pancreas, following oral glucose intake.[22]
### Osmoregulation
Secretin modulates water and electrolyte transport in pancreatic duct cells,[23] liver cholangiocytes,[24] and epididymis epithelial cells.[25] It is found[26] to play a role in the vasopressin-independent regulation of renal water reabsorption.[6]
Secretin is found in the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus and along the neurohypophysial tract to neurohypophysis. During increased osmolality, it is released from the posterior pituitary. In the hypothalamus, it activates vasopressin release.[7] It is also needed to carry out the central effects of angiotensin II. In the absence of secretin or its receptor in the gene knockout animals, central injection of angiotensin II was unable to stimulate water intake and vasopressin release.[27]
It has been suggested that abnormalities in such secretin release could explain the abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).[7] In these individuals, vasopressin release and response are normal, although abnormal renal expression, translocation of aquaporin 2, or both are found.[7] It has been suggested that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades."[7]
### Food intake
Secretin and its receptor are found in discrete nuclei of the hypothalamus, including the paraventricular nucleus and the arcuate nucleus, which are the primary brain sites for regulating body energy homeostasis. It was found that both central and peripheral injection of Sct reduce food intake in mouse, indicating an anorectic role of the peptide. This function of the peptide is mediated by the central melanocortin system.[28]
# Uses
Secretin is used in a diagnostic tests for pancreatic function; secretin is injected and the pancreatic output can then be imaged with magnetic resonance imaging, a noninvasive procedure, or secretions generated as a result can gathered either through an endoscope or through tubes inserted through the mouth, down into the duodenum.[29][30][31]
A recombinant human secretin has been available since 2004 for these diagnostic purposes.[32] There were problems with the availability of this agent from 2012 to 2015.[33]
# Research
A wave of enthusiasm for secretin as a possible treatment for autism arose in the 1990s based on a hypothetical gut-brain connection; as a result the NIH ran a series of clinical trials that showed that secretin was not effective, which brought an end to popular interest.[34][35][36] | https://www.wikidoc.org/index.php/Secretin | |
2b954cde0f956412cc7a5eb7308a7cae6f4ce0a1 | wikidoc | Sections | Sections
# overview
A page can be divided into sections, using the section heading syntax.
# Creation and numbering of sections
Sections are created by creating their headings, as below:
Please do not use only one equals sign on a side (=text here=); this causes a title the size of the page name, which is taken care of automatically.
With the preference setting Auto-number headings section numbering appears at each heading.
Section names can best be unique within a page. This applies even for the names of subsections. Disadvantages of duplicate section names, even as subsections of different sections, include:
- after section editing one confusingly arrives at the wrong section; see also below.
- the automatic edit summary on editing a section is ambiguous
A section (or sections) of a page can be an included separate page (or template), without changing the appearance of a page. See Help:Template#Composite_pages. This way a separate edit history is in effect provided for the section. Also this allows watching it separately.
In a page calling a template with sections, the sections in the template are numbered according to their position in the rendered page, e.g. if the template tag is in the third section, then the first section of the template is numbered four. Any text in the template before its first section shows up as part of the section with the template tag, and any text after the tag before a new heading shows up as part of the last section of the template. This may be done deliberately, but can usually better be avoided (see also below).
# Table of contents (TOC)
For each page with more than three headings, a table of contents (TOC) is automatically generated from the section headings, unless:
- (for a user) preferences are set to turn it off
- (for an article) the magic word __NOTOC__ (with two underscores on either side of the word) is added in the edit box
When either __FORCETOC__ or __TOC__ (with two underscores on either side of the word) is placed in the wikitext, a TOC is added even if the page has fewer than four headings.
With __FORCETOC__, the TOC is placed before the first section heading. With __TOC__, it is placed at the same position where this code is placed. This allows any positioning, e.g. on the right or in a table cell. In old versions of MediaWiki, it also allows multiple occurrence, e.g. in every section (However, this seems only useful if the sections are long, so that the TOCs take up only a small part of the total space.).
There may be some introductory text before the TOC, known as the "lead". Although usually a heading after the TOC is preferable, __TOC__ can be used to avoid being forced to insert a meaningless heading just to position the TOC correctly, i.e., not too low.
Using __NOTOC__ it is possible to disable the normal Table of Contents. Section links as explained below allow to create compact ToCs, e.g. alphabetical ] ] etc.
Summary:
The Table of contents can be forced onto a floating table on the right hand of the screen with the code below:
## Globally limiting the TOC depth
It is possible to limit the depth of sub-sections to show in the TOC globally using $wgMaxTocLevel. If configuration setting $wgMaxTocLevel in LocalSettings.php is set to 3 for example, only first and second level headings show up in the TOC.
Until version 1.10.0rc1, there is a bug in the parser making a limited TOC display incorrectly. A simple solution is proposed in bug report 6204.
# Section linking
In the HTML code for each section there is an anchor Template:H:mlw with both "name" and "id" attributes holding the section title. This enables linking directly to sections. These section anchors are automatically used by MediaWiki when it generates a Table of Contents for the page, and therefore when you click a section heading in the ToC, you will jump to the section. You can also use section anchors to manually link directly to one section within a page.
The html code generated at the beginning of this section, for example, is:
A link to this section (Section Linking) looks like this:
To link to a section in the same page you can use ], and to link to a section in another page ].
The anchors disregard the depth of the section; a link to a subsection or sub-subsection etc. will be ] and ] etc.
An underscore and number are appended to duplicate section names. E.g. for three sections named "Example", the names (for section linking) will be "Example", "Example_2" and "Example_3". However, after editing section "Example_2" or "Example_3" (see below), one, confusingly, arrives at section "Example" from the edit summary.
If a section has a blank space as heading, it results in a link in the TOC that does not work. For a similar effect see NS:0.
To create an anchor target without a section heading, you can use a span, for example:, however this won't work with some very old browsers.
Note that using the date formatting feature in section headings complicates section linking.
An internal link in a section heading does not give complications in terms of section linkng:
- #Demo_a
- Help:Section#Demo_http:.2F.2Fa
- :Section#Demo_http:.2F.2Fa
For linking to an arbitrary position in a page see linking to a page.
## Section linking and redirects
A link that specifies a section of a redirect page corresponds to a link to that section of the target of the redirect.
A redirect to a section of a page may also work in some environments , try e.g. the redirect pageSection linking and redirects. (One might have to force reload CSS style sheets.)
A complication is that, unlike renaming a page, renaming a section does not create some kind of redirect. Also there is no separate backlink feature for sections, pages linking to the section are included in the list of pages linking to the page. Possible workarounds:
- Instead of linking directly to a section, link to a page that redirects to the section; when the name of the section is changed, change the redirect target. This method also provides more or less a "what links here" for sections (look for redirects linking to the page, select the one linking to the section; this may be recognized from the name even if the section name has changed).
- Put an anchor and link to that
- Put a comment in the wikitext at the start of a section listing pages that link to the section
- Make the section a separate page/template and either transclude it into, or just link to it from, its parent page; instead of linking to the section one can then link to the separate page.
Redirect pages can be categorized by adding a category tag after the redirect command. In the case that the target of the redirect is a section this has to some extent the effect of categorizing the section: through the redirect the category page links to the section; however, unless an explicit link is put, the section does not link to the category. On the category page redirects are displayed with class redirect-in-category, so they can be shown in e.g. italics; this can be defined inMediaWiki:Common.css. See also Template:Mlww.
# Section editing
Sections can be separately edited by clicking special edit links labeled "" by the heading, or by right clicking on the section heading, depending on thepreferences set. This is called "section editing feature". Section editing feature will take you to an edit page by a URl such as
:Section&action=edit§ion=2
Note that here section numbers are used, not section titles; subsections have a single number, e.g. section 2.1 may be numbered 3, section 3 is then numbered 4, etc. You can also directly type in such URls in the address bar of your browser.
This is convenient if the edit does not involve other sections and one needs not have the text of other sections at hand during the edit (or if one needs it, open the section edit link in a new window, or during section editing, open the main page in a different window). Section editing alleviates some problems of large pages.
"__NOEDITSECTION__" anywhere on the page will remove the edit links. It will not disable section editing itself; right clicking on the section heading and the url still work.
Inserting a section can be done by editing either the section before or after it, merging with the previous section by deleting the heading.
Adding a section at the end can also be done with a URL like :Sandbox&action=edit§ion=new . On talk pages a special link labeled "+" or "Post a new comment" is provided for this. In this case, a text box titled "Subject/headline" will appear and the content you type in it will become the section heading as well as the edit summary of the edit.
## Editing before the first section
In general, no particular link for editing the introductory text before the first section heading is provided. However, section editing feature can also be applied to this part by giving 0 as the section number such as :Section&action=edit§ion=0 . A less cumbersome way to obtain this link is to use any section edit link of the page, and change the number of the section to zero.
Javascript can also create this URL, see w:en:Wikipedia:WikiProject User scripts/Scripts/Edit Top.
The {{Edit-first-section}} and {{Edit-top-section}}templates create an edit link for the section 0. Both are positioned slightly different. Copy these templates to your wiki.
See also Help:Section editing demo.
## Preview
The preview in section editing does not always show the same as the corresponding part of the full page, e.g. if on the full page an image in the previous section intrudes into the section concerned.
The edit page shows the list of templates used on the whole page, i.e. also the templates used in other sections.
## Subsections
Subsections are included in the part of the section that is edited. Section numbering is relative to the part that is edited, so on the relative top level there is always just number 1, relative subsections all have numbers starting with 1: 1.1., 1.2, etc.; e.g., when editing subsection 3.2, sub-subsection 3.2.4 is numbered 1.4. However, the heading format is according to the absolute level.
## Editing a page with large sections
If a page has very large sections, or is very large and has no division into sections, and one's browser or connection does not allow editing of such a large section, then one can still:
- append a section by specifying a large section number (too large does not matter); however, one has to start with a blank line before the new section heading
- append content to the last section by not starting with a section heading; however, with the limitations of one's browser or connection, one cannot revert this, or edit one's new text.
If one can view the wikitext of a large section, one can divide the page into smaller sections by step by step appending one, and finally deleting the original content (this can be done one large section at a time). Thus temporarily there is partial duplication of the content, so it is useful to put an explanation in the edit summary.
Help:Editing sections of included templates
## Sections within parser functions
If a section heading is created conditionally using a parser function, either directly or by conditionally transcluding a template with sections, edit links of this and subsequent sections will edit the wrong section (although the page (including TOC) is correctly displayed and the TOC links correctly). This is because section counting for producing the edit links is done after expanding the parser functions, whereas when the edit page is loaded, only those sections are counted which statically appear in the page (or the respective template).
This is not a bug but a consequence of the way section editing is implemented, so the solutions are the obvious ones: either avoid creating sections via parser functions, or disable section editing.
## Editing a footnote
To edit a footnote rendered in a section containing the code , edit the section with the footnote mark referring to it, seeHelp:Footnotes.
# Sections vs. separate pages vs. transclusion
Advantages of separate pages:
- what links here feature
- separate edit histories
- the Template:Peisl applies per page
- automatic redirect on renaming
- loading a small page is faster than loading a large page
- can separately be put in categories (however, see also below)
- with Semantic MediaWiki: have separate annotations
Advantages of one large page with sections:
- loading one large page is faster and more convenient than loading several small ones
- searching within one large page (the page itself or the wikitext) with a local search function is faster and in some respects better than searching several pages (for which one has to search the whole project); also the TOC provides for convenient navigation.
- enforces the cohesion of a concept that while having several definitions needs independent editing.
An alternative is composing a page of other pages using the template feature (creating a compound document byTransclusion). This allows easy searching within the combined rendered page, but not in the combined wikitext. As a disadvantage, a title for each page has to be provided. For the pre-expand include size limit this is disadvantageous even compared with one large page: the pre-expand include size is the sum of the pre-expand include sizes of the components plus the sum of sizes of the wikitexts of the components.
# Making a heading that does not show up in ToC
In some quite-older versions, if you wanted a heading not to show up in the generated Table of Contents at the top of the page, you could use HTML to make the heading.
But that no longer is supported; by design, HTML headings now show up in the TOC no matter what; see the discussion at .
A simple extension can give you the ability to create non-TOC headings. Try the following, which was written using instructions fromExtending wiki markup:
Then of course you have to install the extension by adding the following to LocalSettings.php:
To add an heading that won't show up in the TOC, do it as:
This is pretty crude, and only provides for an H3-level heading. Perhaps someone who actually knows PHP (instead of doing monkey-see-monkey-do programming like I just did) could add code to create tags for H1, H2, and H4.
UPDATE: To add it for H1, H2, H3 and H4, the following will do:
# Sections for demo above
## Demo a
This section is linked to from #Section linking.
## Demo
This section is linked to from #Section linking. | Sections
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# overview
A page can be divided into sections, using the section heading syntax.
# Creation and numbering of sections
Sections are created by creating their headings, as below:
Please do not use only one equals sign on a side (=text here=); this causes a title the size of the page name, which is taken care of automatically.
With the preference setting Auto-number headings section numbering appears at each heading.
Section names can best be unique within a page. This applies even for the names of subsections. Disadvantages of duplicate section names, even as subsections of different sections, include:
- after section editing one confusingly arrives at the wrong section; see also below.
- the automatic edit summary on editing a section is ambiguous
A section (or sections) of a page can be an included separate page (or template), without changing the appearance of a page. See Help:Template#Composite_pages. This way a separate edit history is in effect provided for the section. Also this allows watching it separately.
In a page calling a template with sections, the sections in the template are numbered according to their position in the rendered page, e.g. if the template tag is in the third section, then the first section of the template is numbered four. Any text in the template before its first section shows up as part of the section with the template tag, and any text after the tag before a new heading shows up as part of the last section of the template. This may be done deliberately, but can usually better be avoided (see also below).
# Table of contents (TOC)
For each page with more than three headings, a table of contents (TOC) is automatically generated from the section headings, unless:
- (for a user) preferences are set to turn it off
- (for an article) the magic word __NOTOC__ (with two underscores on either side of the word) is added in the edit box
When either __FORCETOC__ or __TOC__ (with two underscores on either side of the word) is placed in the wikitext, a TOC is added even if the page has fewer than four headings.
With __FORCETOC__, the TOC is placed before the first section heading. With __TOC__, it is placed at the same position where this code is placed. This allows any positioning, e.g. on the right or in a table cell. In old versions of MediaWiki, it also allows multiple occurrence, e.g. in every section (However, this seems only useful if the sections are long, so that the TOCs take up only a small part of the total space.).
There may be some introductory text before the TOC, known as the "lead". Although usually a heading after the TOC is preferable, __TOC__ can be used to avoid being forced to insert a meaningless heading just to position the TOC correctly, i.e., not too low.
Using __NOTOC__ it is possible to disable the normal Table of Contents. Section links as explained below allow to create compact ToCs, e.g. alphabetical [[#A|A]] [[#B|B]] etc.
Summary:
Template:H:TOC variables
The Table of contents can be forced onto a floating table on the right hand of the screen with the code below:
## Globally limiting the TOC depth
It is possible to limit the depth of sub-sections to show in the TOC globally using $wgMaxTocLevel. If configuration setting $wgMaxTocLevel in LocalSettings.php is set to 3 for example, only first and second level headings show up in the TOC.
Until version 1.10.0rc1, there is a bug in the parser making a limited TOC display incorrectly. A simple solution is proposed in bug report 6204.
# Section linking
In the HTML code for each section there is an anchor Template:H:mlw with both "name" and "id" attributes holding the section title. This enables linking directly to sections. These section anchors are automatically used by MediaWiki when it generates a Table of Contents for the page, and therefore when you click a section heading in the ToC, you will jump to the section. You can also use section anchors to manually link directly to one section within a page.
The html code generated at the beginning of this section, for example, is:
A link to this section (Section Linking) looks like this:
[[Help:Section#Section_linking|Section Linking]]
To link to a section in the same page you can use [[#section name|displayed text]], and to link to a section in another page [[page name#section name|displayed text]].
The anchors disregard the depth of the section; a link to a subsection or sub-subsection etc. will be [[#subsection name]] and [[#sub-subsection name]] etc.
An underscore and number are appended to duplicate section names. E.g. for three sections named "Example", the names (for section linking) will be "Example", "Example_2" and "Example_3". However, after editing section "Example_2" or "Example_3" (see below), one, confusingly, arrives at section "Example" from the edit summary.
If a section has a blank space as heading, it results in a link in the TOC that does not work. For a similar effect see NS:0.
To create an anchor target without a section heading, you can use a span, for example:<span id="anchor_name"></span>, however this won't work with some very old browsers.
Note that using the date formatting feature in section headings complicates section linking.
An internal link in a section heading does not give complications in terms of section linkng:
- #Demo_a
- Help:Section#Demo_http:.2F.2Fa
- http://meta.wikimedia.org/wiki/Help:Section#Demo_http:.2F.2Fa
For linking to an arbitrary position in a page see linking to a page.
## Section linking and redirects
A link that specifies a section of a redirect page corresponds to a link to that section of the target of the redirect.
A redirect to a section of a page may also work in some environments [2], try e.g. the redirect pageSection linking and redirects. (One might have to force reload CSS style sheets.)
A complication is that, unlike renaming a page, renaming a section does not create some kind of redirect. Also there is no separate backlink feature for sections, pages linking to the section are included in the list of pages linking to the page. Possible workarounds:
- Instead of linking directly to a section, link to a page that redirects to the section; when the name of the section is changed, change the redirect target. This method also provides more or less a "what links here" for sections (look for redirects linking to the page, select the one linking to the section; this may be recognized from the name even if the section name has changed).
- Put an anchor and link to that
- Put a comment in the wikitext at the start of a section listing pages that link to the section
- Make the section a separate page/template and either transclude it into, or just link to it from, its parent page; instead of linking to the section one can then link to the separate page.
Redirect pages can be categorized by adding a category tag after the redirect command. In the case that the target of the redirect is a section this has to some extent the effect of categorizing the section: through the redirect the category page links to the section; however, unless an explicit link is put, the section does not link to the category. On the category page redirects are displayed with class redirect-in-category, so they can be shown in e.g. italics; this can be defined inMediaWiki:Common.css. See also Template:Mlww.
# Section editing
Sections can be separately edited by clicking special edit links labeled "[edit]" by the heading, or by right clicking on the section heading, depending on thepreferences set. This is called "section editing feature". Section editing feature will take you to an edit page by a URl such as
https://www.wikidoc.org/w/wiki.phtml?title=Help:Section&action=edit§ion=2
Note that here section numbers are used, not section titles; subsections have a single number, e.g. section 2.1 may be numbered 3, section 3 is then numbered 4, etc. You can also directly type in such URls in the address bar of your browser.
This is convenient if the edit does not involve other sections and one needs not have the text of other sections at hand during the edit (or if one needs it, open the section edit link in a new window, or during section editing, open the main page in a different window). Section editing alleviates some problems of large pages.
"__NOEDITSECTION__" anywhere on the page will remove the edit links. It will not disable section editing itself; right clicking on the section heading and the url still work.
Inserting a section can be done by editing either the section before or after it, merging with the previous section by deleting the heading.
Adding a section at the end can also be done with a URL like http://meta.wikimedia.org/w/wiki.phtml?title=Meta:Sandbox&action=edit§ion=new . On talk pages a special link labeled "+" or "Post a new comment" is provided for this. In this case, a text box titled "Subject/headline" will appear and the content you type in it will become the section heading as well as the edit summary of the edit.
## Editing before the first section
In general, no particular link for editing the introductory text before the first section heading is provided. However, section editing feature can also be applied to this part by giving 0 as the section number such as https://www.wikidoc.org/w/wiki.phtml?title=Help:Section&action=edit§ion=0 . A less cumbersome way to obtain this link is to use any section edit link of the page, and change the number of the section to zero.
Javascript can also create this URL, see w:en:Wikipedia:WikiProject User scripts/Scripts/Edit Top.
The {{Edit-first-section}} and {{Edit-top-section}}templates create an edit link for the section 0. Both are positioned slightly different. Copy these templates to your wiki.
See also Help:Section editing demo.
## Preview
The preview in section editing does not always show the same as the corresponding part of the full page, e.g. if on the full page an image in the previous section intrudes into the section concerned.
The edit page shows the list of templates used on the whole page, i.e. also the templates used in other sections.
## Subsections
Subsections are included in the part of the section that is edited. Section numbering is relative to the part that is edited, so on the relative top level there is always just number 1, relative subsections all have numbers starting with 1: 1.1., 1.2, etc.; e.g., when editing subsection 3.2, sub-subsection 3.2.4 is numbered 1.4. However, the heading format is according to the absolute level.
## Editing a page with large sections
If a page has very large sections, or is very large and has no division into sections, and one's browser or connection does not allow editing of such a large section, then one can still:
- append a section by specifying a large section number (too large does not matter); however, one has to start with a blank line before the new section heading
- append content to the last section by not starting with a section heading; however, with the limitations of one's browser or connection, one cannot revert this, or edit one's new text.
If one can view the wikitext of a large section, one can divide the page into smaller sections by step by step appending one, and finally deleting the original content (this can be done one large section at a time). Thus temporarily there is partial duplication of the content, so it is useful to put an explanation in the edit summary.
Help:Editing sections of included templates
## Sections within parser functions
If a section heading is created conditionally using a parser function, either directly or by conditionally transcluding a template with sections, edit links of this and subsequent sections will edit the wrong section (although the page (including TOC) is correctly displayed and the TOC links correctly). This is because section counting for producing the edit links is done after expanding the parser functions, whereas when the edit page is loaded, only those sections are counted which statically appear in the page (or the respective template).
This is not a bug but a consequence of the way section editing is implemented, so the solutions are the obvious ones: either avoid creating sections via parser functions, or disable section editing.
## Editing a footnote
To edit a footnote rendered in a section containing the code <references />, edit the section with the footnote mark referring to it, seeHelp:Footnotes.
# Sections vs. separate pages vs. transclusion
Advantages of separate pages:
- what links here feature
- separate edit histories
- the Template:Peisl applies per page
- automatic redirect on renaming
- loading a small page is faster than loading a large page
- can separately be put in categories (however, see also below)
- with Semantic MediaWiki: have separate annotations
Advantages of one large page with sections:
- loading one large page is faster and more convenient than loading several small ones
- searching within one large page (the page itself or the wikitext) with a local search function is faster and in some respects better than searching several pages (for which one has to search the whole project); also the TOC provides for convenient navigation.
- enforces the cohesion of a concept that while having several definitions needs independent editing.
An alternative is composing a page of other pages using the template feature (creating a compound document byTransclusion). This allows easy searching within the combined rendered page, but not in the combined wikitext. As a disadvantage, a title for each page has to be provided. For the pre-expand include size limit this is disadvantageous even compared with one large page: the pre-expand include size is the sum of the pre-expand include sizes of the components plus the sum of sizes of the wikitexts of the components.
# Making a heading that does not show up in ToC
In some quite-older versions, if you wanted a heading not to show up in the generated Table of Contents at the top of the page, you could use HTML to make the heading.
But that no longer is supported; by design, HTML headings now show up in the TOC no matter what; see the discussion at http://bugzilla.wikimedia.org/show_bug.cgi?id=6575.
A simple extension can give you the ability to create non-TOC headings. Try the following, which was written using instructions fromExtending wiki markup:
Then of course you have to install the extension by adding the following to LocalSettings.php:
To add an <h3> heading that won't show up in the TOC, do it as:
This is pretty crude, and only provides for an H3-level heading. Perhaps someone who actually knows PHP (instead of doing monkey-see-monkey-do programming like I just did) could add code to create tags for H1, H2, and H4.
UPDATE: To add it for H1, H2, H3 and H4, the following will do:
# Sections for demo above
## Demo a
This section is linked to from #Section linking.
## Demo http://a
This section is linked to from #Section linking. | https://www.wikidoc.org/index.php/Section | |
45bee0edd9dd7a1a990e1c441479d21ebbd116dd | wikidoc | Sedation | Sedation
# Overview
Sedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.
# Uses
Sedation is typically used in procedures such as endoscopy, vasectomy, or minor surgery and in dentistry for reconstructive surgery, some cosmetic surgeries, removal of impacted wisdom teeth, or for high-anxiety patients. Sedation methods in dentistry include inhalation sedation (using nitrous oxide), oral sedation, and intravenous (IV) sedation. Inhalation sedation is also sometimes referred to as Relative Analgesia.
Sedation is also used extensively in the intensive care unit so that patients who are being ventilated tolerate having an endotracheal tube in their trachea.
# Risks
Airway obstruction, apnoea and hypotension are not uncommon during sedation and require the presence of health professionals who are suitably trained to detect and manage these problems.
# Causes
- Drug side effect:
Butorphanol
Carbinoxamine
Clobazam
Diphenhydramine
Hydrocodone bitartrate and acetaminophen
Metyrapone
Metirosine
Nabilone
Oxaprozin
Papaverine
Sodium oxybate
- Butorphanol
- Carbinoxamine
- Clobazam
- Diphenhydramine
- Hydrocodone bitartrate and acetaminophen
- Metyrapone
- Metirosine
- Nabilone
- Oxaprozin
- Papaverine
- Sodium oxybate
# Levels of sedation
Sedation scales are used in medical situations in conjunction with a medical history in assessing the applicable degree of sedation in patients in order to avoid under-sedation (the patient risks experiencing pain or distress) and over-sedation (the patient risks side effects such as suppression of breathing, which might lead to death). Typically, levels are (i) agitation, (ii) calm, (iii) responsive to voice only, (iv) responsive to shaking only, (v) responsive to pain only, and (vi) not responsive.
Examples of sedation scales include: MSAT (Minnesota Sedation Assessment Tool) and the Ramsay Scale (Ramsay, et al. 1974) | Sedation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.
# Uses
Sedation is typically used in procedures such as endoscopy, vasectomy, or minor surgery and in dentistry for reconstructive surgery, some cosmetic surgeries, removal of impacted wisdom teeth, or for high-anxiety patients. Sedation methods in dentistry include inhalation sedation (using nitrous oxide), oral sedation, and intravenous (IV) sedation. Inhalation sedation is also sometimes referred to as Relative Analgesia.
Sedation is also used extensively in the intensive care unit so that patients who are being ventilated tolerate having an endotracheal tube in their trachea.
# Risks
Airway obstruction, apnoea and hypotension are not uncommon during sedation and require the presence of health professionals who are suitably trained to detect and manage these problems.
# Causes
- Drug side effect:
Butorphanol
Carbinoxamine
Clobazam
Diphenhydramine
Hydrocodone bitartrate and acetaminophen
Metyrapone
Metirosine
Nabilone
Oxaprozin
Papaverine
Sodium oxybate
- Butorphanol
- Carbinoxamine
- Clobazam
- Diphenhydramine
- Hydrocodone bitartrate and acetaminophen
- Metyrapone
- Metirosine
- Nabilone
- Oxaprozin
- Papaverine
- Sodium oxybate
# Levels of sedation
Sedation scales are used in medical situations in conjunction with a medical history in assessing the applicable degree of sedation in patients in order to avoid under-sedation (the patient risks experiencing pain or distress) and over-sedation (the patient risks side effects such as suppression of breathing, which might lead to death). Typically, levels are (i) agitation, (ii) calm, (iii) responsive to voice only, (iv) responsive to shaking only, (v) responsive to pain only, and (vi) not responsive.
Examples of sedation scales include: MSAT (Minnesota Sedation Assessment Tool) and the Ramsay Scale (Ramsay, et al. 1974) | https://www.wikidoc.org/index.php/Sedation | |
e3edecdf11ca488b90fe4c4bc01bdf3c158ff445 | wikidoc | Sedative | Sedative
# Overview
A sedative is a substance that depresses the central nervous system (CNS), resulting in calmness, relaxation, reduction of anxiety, sleepiness, and slowed breathing, as well as slurred speech, staggering gait, poor judgment, and slow, uncertain reflexes. Sedatives may be referred to as tranquilizers, depressants, anxiolytics, soporifics, sleeping pills, or sedative-hypnotics. This, however, may be inaccurate as sedatives are a type of depressant as are tranquilizers which are mild in their action compared to that of sedatives. Also, sedatives only act as hypnotics (sleep-inducing drugs)in relatively high doses. Sedatives can be abused to produce an overly-calming effect (alcohol being the classic and most common sedating drug). At high doses or when they are abused, many of these drugs can cause unconsciousness (see hypnotic) and even death.
# Types of Sedatives
- Antidepressants
mirtazapine (Remeron)
trazodone (Desyrel)
- mirtazapine (Remeron)
- trazodone (Desyrel)
- Barbiturates
amobarbital (Amytal)
pentobarbital (Nembutal)
secobarbital (Seconal)
- amobarbital (Amytal)
- pentobarbital (Nembutal)
- secobarbital (Seconal)
- Benzodiazepines ("minor tranquilizers")
alprazolam (Xanax)
bromazepam (Lexotan)
clonazepam (Klonopin)
diazepam (Valium)
estazolam (Prosom)
flunitrazepam (Rohypnol)
lorazepam (Ativan)
midazolam (Versed)
nitrazepam (Mogadon)
-xazepam (Serax)
triazolam (Halcion)
temazepam (Restoril, Normison, Planum, Tenox and Temaze)
chlordiazepoxide (Librium)
- alprazolam (Xanax)
- bromazepam (Lexotan)
- clonazepam (Klonopin)
- diazepam (Valium)
- estazolam (Prosom)
- flunitrazepam (Rohypnol)
- lorazepam (Ativan)
- midazolam (Versed)
- nitrazepam (Mogadon)
- oxazepam (Serax)
- triazolam (Halcion)
- temazepam (Restoril, Normison, Planum, Tenox and Temaze)
- chlordiazepoxide (Librium)
- Typical antipsychotics ("major tranquilizers")
chlorpromazine (Thorazine, Largactil)
fluphenazine (Prolixin)
haloperidol (Haldol)
loxapine succinate (Loxitane)
perphenazine (Etrafon, Trilafon)
prochlorperazine (Compazine)
thiothixene (Navane)
trifluoperazine (Stelazine, Trifluoperaz)
zuclopentixol (Cisordinol)
- chlorpromazine (Thorazine, Largactil)
- fluphenazine (Prolixin)
- haloperidol (Haldol)
- loxapine succinate (Loxitane)
- perphenazine (Etrafon, Trilafon)
- prochlorperazine (Compazine)
- thiothixene (Navane)
- trifluoperazine (Stelazine, Trifluoperaz)
- zuclopentixol (Cisordinol)
- Atypical antipsychotics
clozapine (Clozaril)
-lanzapine (Zyprexa)
quetiapine (Seroquel)
risperidone (Risperdal)
ziprasidone (Geodon) (May cause somnolence in some, while causing insomnia in others)
- clozapine (Clozaril)
- olanzapine (Zyprexa)
- quetiapine (Seroquel)
- risperidone (Risperdal)
- ziprasidone (Geodon) (May cause somnolence in some, while causing insomnia in others)
- Sedating antihistamines
clemastine
doxylamine
diphenhydramine (Benadryl)
hydroxyzine (Atarax)
niaprazine
promethazine
pyribenzamine
cyproheptadine
- clemastine
- doxylamine
- diphenhydramine (Benadryl)
- hydroxyzine (Atarax)
- niaprazine
- promethazine
- pyribenzamine
- cyproheptadine
- Herbal sedatives
ashwagandha
catnip
kava (Piper methysticum)
mandrake
marijuana
valerian
- ashwagandha
- catnip
- kava (Piper methysticum)
- mandrake
- marijuana
- valerian
- Solvent sedatives
chloral hydrate (Noctec)
diethyl ether (Ether)
ethyl alcohol (alcoholic beverage)
gamma-hydroxybutyrate (GHB)
methyl trichloride (Chloroform)
- chloral hydrate (Noctec)
- diethyl ether (Ether)
- ethyl alcohol (alcoholic beverage)
- gamma-hydroxybutyrate (GHB)
- methyl trichloride (Chloroform)
- Nonbenzodiazepine sedatives
eszopiclone (Lunesta)
zaleplon (Sonata)
zolpidem (Ambien)
zopiclone (Imovane, Zimovane)
- eszopiclone (Lunesta)
- zaleplon (Sonata)
- zolpidem (Ambien)
- zopiclone (Imovane, Zimovane)
- Uncategorized sedatives
ethchlorvynol (Placidyl)
glutethimide (Doriden)
ketamine (Ketalar, Ketaset)
methaqualone (Sopor, Quaalude)
methyprylon (Noludar)
ramelteon (Rozerem)
- ethchlorvynol (Placidyl)
- glutethimide (Doriden)
- ketamine (Ketalar, Ketaset)
- methaqualone (Sopor, Quaalude)
- methyprylon (Noludar)
- ramelteon (Rozerem)
# Therapeutic Use
Doctors and nurses often administer sedatives to patients in order to dull the patient's anxiety related to painful or anxiety-provoking procedures. Although sedatives do not relieve pain in themselves, they can be a useful adjunct to analgesics in preparing patients for surgery, and are commonly given to patients before they are anaesthetized, or before other highly uncomfortable and invasive procedures like cardiac catheterization , colonoscopy or MRI. They increase tractability and compliance of children or troublesome or demanding patients.
Patients in intensive care units are almost always sedated (unless they are unconscious from their condition anyway)
# Sedative Dependence
All sedatives can cause physiological and psychological dependence when taken regularly over a period of time, even at therapeutic doses. Dependent users may get symptoms ranging from restlessness, insomnia to convulsions and death. When users become psychologically dependent, they feel as if they need the drug to function, although there is no physical dependence. In both types of dependences, finding and using the sedative becomes the focus in life. Both physical and psychological dependence can be treated with therapy. (see Sedative Dependence).
# Abuse and Overdoses
All sedatives can be abused, but barbiturates and benzodiazepines are responsible for most of the problems with sedative abuse due to their widespread "recreational" or non-medical use. People who have difficulty dealing with stress, anxiety or sleeplessness may overuse or become dependent on sedatives. Heroin users take them either to supplement their drug or to substitute for it. Stimulant users frequently take sedatives to calm excessive jitteriness. Others take sedatives recreationally to relax and forget their worries. Barbiturate overdose is a factor in nearly one-third of all reported drug-related deaths. These include suicides and accidental drug poisonings. Accidental deaths sometimes occur when a drowsy, confused user repeats doses, or when sedatives are taken with alcohol. In the U.S., in 1998, a total of 70,982 sedative exposures were reported to U.S. poison control centers, of which 2310 (3.2%) resulted in major toxicity and 89 (0.1%) resulted in death. About half of all the people admitted to emergency rooms in the U.S. as a result of nonmedical use of sedatives have a legitimate prescription for the drug, but have taken an excessive dose or combined it with alcohol or other drugs.
See also Other non-therapeutic use.
# Sedatives and Alcohol
Sedatives and alcohol are sometimes combined recreationally or carelessly. Since alcohol is a strong depressant that slows brain function and depresses respiration, the two substances compound each other's actions synergistically and this combination can prove fatal.
# Lookalikes
Lookalikes, or pills made to mimic the appearance and the effects of authentic sedatives, are sold on the street. Lookalikes may contain over-the-counter drugs, such as antihistamines, that cause drowsiness. Since the actual composition is unknown, neither the intensity of the primary effect nor the range of side effects can be predicted.
# Sedatives and Amnesia
Sedation can sometimes leave the patient with long-term or short-term amnesia.
Lorazepam is one such pharmacological agent that can cause anterograde amnesia. Intensive care unit patients who receive higher doses over longer periods of time, typically via IV drip, are more likely to experience such side effects.
# Sedative Drugs and Crime
The sedatives GHB, Flunitrazepam (Rohypnol), and to a lesser extent, temazepam (Restoril), and midazolam (Versed) are known for their use as date rape drugs (also called a Mickey), administered to unsuspecting patrons in bars or guests at parties to reduce the intended victims' defenses. These drugs are also used for robbing people, indeed statistical overviews suggest that the use of sedative-spiked drinks for robbing people is actually much more common than their use for rape.
Cases of criminals taking rohypnol themselves before they commit crimes have also been reported, as the loss of inhibitions from the drug may increase their confidence to commit the offence, and the amnesia produced by the drug makes it difficult for police to interrogate them if they are caught.
# Sedative Withdrawal
## Differential Diagnosis
- Alcohol withdrawal
- Anxiety disorders
- Essential tremor
- Hypoglycemia
- Diabetic ketoacidosis
- Seizure due to infections, head injury, poisonings
## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Withdrawal
# Sedative Intoxication
## Differential Diagnosis
- Alcohol use disorders
- Alcohol intoxication
- Delirium
- Traumatic brain injury
## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Intoxication
# Sedative Use Disorder
## Differential Diagnosis
- Alcohol use disorder
- Clinically appropriate use of the medication
- Generalized anxiety disorder
- Multiple sclerosis
- Subdural hematoma
## Risk Factors
- Availability of the substances
- Alcohol use disorder
- Environmental factors
- Early onset of use
- Genetic predisposition
- Peer use of the substance
## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder | Sedative
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
A sedative is a substance that depresses the central nervous system (CNS), resulting in calmness, relaxation, reduction of anxiety, sleepiness, and slowed breathing, as well as slurred speech, staggering gait, poor judgment, and slow, uncertain reflexes. Sedatives may be referred to as tranquilizers, depressants, anxiolytics, soporifics, sleeping pills, or sedative-hypnotics. This, however, may be inaccurate as sedatives are a type of depressant as are tranquilizers which are mild in their action compared to that of sedatives. Also, sedatives only act as hypnotics (sleep-inducing drugs)in relatively high doses. Sedatives can be abused to produce an overly-calming effect (alcohol being the classic and most common sedating drug). At high doses or when they are abused, many of these drugs can cause unconsciousness (see hypnotic) and even death.
# Types of Sedatives
- Antidepressants
mirtazapine (Remeron)
trazodone (Desyrel)
- mirtazapine (Remeron)
- trazodone (Desyrel)
- Barbiturates
amobarbital (Amytal)
pentobarbital (Nembutal)
secobarbital (Seconal)
- amobarbital (Amytal)
- pentobarbital (Nembutal)
- secobarbital (Seconal)
- Benzodiazepines ("minor tranquilizers")
alprazolam (Xanax)
bromazepam (Lexotan)
clonazepam (Klonopin)
diazepam (Valium)
estazolam (Prosom)
flunitrazepam (Rohypnol)
lorazepam (Ativan)
midazolam (Versed)
nitrazepam (Mogadon)
oxazepam (Serax)
triazolam (Halcion)
temazepam (Restoril, Normison, Planum, Tenox and Temaze)
chlordiazepoxide (Librium)
- alprazolam (Xanax)
- bromazepam (Lexotan)
- clonazepam (Klonopin)
- diazepam (Valium)
- estazolam (Prosom)
- flunitrazepam (Rohypnol)
- lorazepam (Ativan)
- midazolam (Versed)
- nitrazepam (Mogadon)
- oxazepam (Serax)
- triazolam (Halcion)
- temazepam (Restoril, Normison, Planum, Tenox and Temaze)
- chlordiazepoxide (Librium)
- Typical antipsychotics ("major tranquilizers")
chlorpromazine (Thorazine, Largactil)
fluphenazine (Prolixin)
haloperidol (Haldol)
loxapine succinate (Loxitane)
perphenazine (Etrafon, Trilafon)
prochlorperazine (Compazine)
thiothixene (Navane)
trifluoperazine (Stelazine, Trifluoperaz)
zuclopentixol (Cisordinol)
- chlorpromazine (Thorazine, Largactil)
- fluphenazine (Prolixin)
- haloperidol (Haldol)
- loxapine succinate (Loxitane)
- perphenazine (Etrafon, Trilafon)
- prochlorperazine (Compazine)
- thiothixene (Navane)
- trifluoperazine (Stelazine, Trifluoperaz)
- zuclopentixol (Cisordinol)
- Atypical antipsychotics
clozapine (Clozaril)
olanzapine (Zyprexa)
quetiapine (Seroquel)
risperidone (Risperdal)
ziprasidone (Geodon) (May cause somnolence in some, while causing insomnia in others)
- clozapine (Clozaril)
- olanzapine (Zyprexa)
- quetiapine (Seroquel)
- risperidone (Risperdal)
- ziprasidone (Geodon) (May cause somnolence in some, while causing insomnia in others)
- Sedating antihistamines
clemastine
doxylamine
diphenhydramine (Benadryl)
hydroxyzine (Atarax)
niaprazine
promethazine
pyribenzamine
cyproheptadine
- clemastine
- doxylamine
- diphenhydramine (Benadryl)
- hydroxyzine (Atarax)
- niaprazine
- promethazine
- pyribenzamine
- cyproheptadine
- Herbal sedatives
ashwagandha
catnip
kava (Piper methysticum)
mandrake[citation needed]
marijuana
valerian
- ashwagandha
- catnip
- kava (Piper methysticum)
- mandrake[citation needed]
- marijuana
- valerian
- Solvent sedatives
chloral hydrate (Noctec)
diethyl ether (Ether)
ethyl alcohol (alcoholic beverage)
gamma-hydroxybutyrate (GHB)
methyl trichloride (Chloroform)
- chloral hydrate (Noctec)
- diethyl ether (Ether)
- ethyl alcohol (alcoholic beverage)
- gamma-hydroxybutyrate (GHB)
- methyl trichloride (Chloroform)
- Nonbenzodiazepine sedatives
eszopiclone (Lunesta)
zaleplon (Sonata)
zolpidem (Ambien)
zopiclone (Imovane, Zimovane)
- eszopiclone (Lunesta)
- zaleplon (Sonata)
- zolpidem (Ambien)
- zopiclone (Imovane, Zimovane)
- Uncategorized sedatives
ethchlorvynol (Placidyl)
glutethimide (Doriden)
ketamine (Ketalar, Ketaset)
methaqualone (Sopor, Quaalude)
methyprylon (Noludar)
ramelteon (Rozerem)
- ethchlorvynol (Placidyl)
- glutethimide (Doriden)
- ketamine (Ketalar, Ketaset)
- methaqualone (Sopor, Quaalude)
- methyprylon (Noludar)
- ramelteon (Rozerem)
# Therapeutic Use
Doctors and nurses often administer sedatives to patients in order to dull the patient's anxiety related to painful or anxiety-provoking procedures. Although sedatives do not relieve pain in themselves, they can be a useful adjunct to analgesics in preparing patients for surgery, and are commonly given to patients before they are anaesthetized, or before other highly uncomfortable and invasive procedures like cardiac catheterization , colonoscopy or MRI. They increase tractability and compliance of children or troublesome or demanding patients.
Patients in intensive care units are almost always sedated (unless they are unconscious from their condition anyway)
# Sedative Dependence
All sedatives can cause physiological and psychological dependence when taken regularly over a period of time, even at therapeutic doses. Dependent users may get symptoms ranging from restlessness, insomnia to convulsions and death. When users become psychologically dependent, they feel as if they need the drug to function, although there is no physical dependence. In both types of dependences, finding and using the sedative becomes the focus in life. Both physical and psychological dependence can be treated with therapy. (see Sedative Dependence).
# Abuse and Overdoses
All sedatives can be abused, but barbiturates and benzodiazepines are responsible for most of the problems with sedative abuse due to their widespread "recreational" or non-medical use. People who have difficulty dealing with stress, anxiety or sleeplessness may overuse or become dependent on sedatives. Heroin users take them either to supplement their drug or to substitute for it. Stimulant users frequently take sedatives to calm excessive jitteriness. Others take sedatives recreationally to relax and forget their worries. Barbiturate overdose is a factor in nearly one-third of all reported drug-related deaths. These include suicides and accidental drug poisonings. Accidental deaths sometimes occur when a drowsy, confused user repeats doses, or when sedatives are taken with alcohol. In the U.S., in 1998, a total of 70,982 sedative exposures were reported to U.S. poison control centers, of which 2310 (3.2%) resulted in major toxicity and 89 (0.1%) resulted in death. About half of all the people admitted to emergency rooms in the U.S. as a result of nonmedical use of sedatives have a legitimate prescription for the drug, but have taken an excessive dose or combined it with alcohol or other drugs.
See also Other non-therapeutic use.
# Sedatives and Alcohol
Sedatives and alcohol are sometimes combined recreationally or carelessly. Since alcohol is a strong depressant that slows brain function and depresses respiration, the two substances compound each other's actions synergistically and this combination can prove fatal.
# Lookalikes
Lookalikes, or pills made to mimic the appearance and the effects of authentic sedatives, are sold on the street. Lookalikes may contain over-the-counter drugs, such as antihistamines, that cause drowsiness. Since the actual composition is unknown, neither the intensity of the primary effect nor the range of side effects can be predicted.
# Sedatives and Amnesia
Sedation can sometimes leave the patient with long-term or short-term amnesia.
Lorazepam is one such pharmacological agent that can cause anterograde amnesia. Intensive care unit patients who receive higher doses over longer periods of time, typically via IV drip, are more likely to experience such side effects.
# Sedative Drugs and Crime
The sedatives GHB, Flunitrazepam (Rohypnol), and to a lesser extent, temazepam (Restoril), and midazolam (Versed)[1] are known for their use as date rape drugs (also called a Mickey), administered to unsuspecting patrons in bars or guests at parties to reduce the intended victims' defenses. These drugs are also used for robbing people, indeed statistical overviews suggest that the use of sedative-spiked drinks for robbing people is actually much more common than their use for rape.[2]
Cases of criminals taking rohypnol themselves before they commit crimes have also been reported, as the loss of inhibitions from the drug may increase their confidence to commit the offence, and the amnesia produced by the drug makes it difficult for police to interrogate them if they are caught.
# Sedative Withdrawal
## Differential Diagnosis
- Alcohol withdrawal
- Anxiety disorders
- Essential tremor
- Hypoglycemia
- Diabetic ketoacidosis
- Seizure due to infections, head injury, poisonings[3]
## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Withdrawal[3]
# Sedative Intoxication
## Differential Diagnosis
- Alcohol use disorders
- Alcohol intoxication
- Delirium
- Traumatic brain injury[3]
## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Intoxication[3]
# Sedative Use Disorder
## Differential Diagnosis
- Alcohol use disorder
- Clinically appropriate use of the medication
- Generalized anxiety disorder
- Multiple sclerosis
- Subdural hematoma[3]
## Risk Factors
- Availability of the substances
- Alcohol use disorder
- Environmental factors
- Early onset of use
- Genetic predisposition
- Peer use of the substance[3]
## DSM-V Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder[3] | https://www.wikidoc.org/index.php/Sedative | |
224321a0edd4eb211c455a927184effca2632197 | wikidoc | Sediment | Sediment
Sediment is any particulate matter that can be transported by fluid flow and which eventually is deposited as a layer of solid particles on the bed or bottom of a body of water or other liquid. Sedimentation is the deposition by settling of a suspended material.
Sediments are also transported by wind (aeolian processes) and glaciers. Desert sand dunes and loess are examples of aeolian transport and deposition. Glacial moraine deposits and till are ice transported sediments. Simple gravitational collapse also creates sediments such as talus and mountainslide deposits as well as karst collapse features. Each sediment type has different settling velocities, depending on size, volume, density, and shape.
Seas, oceans, and lakes accumulate sediment over time. These materials can be terrestrial (deposited on the land) or marine (deposited in the ocean); terrigenous deposits originate on land, but may be deposited in either terrestrial, marine, or lacustrine (lake) environments. Deposited sediments are the source of sedimentary rocks, which can contain fossils of the inhabitants of the body of water that were, upon death, covered by accumulating sediment. Lake bed sediments that have not solidified into rock can be used to determine past climatic conditions.
# Sediment transport
## Rivers and streams
For a fluid to begin transporting sediment, the bed shear stress exerted by the fluid must exceed the critical shear stress of the bed. Once this critical stress is exceeded, the way in which the sediment is transported depends on the characteristics of the sediment and the fluid. If a fluid, such as water, is flowing, it can carry suspended particles. The settling velocity is the minimum velocity a flow must have in order to transport, rather than deposit, sediments, and (for a dilute suspension) is given by Stokes' Law:
where w is the settling velocity, ρ is density (the subscripts p and f indicate particle and fluid respectively), g is the acceleration due to gravity, r is the radius of the particle and μ is the dynamic viscosity of the fluid. This equation is only valid for particle Reynold's numbers <1.
If the flow velocity is greater than the settling velocity, sediment will be transported downstream as suspended load. As there will always be a range of different particle sizes in the flow, some will have sufficiently large diameters that they settle on the river or stream bed, but still move downstream. This is known as bed load and the particles are transported via such mechanisms as saltation (jumping up into the flow, being transported a short distance then settling again), rolling and sliding. Saltation marks are often preserved in solid rocks and can be used to estimate the flow rate of the rivers that originally deposited the sediments.
The overall balance between sediment in transport and sediment being deposited on the bed is given by the Exner equation. This equation is important in that changes in flow depth and slope (see: depth-slope product) will change the basal shear stress, thus causing local areas of erosion and deposition. More large-scale changes such as dam emplacement and removal and sea-level variation change Base level and cause the river to either pool (and deposit its entire load) or rapidly erode into its underlying substrate.
Early applications of mathematical modeling of sediment transport in riverine systems were observed in the late 1970s. One such application was conducted by Santa Cruz County for the San Lorenzo River to study erosion from surface runoff and the resulting turbidity and bedload transport to downstream reaches. This work was used to analyze effects of land use practices in this drainage basin.
One of the main causes of riverine sediment load siltation stems from slash and burn treatment of tropical forests. When the ground surface is stripped of vegetation and then seared of all living organisms, the upper soils are vulnerable to both wind and water erosion. In a number of regions of the earth, entire sectors of a country have been rendered erosive; for example, on the Madagascar high central plateau, comprising approximately ten percent of that country's land area, virtually the entire landscape is sterile of vegetation, with gully erosive furrows typically in excess of 50 meters deep and one kilometer wide. Shifting cultivation is a farming system which sometimes incorporates the slash and burn method in some regions of the world. The resulting sediment load in rivers flowing to the west is ongoing, with most rivers a dark red brown colour, also leading to massive fish kills.
## Surface runoff
Surface runoff water can pick up soil particles and transport them in overland flow for deposition at a lower land elevation or deliver that sediment to receiving waters. In this case the sediment is usually deemed to result from erosion. If the initial impact of rain droplets dislodges soil, the phenomenon is called splash erosion". If the effects are diffuse for a larger area and the velocity of moving runoff is responsible for sediment pickup, the effect is called "sheet erosion". If there are massive gouges in the earth from high velocity flow for uncovered soil, then "gully erosion" may result.
### Fluvial bedforms
Any particle that is larger in diameter than approximately 0.7 mm will form visible topographic features on the river or stream bed. These are known as and include ripples, dunes, plane beds and antidunes. See bedforms for more detail. Again, bedforms are often preserved in sedimentary rocks and can be used to estimate the direction and magnitude of the depositing flow.
### Key depositional environments
The major fluvial (river and stream) environments for deposition of sediments include:
- Deltas (arguably an intermediate environment between fluvial and marine)
- Point-bars
- Alluvial fans
- Braided rivers
- Oxbow lakes
- Levees
# Shores and shallow seas
The second major environment where sediment may be suspended in a fluid is in seas and oceans. The sediment could consist of terrigenous material supplied by nearby rivers and streams or reworked marine sediment (e.g. sand). In the mid-ocean, living organisms are primarily responsible for the sediment accumulation, their shells sinking to the ocean floor upon death.
### Marine bedforms
Marine environments also see the formation of bedforms, whose characteristics are influenced by the tides or currents.
### Key depositional environments
The major areas for deposition of sediments in the marine environment include:
- Littoral sands (e.g. beach sands, runoff river sands, coastal bars and spits, largely clastic with little faunal content)
- The continental shelf (silty clays, increasing marine faunal content).
- The shelf margin (low terrigenous supply, mostly calcareous faunal skeletons)
- The shelf slope (much more fine-grained silts and clays)
- Beds of estuaries with the resultant deposits called "bay mud".
One other depositional environment which is a mixture of fluvial and marine is the turbidite system, which is a major source of sediment to the deep sedimentary and abyssal basins as well as the deep oceanic trenches. | Sediment
Sediment is any particulate matter that can be transported by fluid flow and which eventually is deposited as a layer of solid particles on the bed or bottom of a body of water or other liquid. Sedimentation is the deposition by settling of a suspended material.
Sediments are also transported by wind (aeolian processes) and glaciers. Desert sand dunes and loess are examples of aeolian transport and deposition. Glacial moraine deposits and till are ice transported sediments. Simple gravitational collapse also creates sediments such as talus and mountainslide deposits as well as karst collapse features. Each sediment type has different settling velocities, depending on size, volume, density, and shape.
Seas, oceans, and lakes accumulate sediment over time. These materials can be terrestrial (deposited on the land) or marine (deposited in the ocean); terrigenous deposits originate on land, but may be deposited in either terrestrial, marine, or lacustrine (lake) environments. Deposited sediments are the source of sedimentary rocks, which can contain fossils of the inhabitants of the body of water that were, upon death, covered by accumulating sediment. Lake bed sediments that have not solidified into rock can be used to determine past climatic conditions.
# Sediment transport
## Rivers and streams
For a fluid to begin transporting sediment, the bed shear stress exerted by the fluid must exceed the critical shear stress of the bed. Once this critical stress is exceeded, the way in which the sediment is transported depends on the characteristics of the sediment and the fluid. If a fluid, such as water, is flowing, it can carry suspended particles. The settling velocity is the minimum velocity a flow must have in order to transport, rather than deposit, sediments, and (for a dilute suspension) is given by Stokes' Law:
where w is the settling velocity, ρ is density (the subscripts p and f indicate particle and fluid respectively), g is the acceleration due to gravity, r is the radius of the particle and μ is the dynamic viscosity of the fluid. This equation is only valid for particle Reynold's numbers <1.
If the flow velocity is greater than the settling velocity, sediment will be transported downstream as suspended load. As there will always be a range of different particle sizes in the flow, some will have sufficiently large diameters that they settle on the river or stream bed, but still move downstream. This is known as bed load and the particles are transported via such mechanisms as saltation (jumping up into the flow, being transported a short distance then settling again), rolling and sliding. Saltation marks are often preserved in solid rocks and can be used to estimate the flow rate of the rivers that originally deposited the sediments.
The overall balance between sediment in transport and sediment being deposited on the bed is given by the Exner equation. This equation is important in that changes in flow depth and slope (see: depth-slope product) will change the basal shear stress, thus causing local areas of erosion and deposition. More large-scale changes such as dam emplacement and removal and sea-level variation change Base level and cause the river to either pool (and deposit its entire load) or rapidly erode into its underlying substrate.
Early applications of mathematical modeling of sediment transport in riverine systems were observed in the late 1970s. One such application was conducted by Santa Cruz County for the San Lorenzo River to study erosion from surface runoff and the resulting turbidity and bedload transport to downstream reaches. This work was used to analyze effects of land use practices in this drainage basin.
One of the main causes of riverine sediment load siltation stems from slash and burn treatment of tropical forests. When the ground surface is stripped of vegetation and then seared of all living organisms, the upper soils are vulnerable to both wind and water erosion. In a number of regions of the earth, entire sectors of a country have been rendered erosive; for example, on the Madagascar high central plateau, comprising approximately ten percent of that country's land area, virtually the entire landscape is sterile of vegetation, with gully erosive furrows typically in excess of 50 meters deep and one kilometer wide. Shifting cultivation is a farming system which sometimes incorporates the slash and burn method in some regions of the world. The resulting sediment load in rivers flowing to the west is ongoing, with most rivers a dark red brown colour, also leading to massive fish kills.
## Surface runoff
Surface runoff water can pick up soil particles and transport them in overland flow for deposition at a lower land elevation or deliver that sediment to receiving waters. In this case the sediment is usually deemed to result from erosion. If the initial impact of rain droplets dislodges soil, the phenomenon is called splash erosion". If the effects are diffuse for a larger area and the velocity of moving runoff is responsible for sediment pickup, the effect is called "sheet erosion". If there are massive gouges in the earth from high velocity flow for uncovered soil, then "gully erosion" may result.
### Fluvial bedforms
Any particle that is larger in diameter than approximately 0.7 mm will form visible topographic features on the river or stream bed. These are known as and include ripples, dunes, plane beds and antidunes. See bedforms for more detail. Again, bedforms are often preserved in sedimentary rocks and can be used to estimate the direction and magnitude of the depositing flow.
### Key depositional environments
The major fluvial (river and stream) environments for deposition of sediments include:
- Deltas (arguably an intermediate environment between fluvial and marine)
- Point-bars
- Alluvial fans
- Braided rivers
- Oxbow lakes
- Levees
# Shores and shallow seas
The second major environment where sediment may be suspended in a fluid is in seas and oceans. The sediment could consist of terrigenous material supplied by nearby rivers and streams or reworked marine sediment (e.g. sand). In the mid-ocean, living organisms are primarily responsible for the sediment accumulation, their shells sinking to the ocean floor upon death.
### Marine bedforms
Marine environments also see the formation of bedforms, whose characteristics are influenced by the tides or currents.
### Key depositional environments
The major areas for deposition of sediments in the marine environment include:
- Littoral sands (e.g. beach sands, runoff river sands, coastal bars and spits, largely clastic with little faunal content)
- The continental shelf (silty clays, increasing marine faunal content).
- The shelf margin (low terrigenous supply, mostly calcareous faunal skeletons)
- The shelf slope (much more fine-grained silts and clays)
- Beds of estuaries with the resultant deposits called "bay mud".
One other depositional environment which is a mixture of fluvial and marine is the turbidite system, which is a major source of sediment to the deep sedimentary and abyssal basins as well as the deep oceanic trenches. | https://www.wikidoc.org/index.php/Sediment | |
7663e990186f928d496ab95273f738e668b5218f | wikidoc | Selectin | Selectin
Selectins are a family of cell adhesion molecules (or CAM's). All selectins are single-chain transmembrane glycoproteins which share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding.
# Types
There are three subsets of selectins:
- E-selectin (in endothelial cells)
- L-selectin (in leukocytes)
- P-selectin (in platelets and endothelial cells)
# Etymology
The name selectin comes from the words "selected" and "lectins" which are a type of carbohydrate recognizing proteins.
# Function
During an inflammatory response stimuli such as histamine and thrombin cause endothelial cells to mobilize P-selectin from stores inside the cell to the cell surface. In addition, cytokines such as TNF-alpha stimulate the expression of E-selectin and additional P-selectin a few hours later.
As the leukocyte rolls along the blood vessel wall, the distal lectin-like domain of the selectin binds to certain carbohydrate groups presented on proteins (such as PSGL-1) on the leukocyte, which slows the cell and allows it to leave the blood vessel and enter the site of infection. The low-affinity nature of selectins is what allows the characteristic "rolling" action attributed to leukocytes during the leukocyte adhesion cascade.
The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-1), which is a mucin-type glycoprotein expressed on all white blood cells.
Neutrophils and eosinophils bind to E-selectin. One of the reported ligands for E-selectin is the sialylated Lewis X Ag (sLe(x)). Eosinophils, like neutrophils, use sialylated, protease-resistant structures to bind to E-selectin, although the eosinophil expresses much lower levels of these structures on its surface.
Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different than those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses. | Selectin
Selectins are a family of cell adhesion molecules (or CAM's). All selectins are single-chain transmembrane glycoproteins which share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding[1].
# Types
There are three subsets of selectins:
- E-selectin (in endothelial cells)
- L-selectin (in leukocytes)
- P-selectin (in platelets and endothelial cells)
# Etymology
The name selectin comes from the words "selected" and "lectins" which are a type of carbohydrate recognizing proteins.
# Function
During an inflammatory response stimuli such as histamine and thrombin cause endothelial cells to mobilize P-selectin from stores inside the cell to the cell surface. In addition, cytokines such as TNF-alpha stimulate the expression of E-selectin and additional P-selectin a few hours later.
As the leukocyte rolls along the blood vessel wall, the distal lectin-like domain of the selectin binds to certain carbohydrate groups presented on proteins (such as PSGL-1) on the leukocyte, which slows the cell and allows it to leave the blood vessel and enter the site of infection. The low-affinity nature of selectins is what allows the characteristic "rolling" action attributed to leukocytes during the leukocyte adhesion cascade[1].
The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-1), which is a mucin-type glycoprotein expressed on all white blood cells.
Neutrophils and eosinophils bind to E-selectin. One of the reported ligands for E-selectin is the sialylated Lewis X Ag (sLe(x)). Eosinophils, like neutrophils, use sialylated, protease-resistant structures to bind to E-selectin, although the eosinophil expresses much lower levels of these structures on its surface. [2]
Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different than those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses.
[3]
# External links
- Computer-generated movie of the mobilization of P-selectin inside a leukocyte at mcb.harvard.edu | https://www.wikidoc.org/index.php/Selectin | |
c53526ea08671ed8c035deda09bd3290775a7ca7 | wikidoc | Separase | Separase
Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.
# Discovery
In S. cerevisiae, separase is encoded by the esp1 gene. Esp1 was discovered by Kim Nasmyth and coworkers in 1998.
# Function
Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for cell division and chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 or STAG2 in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21) by separase, which initiates the final separation of sister chromatids.
In S. cerevisiae, Esp1 is coded by ESP1 and is regulated by the securin Pds1. The two sister chromatids are initially bound together by the cohesin complex until the beginning of anaphase, at which point the mitotic spindle pulls the two sister chromatids apart, leaving each of the two daughter cells with an equivalent number of sister chromatids. The proteins that bind the two sister chromatids, disallowing any premature sister chromatid separation, are a part of the cohesin protein family. One of these cohesin proteins crucial for sister chromatid cohesion is Scc1. Esp1 is a separase protein that cleaves the cohesin subunit Scc1 (RAD21), allowing sister chromatids to separate at the onset of anaphase during mitosis.
# Regulation
When the cell is not dividing, separase is prevented from cleaving cohesin through its association with another protein, securin, as well as phosphorylation by the cyclin-CDK complex. This provides two layers of negative regulation to prevent inappropriate cohesin cleavage. Note that separase cannot function without initially forming the securin-separase complex in most organisms. This is because securin helps properly fold separase into the functional conformation. However, yeast does not appear to require securin to form functional separase because anaphase occurs in yeast even with a securin deletion.
On the signal for anaphase, securin is ubiquitinated and hydrolysed, releasing separase for dephosphorylation by the APC-Cdc20 complex. Active separase can then cleave Scc1 for release of the sister chromatids.
Separase initiates the activation of Cdc14 in early anaphase and Cdc14 has been found to dephosphorylate securin, thereby increasing its efficiency as a substrate for degradation. The presence of this positive feedback loop offers a potential mechanism for giving anaphase a more switch-like behavior. | Separase
Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase.[1] In humans, separin is encoded by the ESPL1 gene.[2]
# Discovery
In S. cerevisiae, separase is encoded by the esp1 gene. Esp1 was discovered by Kim Nasmyth and coworkers in 1998.[3][4]
# Function
Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for cell division and chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 or STAG2 in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21) by separase, which initiates the final separation of sister chromatids.[6]
In S. cerevisiae, Esp1 is coded by ESP1 and is regulated by the securin Pds1. The two sister chromatids are initially bound together by the cohesin complex until the beginning of anaphase, at which point the mitotic spindle pulls the two sister chromatids apart, leaving each of the two daughter cells with an equivalent number of sister chromatids. The proteins that bind the two sister chromatids, disallowing any premature sister chromatid separation, are a part of the cohesin protein family. One of these cohesin proteins crucial for sister chromatid cohesion is Scc1. Esp1 is a separase protein that cleaves the cohesin subunit Scc1 (RAD21), allowing sister chromatids to separate at the onset of anaphase during mitosis.[4]
# Regulation
When the cell is not dividing, separase is prevented from cleaving cohesin through its association with another protein, securin, as well as phosphorylation by the cyclin-CDK complex. This provides two layers of negative regulation to prevent inappropriate cohesin cleavage. Note that separase cannot function without initially forming the securin-separase complex in most organisms. This is because securin helps properly fold separase into the functional conformation. However, yeast does not appear to require securin to form functional separase because anaphase occurs in yeast even with a securin deletion.[5]
On the signal for anaphase, securin is ubiquitinated and hydrolysed, releasing separase for dephosphorylation by the APC-Cdc20 complex. Active separase can then cleave Scc1 for release of the sister chromatids.
Separase initiates the activation of Cdc14 in early anaphase[8] and Cdc14 has been found to dephosphorylate securin, thereby increasing its efficiency as a substrate for degradation. The presence of this positive feedback loop offers a potential mechanism for giving anaphase a more switch-like behavior.[7] | https://www.wikidoc.org/index.php/Separase | |
f997c3cdc0b9b2dafc43385984ac648a401044a8 | wikidoc | Serology | Serology
Serology is the scientific study of blood serum. In practice, the term usually refers to the diagnostic identification of antibodies in the serum. Such antibodies are typically formed in response to an infection (against a given microorganism), against other foreign proteins (in response, for example, to a mismatched blood transfusion), or to one's own proteins (in instances of autoimmune disease).
Serological tests may be performed for diagnostic purposes when an infection is suspected, in rheumatic illnesses, and in many other situations, such as checking an individual's blood type.
Serology blood tests help to diagnose patients with certain immune deficiencies associated with the lack of antibodies, such as X-linked agammaglobulinemia. In such cases, tests for antibodies will be consistently negative.
There are several serology techniques that can be used depending on the antibodies being studied. These include agglutination, precipitation, complement-fixation and fluorescent antibodies.
Some serological tests are not limited to blood serum, but can also be performed on other bodily fluids such as semen and saliva, which have (roughly) similar properties to serum.
Serological tests may also be used forensically, generally to link a perpetrator to a piece of evidence (e.g., linking a rapist to a semen sample). | Serology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Serology is the scientific study of blood serum. In practice, the term usually refers to the diagnostic identification of antibodies in the serum.[1] Such antibodies are typically formed in response to an infection (against a given microorganism)[2], against other foreign proteins (in response, for example, to a mismatched blood transfusion), or to one's own proteins (in instances of autoimmune disease).
Serological tests may be performed for diagnostic purposes when an infection is suspected, in rheumatic illnesses, and in many other situations, such as checking an individual's blood type.[1]
Serology blood tests help to diagnose patients with certain immune deficiencies associated with the lack of antibodies, such as X-linked agammaglobulinemia. In such cases, tests for antibodies will be consistently negative.
There are several serology techniques that can be used depending on the antibodies being studied. These include agglutination, precipitation, complement-fixation and fluorescent antibodies.
Some serological tests are not limited to blood serum, but can also be performed on other bodily fluids such as semen and saliva, which have (roughly) similar properties to serum.
Serological tests may also be used forensically, generally to link a perpetrator to a piece of evidence (e.g., linking a rapist to a semen sample). | https://www.wikidoc.org/index.php/Serologic | |
02b0060787e4ff8cf43e81503aa7195daade7a03 | wikidoc | Serotype | Serotype
# Overview
For the term's use in bacteriology, see serovar.
# Serotype (Allograft)
Transplants between genetically non-identical humans induce the creation of antibodies in the recipient. These non-identical cell-surface receptors between the donor and recipient produce antiserum reactive to the donor proteins. Under selection conditions
-ne or two isoform specificities are obtained. This results in a serotype that is capable of identifying other individuals who have those proteins. This serotyping along
with new-PCR based techniques are how tissues for organ-donor programs are characterized.
(for more detailed information see Human leukocyte antigens and HLA Serotype tutorial) | Serotype
# Overview
For the term's use in bacteriology, see serovar.
# Serotype (Allograft)
Transplants between genetically non-identical humans induce the creation of antibodies in the recipient. These non-identical cell-surface receptors between the donor and recipient produce antiserum reactive to the donor proteins. Under selection conditions
one or two isoform specificities are obtained. This results in a serotype that is capable of identifying other individuals who have those proteins. This serotyping along
with new-PCR based techniques are how tissues for organ-donor programs are characterized.
(for more detailed information see Human leukocyte antigens and HLA Serotype tutorial)
# External links
- Molecular Anthropology Yahoo Group
- HLA Allele and Haplotype Frequency Database
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Serotype | |
9615077dc70fdcbd97fc69bec7e48badb44bc915 | wikidoc | Shigella | Shigella
# Overview
Shigella is a genus of Gram-negative, facultative anaerobic, nonspore-forming, nonmotile, rod-shaped bacteria closely related to Salmonella. The genus is named after Kiyoshi Shiga, who first discovered it in 1897.
The causative agent of human shigellosis, Shigella causes disease in primates, but not in other mammals. It is only naturally found in humans and apes. During infection, it typically causes dysentery.
Shigella is one of the leading bacterial causes of diarrhea worldwide. Insufficient data exist, but conservative estimates suggest Shigella causes about 90 million cases of severe dysentery, with at least 100,000 of these resulting in death each year, mostly among children in the developing world.
# Classification
Shigella species are classified by four serogroups:
- Serogroup A: S. dysenteriae (15 serotypes)
- Serogroup B: S. flexneri (six serotypes)
- Serogroup C: S. boydii (19 serotypes)
- Serogroup D: S. sonnei (one serotype)
Groups A–C are physiologically similar; S. sonnei (group D) can be differentiated on the basis of biochemical metabolism assays. Three Shigella groups are the major disease-causing species: S. flexneri is the most frequently isolated species worldwide, and accounts for 60% of cases in the developing world; S. sonnei causes 77% of cases in the developed world, compared to only 15% of cases in the developing world; and S. dysenteriae is usually the cause of epidemics of dysentery, particularly in confined populations such as refugee camps.
Each of the Shigella genomes includes a virulence plasmid that encodes conserved primary virulence determinants. The Shigella chromosomes share most of their genes with those of E. coli K12 strain MG1655. Phylogenetic studies indicate Shigella is more appropriately treated as subgenus of Escherichia, and that certain strains generally considered E. coli – such as E. coli O157:H7 – are better placed in Shigella.
# Pathogenesis
Shigella infection is typically by ingestion (fecal–oral contamination); depending on age and condition of the host, fewer than 100 bacterial cells can be enough to cause an infection. Shigella causes dysentery that results in the destruction of the epithelial cells of the intestinal mucosa in the cecum and rectum. Some strains produce the enterotoxin shiga toxin, which is similar to the verotoxin of E. coli O157:H7 and other verotoxin-producing E. coli. Both shiga toxin and verotoxin are associated with causing hemolytic uremic syndrome. As noted above, these supposed E. coli strains are at least in part actually more closely related to Shigella than to the "typical" E. coli.
Shigella species invade the host through the M-cells interspersed in the gut epithelia of the small intestine, as they do not interact with the apical surface of epithelial cells, preferring the basolateral side. Shigella uses a type-III secretion system, which acts as a biological syringe to translocate toxic effector proteins to the target human cell. The effector proteins can alter the metabolism of the target cell, for instance leading to the lysis of vacuolar membranes or reorganization of actin polymerization to facilitate intracellular motility of Shigella bacteria inside the host cell. For instance, the IcsA effector protein triggers actin reorganization by N-WASP recruitment of Arp2/3 complexes, helping cell-to-cell spread.
After invasion, Shigella cells multiply intracellularly and spread to neighboring epithelial cells, resulting in tissue destruction and characteristic pathology of shigellosis.
The most common symptoms are diarrhea, fever, nausea, vomiting, stomach cramps, and flatulence. It is also commonly known to cause large and painful bowel movements. The stool may contain blood, mucus, or pus. Hence, Shigella cells may cause dysentery. In rare cases, young children may have seizures. Symptoms can take as long as a week to appear, but most often begin two to four days after ingestion. Symptoms usually last for several days, but can last for weeks. Shigella is implicated as one of the pathogenic causes of reactive arthritis worldwide.
# Diagnosis
The diagnosis of shigellosis is made by isolating the organism from diarrheal fecal sample cultures. Shigella species are negative for motility and are generally not lactose fermenters, but S. sonnei can ferment lactose. They typically do not produce gas from carbohydrates (with the exception of certain strains of S. flexneri) and tend to be overall biochemically inert. Shigella should also be urea hydrolysis negative . When inoculated to a triple sugar iron (TSI) slant, they react as follows: K/A, gas -, and H2S -. Indole reactions are mixed, positive and negative, with the exception of S. sonnei, which is always indole negative. Growth on Hektoen enteric agar will produce bluish-green colonies for Shigella and bluish-green colonies with black centers for Salmonella.
# Prevention and treatment
Hand washing before handling food and thoroughly cooking all food before eating decreases the risk of getting shigellosis.
Severe dysentery can be treated with ampicillin, TMP-SMX, or fluoroquinolones, such as ciprofloxacin, and of course rehydration. Medical treatment should only be used in severe cases or for certain populations with mild symptoms (elderly, immunocompromised, food service industry workers, child care workers). Antibiotics are usually avoided in mild cases because some Shigella species are resistant to antibiotics, and their use may make the bacteria even more resistant. Antidiarrheal agents may worsen the sickness, and should be avoided. For Shigella-associated diarrhea, antibiotics shorten the length of infection.
Currently, no licenced vaccine targeting Shigella exists. Shigella has been a longstanding World Health Organization target for vaccine development, and sharp declines in age-specific diarrhea/dysentery attack rates for this pathogen indicate natural immunity does develop following exposure; thus, vaccination to prevent the disease should be feasible. Several vaccine candidates for Shigella are in various stages of development.
Also extensive research has been conducted into therapies, involving treatment with bacteriophages, as described in. | Shigella
Template:Seealso
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Shigella is a genus of Gram-negative, facultative anaerobic, nonspore-forming, nonmotile, rod-shaped bacteria closely related to Salmonella. The genus is named after Kiyoshi Shiga, who first discovered it in 1897.[1]
The causative agent of human shigellosis, Shigella causes disease in primates, but not in other mammals.[2][page needed] It is only naturally found in humans and apes.[3][4] During infection, it typically causes dysentery.[5]
Shigella is one of the leading bacterial causes of diarrhea worldwide. Insufficient data exist, but conservative estimates suggest Shigella causes about 90 million cases of severe dysentery, with at least 100,000 of these resulting in death each year, mostly among children in the developing world.[6]
# Classification
Shigella species are classified by four serogroups:
- Serogroup A: S. dysenteriae (15 serotypes)[7]
- Serogroup B: S. flexneri (six serotypes)
- Serogroup C: S. boydii (19 serotypes)[8]
- Serogroup D: S. sonnei (one serotype)
Groups A–C are physiologically similar; S. sonnei (group D) can be differentiated on the basis of biochemical metabolism assays.[9] Three Shigella groups are the major disease-causing species: S. flexneri is the most frequently isolated species worldwide, and accounts for 60% of cases in the developing world; S. sonnei causes 77% of cases in the developed world, compared to only 15% of cases in the developing world; and S. dysenteriae is usually the cause of epidemics of dysentery, particularly in confined populations such as refugee camps.[6]
Each of the Shigella genomes includes a virulence plasmid that encodes conserved primary virulence determinants. The Shigella chromosomes share most of their genes with those of E. coli K12 strain MG1655.[10] Phylogenetic studies indicate Shigella is more appropriately treated as subgenus of Escherichia, and that certain strains generally considered E. coli – such as E. coli O157:H7 – are better placed in Shigella.
# Pathogenesis
Shigella infection is typically by ingestion (fecal–oral contamination); depending on age and condition of the host, fewer than 100 bacterial cells can be enough to cause an infection.[11] Shigella causes dysentery that results in the destruction of the epithelial cells of the intestinal mucosa in the cecum and rectum. Some strains produce the enterotoxin shiga toxin, which is similar to the verotoxin of E. coli O157:H7[9] and other verotoxin-producing E. coli. Both shiga toxin and verotoxin are associated with causing hemolytic uremic syndrome. As noted above, these supposed E. coli strains are at least in part actually more closely related to Shigella than to the "typical" E. coli.
Shigella species invade the host through the M-cells interspersed in the gut epithelia of the small intestine, as they do not interact with the apical surface of epithelial cells, preferring the basolateral side.[12] Shigella uses a type-III secretion system, which acts as a biological syringe to translocate toxic effector proteins to the target human cell. The effector proteins can alter the metabolism of the target cell, for instance leading to the lysis of vacuolar membranes or reorganization of actin polymerization to facilitate intracellular motility of Shigella bacteria inside the host cell. For instance, the IcsA effector protein triggers actin reorganization by N-WASP recruitment of Arp2/3 complexes, helping cell-to-cell spread.
After invasion, Shigella cells multiply intracellularly and spread to neighboring epithelial cells, resulting in tissue destruction and characteristic pathology of shigellosis.[13][14]
The most common symptoms are diarrhea, fever, nausea, vomiting, stomach cramps, and flatulence. It is also commonly known to cause large and painful bowel movements. The stool may contain blood, mucus, or pus. Hence, Shigella cells may cause dysentery. In rare cases, young children may have seizures. Symptoms can take as long as a week to appear, but most often begin two to four days after ingestion. Symptoms usually last for several days, but can last for weeks. Shigella is implicated as one of the pathogenic causes of reactive arthritis worldwide.[15]
# Diagnosis
The diagnosis of shigellosis is made by isolating the organism from diarrheal fecal sample cultures. Shigella species are negative for motility and are generally not lactose fermenters, but S. sonnei can ferment lactose.[16] They typically do not produce gas from carbohydrates (with the exception of certain strains of S. flexneri) and tend to be overall biochemically inert. Shigella should also be urea hydrolysis negative . When inoculated to a triple sugar iron (TSI) slant, they react as follows: K/A, gas -, and H2S -. Indole reactions are mixed, positive and negative, with the exception of S. sonnei, which is always indole negative. Growth on Hektoen enteric agar will produce bluish-green colonies for Shigella and bluish-green colonies with black centers for Salmonella.
# Prevention and treatment
Hand washing before handling food and thoroughly cooking all food before eating decreases the risk of getting shigellosis.[17]
Severe dysentery can be treated with ampicillin, TMP-SMX, or fluoroquinolones, such as ciprofloxacin, and of course rehydration. Medical treatment should only be used in severe cases or for certain populations with mild symptoms (elderly, immunocompromised, food service industry workers, child care workers). Antibiotics are usually avoided in mild cases because some Shigella species are resistant to antibiotics, and their use may make the bacteria even more resistant. Antidiarrheal agents may worsen the sickness, and should be avoided.[18] For Shigella-associated diarrhea, antibiotics shorten the length of infection.[19]
Currently, no licenced vaccine targeting Shigella exists. Shigella has been a longstanding World Health Organization target for vaccine development, and sharp declines in age-specific diarrhea/dysentery attack rates for this pathogen indicate natural immunity does develop following exposure; thus, vaccination to prevent the disease should be feasible. Several vaccine candidates for Shigella are in various stages of development.[6]
Also extensive research has been conducted into therapies, involving treatment with bacteriophages, as described in.[20] | https://www.wikidoc.org/index.php/Shigella | |
df8add3fa92fd2a0cdc7076926a9b583b320ded5 | wikidoc | Shoulder | Shoulder
In human anatomy, the shoulder comprises the part of the body where the arm attaches to the torso. It is made up of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder make up the shoulder joints. The shoulder must be flexible for the wide range of motion required in the arms and hands and also strong enough to allow for actions such as lifting, pushing and pulling. The compromise between these two functions results in a large number of shoulder problems not faced by other joints such as the hip.
# Joints of the shoulder
There are three joints of the shoulder: The glenohumeral, acromioclavicular, and the sternoclavicular joints.
## Glenohumeral joint
The glenohumeral joint is the main joint of the shoulder and the generic term "shoulder joint" usually refers to it. It is a ball and socket joint that allows the arm to rotate in a circular fashion or to hinge out and up away from the body. It is formed by the articulation between the head of the humerus and the lateral scapula. The "ball" of the joint is the rounded, medial anterior surface of the humerus and the "socket" is formed by the glenoid fossa, the dish-shaped portion of the lateral scapula. The shallowness of the fossa and relatively loose connections between the shoulder and the rest of the body allows the arm to have tremendous mobility, at the expense of being much easier to dislocate than most other joints in the body.
The capsule is a soft tissue envelope that encircles the glenohumeral joint and attaches to the scapula, humerus, and head of the biceps. It is lined by a thin, smooth synovial membrane. This capsule is strengthened by the coracohumeral ligament which attaches the coracoid process of the scapula to the greater tubercle of the humerus. There are also three other ligaments attaching the lesser tubercle of the humerus to lateral scapula and are collectively called the glenohumeral ligaments.
There is also a ligament called semicirculare humeri which is a transversal band between the posterior sides of the tuberculum minus and majus of the humerus. This band is one of the most important strengtening ligaments of the joint capsule.
## Acromioclavicular joint
The acromioclavicular (AC) joint is located between the acromion process of the scapula (part of the scapula that forms the highest point of the shoulder) and the distal end of the clavicle.
The capsule of this joint is reinforced by the coracoclavicular ligament between the scapula and clavicle at the point of articulation. The coracoclavicular ligament in further detail is created by the conoid ligament, medial from the coracoid process of the scapula and inserts on the conoid tubercle of the clavicle. Lateral to the conoid ligament is the trapezoid ligament, which runs from the coracoid process of the scapula to the trapezoid line of the clavicle. One more ligament, the coracoacromial ligament, running from the corocoid process to the acromion of the scapula contributes to the integrity of the acromioclavicular joint.
## Sternoclavicular joint
The sternoclavicular occurs at the medial end of the clavicle with the manubrium or top most portion of the sternum. The clavicle is triangular and rounded and the manubrium is convex the two bones articulate.
# Movements of the shoulder
The muscles and joints of the shoulder allow it to move through a remarkable range of motion, making it the most mobile joint in the human body. The shoulder can abduct, adduct (such as during the shoulder fly), rotate, be raised in front of and behind the torso and move through a full 360° in the sagittal plane. This tremendous range of motion also makes the shoulder extremely unstable, far more prone to dislocation and injury than other joints.
# Major muscles
The muscles that are responsible for movement in the shoulder attach to the scapula, humerus, and clavicle. The muscles that surround the shoulder form the shoulder cap and underarm.
# Rotator cuff
The rotator cuff is a structure composed of tendons that, with associated muscles (supraspinatus, infraspinatus, teres minor and subscapularis), holds the ball at the top of the humerus in the glenoid socket and provideoulder joint. The tendons of the rotator cuff muscles also connect to the capsule of the glenohumeral joint.
Two filmy sac-like structures called bursae permit smooth gliding between bone, muscle, and tendon. They cushion and protect the rotator cuff from the bony arch of the acromion.
# Measurement of shoulder loads
For understanding normal and pathologic shoulder function knowledge of forces in the glenohumeral joint is essential. It forms the basis for performing fracture treatment or joint replacement surgery, for optimizing implant design and fixation and for improving and verifying analytical biomechanical models of the shoulder. With instrumented shoulder implants the joint contact forces and moments can be measured in vivo during different activities.
# Additional images
- The left shoulder and acromioclavicular joints, and the proper ligaments of the scapula.
# Medical problems
- Shoulder problems
- Rotator cuff tear | Shoulder
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In human anatomy, the shoulder comprises the part of the body where the arm attaches to the torso. It is made up of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder make up the shoulder joints. The shoulder must be flexible for the wide range of motion required in the arms and hands and also strong enough to allow for actions such as lifting, pushing and pulling. The compromise between these two functions results in a large number of shoulder problems not faced by other joints such as the hip.
# Joints of the shoulder
There are three joints of the shoulder: The glenohumeral, acromioclavicular, and the sternoclavicular joints.
## Glenohumeral joint
The glenohumeral joint is the main joint of the shoulder and the generic term "shoulder joint" usually refers to it. It is a ball and socket joint that allows the arm to rotate in a circular fashion or to hinge out and up away from the body. It is formed by the articulation between the head of the humerus and the lateral scapula. The "ball" of the joint is the rounded, medial anterior surface of the humerus and the "socket" is formed by the glenoid fossa, the dish-shaped portion of the lateral scapula. The shallowness of the fossa and relatively loose connections between the shoulder and the rest of the body allows the arm to have tremendous mobility, at the expense of being much easier to dislocate than most other joints in the body.
The capsule is a soft tissue envelope that encircles the glenohumeral joint and attaches to the scapula, humerus, and head of the biceps. It is lined by a thin, smooth synovial membrane. This capsule is strengthened by the coracohumeral ligament which attaches the coracoid process of the scapula to the greater tubercle of the humerus. There are also three other ligaments attaching the lesser tubercle of the humerus to lateral scapula and are collectively called the glenohumeral ligaments.
There is also a ligament called semicirculare humeri which is a transversal band between the posterior sides of the tuberculum minus and majus of the humerus. This band is one of the most important strengtening ligaments of the joint capsule.
## Acromioclavicular joint
The acromioclavicular (AC) joint is located between the acromion process of the scapula (part of the scapula that forms the highest point of the shoulder) and the distal end of the clavicle.
The capsule of this joint is reinforced by the coracoclavicular ligament between the scapula and clavicle at the point of articulation. The coracoclavicular ligament in further detail is created by the conoid ligament, medial from the coracoid process of the scapula and inserts on the conoid tubercle of the clavicle. Lateral to the conoid ligament is the trapezoid ligament, which runs from the coracoid process of the scapula to the trapezoid line of the clavicle. One more ligament, the coracoacromial ligament, running from the corocoid process to the acromion of the scapula contributes to the integrity of the acromioclavicular joint.
## Sternoclavicular joint
The sternoclavicular occurs at the medial end of the clavicle with the manubrium or top most portion of the sternum. The clavicle is triangular and rounded and the manubrium is convex the two bones articulate.
# Movements of the shoulder
The muscles and joints of the shoulder allow it to move through a remarkable range of motion, making it the most mobile joint in the human body. The shoulder can abduct, adduct (such as during the shoulder fly), rotate, be raised in front of and behind the torso and move through a full 360° in the sagittal plane. This tremendous range of motion also makes the shoulder extremely unstable, far more prone to dislocation and injury than other joints.
# Major muscles
The muscles that are responsible for movement in the shoulder attach to the scapula, humerus, and clavicle. The muscles that surround the shoulder form the shoulder cap and underarm.
# Rotator cuff
The rotator cuff is a structure composed of tendons that, with associated muscles (supraspinatus, infraspinatus, teres minor and subscapularis), holds the ball at the top of the humerus in the glenoid socket and provideoulder joint. The tendons of the rotator cuff muscles also connect to the capsule of the glenohumeral joint.
Two filmy sac-like structures called bursae permit smooth gliding between bone, muscle, and tendon. They cushion and protect the rotator cuff from the bony arch of the acromion.
# Measurement of shoulder loads
For understanding normal and pathologic shoulder function knowledge of forces in the glenohumeral joint is essential. It forms the basis for performing fracture treatment or joint replacement surgery, for optimizing implant design and fixation and for improving and verifying analytical biomechanical models of the shoulder. With instrumented shoulder implants the joint contact forces and moments can be measured in vivo during different activities.
# Additional images
- The left shoulder and acromioclavicular joints, and the proper ligaments of the scapula.
# Medical problems
- Shoulder problems
- Rotator cuff tear | https://www.wikidoc.org/index.php/Shoulder | |
0e20bd5f5574d3b7dd0b808d626b0ec04991c775 | wikidoc | Shrapnel | Shrapnel
Shrapnel is the term originally applied to an anti-personnel artillery shell which carried a large number of individual bullets to the target and then ejected them forwards. Today the term is commonly used to describe the metal fragments and debris thrown out by any exploding object, be it a high explosive (HE) filled shell or a homemade bomb wrapped with nails or steel balls.
# Origin of term shrapnel
The word shrapnel is derived from the name of Major-General Henry Shrapnel (1761–1842), an English artillery officer, whose experiments—initially conducted in his own time, and at his own expense—culminated in the design and development of a new type of artillery shell.
The term "Shrapnel" originally referred only to the spherical shot or musket balls dispersed when a shrapnel shell bursts, and this is still the technical meaning of the term, although it is now used to describe all types of high velocity debris thrown out from an explosion, and makes no differentiation to the process which created or produced the debris.
# Dictionary definition
The Oxford English Dictionary documents that the term Shrapnel is often used to describe fragments or shot intentionally included in explosive devices, such as pipe casings, nails, or steel balls.
For shells, bombs or other munitions, the technical term for these particles is fragments, splinters or shards, fragments being the preferred name in scientific documents on the subject.
Another term which can be used to describe a particle other than a bullet which causes a wound is "bomb fragment" or "bomb shard". These terms also include items which were not part of the original explosive device, but which are propelled as projectiles by the force of the explosive or impact.
# Development of shrapnel shell
In 1784 Lieutenant Shrapnel of the Royal Artillery began the course to develop an anti-personnel weapon. At the time artillery could use "canister shot" to defend themselves from infantry or cavalry attack.
Instead of a cannonball, a tin or canvas container filled with small iron or lead balls was loaded. When fired, the container burst open during passage through the bore or at the muzzle, giving the effect of an oversized shotgun shell. At ranges of up to 300 m canister shot was still highly lethal, though at this range the shots’ density was much lower, making a hit on a human target less likely. At longer ranges, solid shot or the common shell — a hollow cast iron sphere filled with black powder — was used, although with more of a concussive than a fragmentation effect, as the pieces of the shell were very large and sparse in number.
Shrapnel's innovation was to combine the multi-projectile shotgun effect of canister shot, with a delayed-action fuse to take the effect of canister shot to the enemy at a distance. His shell was a hollow cast-iron sphere filled with a mixture of balls and powder, with a crude time fuse. If the fuse was set correctly then the shell would break open, either in front or above the intended target, releasing its contents (of musket balls). The shrapnel balls would carry on with the "remaining velocity" of the shell. In addition to a denser pattern of musket balls, the retained velocity could be higher as well, since the shrapnel shell as a whole would likely have a higher ballistic coefficient than the individual musket balls (see external ballistics).
The explosive charge in the shell was to be just enough to break the casing rather than scatter the shot in all directions. As such his invention increased the effective range of canister shot from 300 to about 1100 m.
He called his device 'spherical case' shot, but in time it came to be called after him; a position formalised in 1852 by the British Government.
Initial designs suffered from the potentially catastrophic problem that friction between the shot and black powder during the high acceleration down the gun bore could sometimes cause premature ignition of the powder. This problem was overcome by placing the powder within a central metal tube, or a separate area within the hollow shell. As a buffer to prevent lead shot deforming, a resin was used as a packing material between the shot. A useful side effect of using the resin was that the combustion also gave a visual reference upon the shell bursting, as the resin shattered into a cloud of dust.
# British artillery adoption
It took until 1803 for the British artillery to adopt it, albeit with great enthusiasm when it did. Shrapnel was promoted to Major in the same year. The Duke of Wellington used it beginning in 1808 against Napoleon, including in the Battle of Waterloo, and wrote admiringly of its effectiveness.
The design was improved by Captain E M Boxer RA in the 1840s and crossed over when cylindrical shells for rifled guns were introduced.
# World War I era
The size of shrapnel balls in World War I was based on the premise that a projectile energy of 58 foot-pounds (US) to 60 foot-pounds (British) was required to disable an enemy soldier. At the velocity of a typical World War I 3 inch (76.2 mm) field gun shell after travelling 6,000 yards (Expression error: Missing operand for *. ), plus the additional velocity from the shrapnel bursting charge, this was the minimum energy of a single half-inch lead-antimony ball of approximately 170 (Expression error: Missing operand for *. ), or 41-42 balls = 1 pound. Hence this was a typical field gun shrapnel bullet size. Hence the field gun shrapnel shell performed a role which today is typically performed by a .50 caliber machine-gun. For larger guns which had lower velocities, correspondingly larger balls were used so that each individual ball was lethal.
During the initial stages of World War I, shrapnel was widely used by all sides to attack troops in the open, though trench warfare reduced its use as high explosive shells became the predominant type of 'explosive' shell used. While shrapnel made no impression on trenches and other earthworks it remained the favoured weapon of the British (at least) to support their infantry assaults. It prevented the Germans manning their trench parapets and was less hazardous to the assaulting British infantry than high explosives. Shrapnel being non-cratering was also advantageous in an assault. Shrapnel was also useful against counter-attacks, working parties and any other troops in the open. However, shrapnel was unable to cut the barbed wire entanglements in no man's land, defeat troops under protection, or destroy positions all of which were required in the preliminary bombardment to an attack.
With the advent of relatively insensitive high explosives which could be used as the filling for shells, it was found that the casing of a properly designed high explosive shell fragmented effectively. However, this fragmentation was often lost when shells penetrated soft ground and because some fragments went in all directions it was a hazard to assaulting troops. For example, the detonation of an average 105 mm shell produces several thousand high velocity (1,000 to 1,500 m/s) fragments, a lethal (at close range) blast overpressure and, if a surface or sub-surface burst, a useful cratering and anti-material effect — all in a munition much less complex to make than the later versions of the shrapnel shell.
One item of note is the 'Universal Shell', a type of field gun shell developed by Krupp of Germany in the early 1900s. This shell could function as either a shrapnel shell, or high explosive projectile. The shell had a modified fuse and instead of resin as the packing between the shrapnel balls, TNT was used. When the fuse was set to time, the fuse functioned in the normal way, ejecting the balls and igniting (not detonating) the TNT, the TNT giving a visual puff of black smoke. In impact mode the TNT filling was detonated, so becoming an high explosive shell with a very large amount of low velocity fragmentation and a milder blast. Again due to its complexity, it was dropped in favour of the simple high explosive shell.
When World War I began the United States also had what it referred to as the "Ehrhardt High-Explosive Shrapnel" in its inventory. It appears to be the same as the German design, with bullets embedded in TNT rather than resin. Douglas Hamilton mentions this shell type in passing, as "not as common as other types" in his comprehensive treatises on manufacturing Shrapnel and High Explosive shells of 1915 and 1916, but gives no manufacturing details. Nor does Ethan Viall in 1917. Hence the US appears to have ceased its manufacture early in the war, presumably based on the experience of other combatants.
# World War II era
By World War II shrapnel shells, in the strict sense of the word, fell out of use, the last recorded use of shrapnel being 60 pdr shells fired in Burma in 1943. A new shrapnel shell, Mk 3D a steamlined shell had been developed for 60 pdr in the early 1930s, it contained 760 bullets of 41/lb size. There was some use of shrapnel by the British in the campaigns in East and North East Africa at the beginning of the war where 18-pdr and 4.5 inch (114.3 mm) Howitzers were used. In 1945 the British conducted successful trials with shrapnel shells fuzed with VT. However, shrapnel was not developed for any of the post World War I guns.
# Vietnam era
Although not strictly shrapnel, a 1960s weapons project produced splintex shells for 90 and 106 mm RCLs and for 105 mm Howitzer where it was called 'Beehive'. Unlike the shrapnel shells’ balls, the splintex shell contained flechettes. The result was the 105 mm M546 APERS-T, first used in the Vietnam War in 1966. The shell consisted of approximately 8,000 half gram flechettes, these arranged in five tiers, a time fuse, body shearing detonators, central flash tube, smokeless propellant charge with a dye marker contained in the base and tracer element. The functioning of the shell was as follows; the time fuse fires, flash sent down the flash tube, shearing detonators fire, and the forward body splits into four pieces, body and first four tiers dispersed by the projectile's spin, last tier and visual marker by the powder charge. The flechettes spread, mainly due to spin, from the point of burst in an ever widening cone along the projectile's previous trajectory prior to burst. The round is a highly effective anti-personnel weapon — soldiers report that after beehive rounds were fired during an over-run attack, many enemy dead had their hands nailed to the wooden stocks of their rifles, and these dead could be dragged to mass graves by the rifle — but complex to make. It is said that the name beehive was given to the munition type due to the noise of the flechettes moving through the air resembling that of a swam of angry bees.
# Modern era
Though shrapnel rounds are now rarely used, there are other modern rounds, apart from the Beehive shell, that use, or have used the shrapnel principle. The DM 111 20 mm cannon round used for close range air defense, the flechette filled 40 mm HVCC (40 x 53 mm HV grenade), the 35 mm cannon (35 × 228 mm) AHEAD ammunition (152 x 3.3 g tungsten cylinders), RWM Schweiz 30 × 173 mm Air-Bursting munition, 5-Inch Shotgun Projectile (KE-ET) and possibility many more. Also many modern armies have canister shot ammunition for tank and artillery guns, the XM1028 round for the 120 mm M256 tank gun being one example (approx 1150 tungsten balls at 1400 m/s).
At least some Anti-Ballistic Missiles (ABMs) use shrapnel like warhead instead of the more common blast/fragmentation (blast/frag) type. As with a blast/frag warhead, the use of this type of warhead does not require a direct body-on-body impact, so greatly reducing tracking and steering accuracy requirements.
At a predetermined distance from the incoming re-entry vehicle (RV) the warhead releases, in the case of the ABM warhead by an explosive expulsion charge, an array of mainly rod-like sub-projectiles into the RV's flight path.
Unlike a blast/frag warhead, the expulsion charge is only needed to release the sub-projectiles from the main warhead, not to accelerate them to high velocity. The velocity required to penetrate the RV's casing comes from the high terminal velocity of the warhead, similar to the shrapnel shell's principle.
The reason for the use of this type of warhead and not a blast/frag is that the fragments produced by a blast/frag warhead cannot guarantee penetration of the RV's casing. By using rod like sub-projectiles, a much greater thickness of material can be penetrated, greatly increasing the potential for disruption of the incoming RV.
# Gallery of images
- Shrapnel from the First World War.
Shrapnel from the First World War.
- Shrapnel from the Gulf War.
Shrapnel from the Gulf War. | Shrapnel
Shrapnel is the term originally applied to an anti-personnel artillery shell which carried a large number of individual bullets to the target and then ejected them forwards. Today the term is commonly used to describe the metal fragments and debris thrown out by any exploding object, be it a high explosive (HE) filled shell or a homemade bomb wrapped with nails or steel balls.
# Origin of term shrapnel
The word shrapnel is derived from the name of Major-General Henry Shrapnel (1761–1842), an English artillery officer, whose experiments—initially conducted in his own time, and at his own expense—culminated in the design and development of a new type of artillery shell.
The term "Shrapnel" originally referred only to the spherical shot or musket balls dispersed when a shrapnel shell bursts, and this is still the technical meaning of the term, although it is now used to describe all types of high velocity debris thrown out from an explosion, and makes no differentiation to the process which created or produced the debris.
# Dictionary definition
The Oxford English Dictionary documents that the term Shrapnel is often used to describe fragments or shot intentionally included in explosive devices, such as pipe casings, nails, or steel balls.
For shells, bombs or other munitions, the technical term for these particles is fragments, splinters or shards, fragments being the preferred name in scientific documents on the subject.
Another term which can be used to describe a particle other than a bullet which causes a wound is "bomb fragment" or "bomb shard". These terms also include items which were not part of the original explosive device, but which are propelled as projectiles by the force of the explosive or impact.
# Development of shrapnel shell
In 1784 Lieutenant Shrapnel of the Royal Artillery began the course to develop an anti-personnel weapon. At the time artillery could use "canister shot" to defend themselves from infantry or cavalry attack.
Instead of a cannonball, a tin or canvas container filled with small iron or lead balls was loaded. When fired, the container burst open during passage through the bore or at the muzzle, giving the effect of an oversized shotgun shell. At ranges of up to 300 m canister shot was still highly lethal, though at this range the shots’ density was much lower, making a hit on a human target less likely. At longer ranges, solid shot or the common shell — a hollow cast iron sphere filled with black powder — was used, although with more of a concussive than a fragmentation effect, as the pieces of the shell were very large and sparse in number.
Shrapnel's innovation was to combine the multi-projectile shotgun effect of canister shot, with a delayed-action fuse to take the effect of canister shot to the enemy at a distance. His shell was a hollow cast-iron sphere filled with a mixture of balls and powder, with a crude time fuse. If the fuse was set correctly then the shell would break open, either in front or above the intended target, releasing its contents (of musket balls). The shrapnel balls would carry on with the "remaining velocity" of the shell. In addition to a denser pattern of musket balls, the retained velocity could be higher as well, since the shrapnel shell as a whole would likely have a higher ballistic coefficient than the individual musket balls (see external ballistics).
The explosive charge in the shell was to be just enough to break the casing rather than scatter the shot in all directions. As such his invention increased the effective range of canister shot from 300 to about 1100 m.
He called his device 'spherical case' shot, but in time it came to be called after him; a position formalised in 1852 by the British Government.
Initial designs suffered from the potentially catastrophic problem that friction between the shot and black powder during the high acceleration down the gun bore could sometimes cause premature ignition of the powder. This problem was overcome by placing the powder within a central metal tube, or a separate area within the hollow shell. As a buffer to prevent lead shot deforming, a resin was used as a packing material between the shot. A useful side effect of using the resin was that the combustion also gave a visual reference upon the shell bursting, as the resin shattered into a cloud of dust.
# British artillery adoption
It took until 1803 for the British artillery to adopt it, albeit with great enthusiasm when it did. Shrapnel was promoted to Major in the same year. The Duke of Wellington used it beginning in 1808 against Napoleon, including in the Battle of Waterloo, and wrote admiringly of its effectiveness.
The design was improved by Captain E M Boxer RA in the 1840s and crossed over when cylindrical shells for rifled guns were introduced.
# World War I era
The size of shrapnel balls in World War I was based on the premise that a projectile energy of 58 foot-pounds (US)[1] to 60 foot-pounds (British)[2] was required to disable an enemy soldier. At the velocity of a typical World War I 3 inch (76.2 mm) field gun shell after travelling 6,000 yards (Expression error: Missing operand for *. ), plus the additional velocity from the shrapnel bursting charge, this was the minimum energy of a single half-inch lead-antimony ball of approximately 170 (Expression error: Missing operand for *. ), or 41-42 balls = 1 pound. Hence this was a typical field gun shrapnel bullet size. Hence the field gun shrapnel shell performed a role which today is typically performed by a .50 caliber machine-gun. For larger guns which had lower velocities, correspondingly larger balls were used so that each individual ball was lethal.
During the initial stages of World War I, shrapnel was widely used by all sides to attack troops in the open, though trench warfare reduced its use as high explosive shells became the predominant type of 'explosive' shell used. While shrapnel made no impression on trenches and other earthworks it remained the favoured weapon of the British (at least) to support their infantry assaults. It prevented the Germans manning their trench parapets and was less hazardous to the assaulting British infantry than high explosives. Shrapnel being non-cratering was also advantageous in an assault. Shrapnel was also useful against counter-attacks, working parties and any other troops in the open. However, shrapnel was unable to cut the barbed wire entanglements in no man's land, defeat troops under protection, or destroy positions all of which were required in the preliminary bombardment to an attack.
With the advent of relatively insensitive high explosives which could be used as the filling for shells, it was found that the casing of a properly designed high explosive shell fragmented effectively. However, this fragmentation was often lost when shells penetrated soft ground and because some fragments went in all directions it was a hazard to assaulting troops. For example, the detonation of an average 105 mm shell produces several thousand high velocity (1,000 to 1,500 m/s) fragments, a lethal (at close range) blast overpressure and, if a surface or sub-surface burst, a useful cratering and anti-material effect — all in a munition much less complex to make than the later versions of the shrapnel shell.
One item of note is the 'Universal Shell', a type of field gun shell developed by Krupp of Germany in the early 1900s. This shell could function as either a shrapnel shell, or high explosive projectile. The shell had a modified fuse and instead of resin as the packing between the shrapnel balls, TNT was used. When the fuse was set to time, the fuse functioned in the normal way, ejecting the balls and igniting (not detonating) the TNT, the TNT giving a visual puff of black smoke. In impact mode the TNT filling was detonated, so becoming an high explosive shell with a very large amount of low velocity fragmentation and a milder blast. Again due to its complexity, it was dropped in favour of the simple high explosive shell.
When World War I began the United States also had what it referred to as the "Ehrhardt High-Explosive Shrapnel" in its inventory.[3] It appears to be the same as the German design, with bullets embedded in TNT rather than resin. Douglas Hamilton mentions this shell type in passing, as "not as common as other types" in his comprehensive treatises on manufacturing Shrapnel[4] and High Explosive shells[5] of 1915 and 1916, but gives no manufacturing details. Nor does Ethan Viall in 1917[6]. Hence the US appears to have ceased its manufacture early in the war, presumably based on the experience of other combatants.
# World War II era
By World War II shrapnel shells, in the strict sense of the word, fell out of use, the last recorded use of shrapnel being 60 pdr shells fired in Burma in 1943. A new shrapnel shell, Mk 3D a steamlined shell had been developed for 60 pdr in the early 1930s, it contained 760 bullets of 41/lb size. There was some use of shrapnel by the British in the campaigns in East and North East Africa at the beginning of the war where 18-pdr and 4.5 inch (114.3 mm) Howitzers were used. In 1945 the British conducted successful trials with shrapnel shells fuzed with VT. However, shrapnel was not developed for any of the post World War I guns.
# Vietnam era
Although not strictly shrapnel, a 1960s weapons project produced splintex shells for 90 and 106 mm RCLs and for 105 mm Howitzer where it was called 'Beehive'. Unlike the shrapnel shells’ balls, the splintex shell contained flechettes. The result was the 105 mm M546 APERS-T, first used in the Vietnam War in 1966. The shell consisted of approximately 8,000 half gram flechettes, these arranged in five tiers, a time fuse, body shearing detonators, central flash tube, smokeless propellant charge with a dye marker contained in the base and tracer element. The functioning of the shell was as follows; the time fuse fires, flash sent down the flash tube, shearing detonators fire, and the forward body splits into four pieces, body and first four tiers dispersed by the projectile's spin, last tier and visual marker by the powder charge. The flechettes spread, mainly due to spin, from the point of burst in an ever widening cone along the projectile's previous trajectory prior to burst. The round is a highly effective anti-personnel weapon — soldiers report that after beehive rounds were fired during an over-run attack, many enemy dead had their hands nailed to the wooden stocks of their rifles, and these dead could be dragged to mass graves by the rifle — but complex to make. It is said that the name beehive was given to the munition type due to the noise of the flechettes moving through the air resembling that of a swam of angry bees.
# Modern era
Though shrapnel rounds are now rarely used, there are other modern rounds, apart from the Beehive shell, that use, or have used the shrapnel principle. The DM 111 20 mm cannon round used for close range air defense, the flechette filled 40 mm HVCC (40 x 53 mm HV grenade), the 35 mm cannon (35 × 228 mm) AHEAD ammunition (152 x 3.3 g tungsten cylinders), RWM Schweiz 30 × 173 mm Air-Bursting munition, 5-Inch Shotgun Projectile (KE-ET) and possibility many more. Also many modern armies have canister shot ammunition for tank and artillery guns, the XM1028 round for the 120 mm M256 tank gun being one example (approx 1150 tungsten balls at 1400 m/s).
At least some Anti-Ballistic Missiles (ABMs) use shrapnel like warhead instead of the more common blast/fragmentation (blast/frag) type. As with a blast/frag warhead, the use of this type of warhead does not require a direct body-on-body impact, so greatly reducing tracking and steering accuracy requirements.
At a predetermined distance from the incoming re-entry vehicle (RV) the warhead releases, in the case of the ABM warhead by an explosive expulsion charge, an array of mainly rod-like sub-projectiles into the RV's flight path.
Unlike a blast/frag warhead, the expulsion charge is only needed to release the sub-projectiles from the main warhead, not to accelerate them to high velocity. The velocity required to penetrate the RV's casing comes from the high terminal velocity of the warhead, similar to the shrapnel shell's principle.
The reason for the use of this type of warhead and not a blast/frag is that the fragments produced by a blast/frag warhead cannot guarantee penetration of the RV's casing. By using rod like sub-projectiles, a much greater thickness of material can be penetrated, greatly increasing the potential for disruption of the incoming RV.
# Gallery of images
- Shrapnel from the First World War.
Shrapnel from the First World War.
- Shrapnel from the Gulf War.
Shrapnel from the Gulf War. | https://www.wikidoc.org/index.php/Shrapnel | |
6be55c3d0162cef00e2ecb1aa9d380936dc027fe | wikidoc | Siloxane | Siloxane
Siloxanes are a class of organosilicon compounds with the empirical formula R2SiO, where R is an organic group. Representative examples are n (dimethylsiloxane) and n (diphenylsiloxane), where n is typically > 4. These compounds can be viewed as a hybrid of both organic and inorganic chemical compounds. The organic side chains confer hydrophobic properties while the -Si-O-Si-O- backbone is purely inorganic.
The word siloxane is derived from the words Silicon, Oxygen, and alkane.
Siloxanes can be found in products such as cosmetics, deodorant, water repelling windshield coatings, food additives such as those used in certain McDonalds fast food products, and some soaps. They occur in landfill gas and are being evaluated as alternatives to perchloroethylene for drycleaning. Perchloroethylene is widely considered environmentally undesirable.
Polymerized siloxanes are commonly known as silicones, although this name is somewhat of a misnomer. A true silicone group has a double bond between oxygen and silicon (hence the derivation of the word silicone from ketone), and polymerized siloxanes do not contain such groups. Accordingly, polysiloxane is the preferred name of such compounds among chemists
# External link
- EPA report: Siloxane D5 in Dry-cleaning | Siloxane
Siloxanes are a class of organosilicon compounds with the empirical formula R2SiO, where R is an organic group. Representative examples are [SiO(CH3)2]n (dimethylsiloxane) and [SiO(C6H5)2]n (diphenylsiloxane), where n is typically > 4. These compounds can be viewed as a hybrid of both organic and inorganic chemical compounds. The organic side chains confer hydrophobic properties while the -Si-O-Si-O- backbone is purely inorganic.
The word siloxane is derived from the words Silicon, Oxygen, and alkane.
Siloxanes can be found in products such as cosmetics, deodorant, water repelling windshield coatings, food additives such as those used in certain McDonalds fast food products,[1] and some soaps. They occur in landfill gas and are being evaluated as alternatives to perchloroethylene for drycleaning. Perchloroethylene is widely considered environmentally undesirable.
Polymerized siloxanes are commonly known as silicones, although this name is somewhat of a misnomer. A true silicone group has a double bond between oxygen and silicon (hence the derivation of the word silicone from ketone), and polymerized siloxanes do not contain such groups. Accordingly, polysiloxane is the preferred name of such compounds among chemists
## External link
- EPA report: Siloxane D5 in Dry-cleaning | https://www.wikidoc.org/index.php/Siloxane | |
fbb3562a95d8fa10422655a2e76ec60f66090138 | wikidoc | Skeleton | Skeleton
In biology, the skeleton or skeletal system is the biological system providing physical support in living organisms. (By extension, non-biological outline structures such as gantries or buildings may also acquire skeletons.)
# Types and Classification
Skeletal systems are commonly divided into three types—external (an exoskeleton), internal (an endoskeleton), and fluid based (a hydrostatic skeleton), although hydrostatic skeletal systems may be classified separately from the other two, because they lack hardened support structures. An internal skeletal system consists of rigid or semi-rigid structures, within the body, moved by the muscular system. If the structures are mineralized or ossified, as they are in humans and other mammals, they are referred to as bones. Cartilage is another common component of skeletal systems, supporting and supplementing the skeleton. The human ear and nose are shaped by cartilage. Some organisms have a skeleton consisting entirely of cartilage and without any calcified bones at all, for example sharks. The bones or other rigid structures are connected by ligaments and connected to the muscular system via tendons.
Hydrostatic skeletons are similar to a water-filled balloon. Located internally in cnidarians (coral, jellyfish etc.) and annelids (leeches, earthworms etc.), among others, these animals can move by contracting the muscles surrounding the fluid-filled pouch, creating pressure within the pouch that causes movement. Animals such as earthworms use their hydrostatic skeletons to change their body shape, as they move forward, from long and thin to shorter and wider. | Skeleton
In biology, the skeleton or skeletal system is the biological system providing physical support in living organisms. (By extension, non-biological outline structures such as gantries or buildings may also acquire skeletons.)
# Types and Classification
Skeletal systems are commonly divided into three types—external (an exoskeleton), internal (an endoskeleton), and fluid based (a hydrostatic skeleton), although hydrostatic skeletal systems may be classified separately from the other two, because they lack hardened support structures. An internal skeletal system consists of rigid or semi-rigid structures, within the body, moved by the muscular system. If the structures are mineralized or ossified, as they are in humans and other mammals, they are referred to as bones. Cartilage is another common component of skeletal systems, supporting and supplementing the skeleton. The human ear and nose are shaped by cartilage. Some organisms have a skeleton consisting entirely of cartilage and without any calcified bones at all, for example sharks. The bones or other rigid structures are connected by ligaments and connected to the muscular system via tendons.
Hydrostatic skeletons are similar to a water-filled balloon. Located internally in cnidarians (coral, jellyfish etc.) and annelids (leeches, earthworms etc.), among others, these animals can move by contracting the muscles surrounding the fluid-filled pouch, creating pressure within the pouch that causes movement. Animals such as earthworms use their hydrostatic skeletons to change their body shape, as they move forward, from long and thin to shorter and wider. | https://www.wikidoc.org/index.php/Skeletal | |
fd19d7d4313aa3835f9572f4a0f190b2f851637e | wikidoc | Soapwort | Soapwort
Soapwort (Saponaria officinalis) is a vespertine flower, and a common perennial plant from the carnation family (Caryophyllaceae). Other common names are Bouncing Bet and Sweet William.
The Latin name is derived from the toxic substance saponin, contained in the roots. It starts producing a lather when in contact with water. The epithet officinalis indicates its medicinal functions. However, it acquired its common name through utility in cleaning.
Soapwort's native range extends throughout Europe to western Siberia. It grows in cool places at low or moderate elevations under hedgerows and along the shoulders of roadways.
The plants possesses leafy, unbranched stems (often tinged with red) grow in patches, attaining a height of 70 cm. The broad, lanceolate, sessile leaves are opposite and between 4 and 12 cm long. It's sweetly scented flowers are radially symmetrical and pink, or sometimes white. Each of the five flat petals have two small scales in the throat of the corolla. They are about 2.5 cm wide. They are arranged in dense, terminal clusters on the main stem and its branches. The long tubular calyx has five pointed red teeth.
In the northern hemisphere soapwort blooms from May to September, and in the southern hemisphere October to March.
# Internal use
Soapwort has various medicinal functions as an expectorant and laxative, but care should be taken when used as saponins may be toxic. An overdose can cause nausea, diarrhoea and vomiting.
Despite its toxic potential, soapwort finds culinary use as an emulsifier in the commercial preparation of tahini halva, and in brewing to create beer with a good "head". In India, the rhizome is used as a galactagogue. | Soapwort
Soapwort (Saponaria officinalis) is a vespertine flower, and a common perennial plant from the carnation family (Caryophyllaceae). Other common names are Bouncing Bet and Sweet William.
The Latin name is derived from the toxic substance saponin, contained in the roots. It starts producing a lather when in contact with water. The epithet officinalis indicates its medicinal functions. However, it acquired its common name through utility in cleaning.
Soapwort's native range extends throughout Europe to western Siberia. It grows in cool places at low or moderate elevations under hedgerows and along the shoulders of roadways.
The plants possesses leafy, unbranched stems (often tinged with red) grow in patches, attaining a height of 70 cm. The broad, lanceolate, sessile leaves are opposite and between 4 and 12 cm long. It's sweetly scented flowers are radially symmetrical and pink, or sometimes white. Each of the five flat petals have two small scales in the throat of the corolla. They are about 2.5 cm wide. They are arranged in dense, terminal clusters on the main stem and its branches. The long tubular calyx has five pointed red teeth.
In the northern hemisphere soapwort blooms from May to September, and in the southern hemisphere October to March.
# Internal use
Soapwort has various medicinal functions as an expectorant and laxative, but care should be taken when used as saponins may be toxic. An overdose can cause nausea, diarrhoea and vomiting.
Despite its toxic potential, soapwort finds culinary use as an emulsifier in the commercial preparation of tahini halva,[1] and in brewing to create beer with a good "head". In India, the rhizome is used as a galactagogue.[2] | https://www.wikidoc.org/index.php/Soapwort | |
06722c0ab825d05265dd8964a986b66a9b6ce313 | wikidoc | Solitude | Solitude
Solitude is a state of seclusion or isolation, i.e. lack of contact with people. It may stem from deliberate choice, contagious disease, disfiguring features, repulsive personal habits, or circumstances of employment or situation (see castaway).
Short-term solitude is often valued as a time when one may work, think or rest without being disturbed. It may be desired for the sake of privacy.
A distinction can be made between physical and mental seclusion. People may seek physical seclusion to remove distractions and make it easier to concentrate, reflect, or meditate. However, this is not necessarily an end in and of itself. Once a certain capacity to resist distractions is achieved, people become less sensitive to distractions and more capable of maintaining mindfulness and staying inwardly absorbed and concentrated. Such people, unless on a mission of helping others, don't seek any interaction with the external physical world. Their mindfulness is their world, at least ostensibly.
# Health effects
Symptoms from externally imposed isolation often include anxiety, sensory illusions, or even distortions of time and perception. However, this is the case when there is no stimulation of the sensory systems at all, and not only lack of contact with people. Thus, by having other things to keep one's mind busy, this is avoided.
Still, long-term solitude is often seen as undesirable, causing loneliness or reclusion resulting from inability to establish relationships. Furthermore, it might even lead to clinical depression. However, for some people, solitude is not totally depressing. Still others (e.g. monks) regard long-term solitude as a means of spiritual enlightenment. Indeed, marooned people have been left in solitude for years without any report of psychological symptoms afterwards.
In contrast, some psychological conditions (such as schizophrenia) are strongly linked to a tendency to seek solitude.
# Different types
There are two different common types of human isolation. These are known as protective isolation and source isolation. They are different in that one is voluntary, while the other is not.
Protective isolation is the type of isolation created in tests. This can usually be classified by the fact that one can opt out of the experiment, or the isolation. It can often be prepared for, and is generally not a negative thing. (More often than not, there is a reward for the subject's time as an experiment.)
Source isolation includes no benefits, and cannot be prepared for. Thus, it is usually undesirable, and is not very common.
Emotional isolation is a term used to describe a state of isolation where the individual is emotionally isolated, but may have a well functioning social network.
# Other uses
## As a punishment
Isolation, in the form of solitary confinement is a punishment used in many countries throughout the world for prisoners accused of serious crimes, those who may be at risk in the prison population (such as pedophiles), those who may commit suicide and those unable to participate in the prison population due to sickness or injury.
## As a treatment
In addition, psychiatric institutions may also institute full isolation or partial isolation for certain patients, particularly the violent or subversive, in order to minister to their particular needs and protect the rest of the recovering population from their influence. | Solitude
Solitude is a state of seclusion or isolation, i.e. lack of contact with people. It may stem from deliberate choice, contagious disease, disfiguring features, repulsive personal habits, or circumstances of employment or situation (see castaway).
Short-term solitude is often valued as a time when one may work, think or rest without being disturbed. It may be desired for the sake of privacy.
A distinction can be made between physical and mental seclusion. People may seek physical seclusion to remove distractions and make it easier to concentrate, reflect, or meditate. However, this is not necessarily an end in and of itself. Once a certain capacity to resist distractions is achieved, people become less sensitive to distractions and more capable of maintaining mindfulness and staying inwardly absorbed and concentrated. Such people, unless on a mission of helping others, don't seek any interaction with the external physical world. Their mindfulness is their world, at least ostensibly.
# Health effects
Symptoms from externally imposed isolation often include anxiety, sensory illusions, or even distortions of time and perception. However, this is the case when there is no stimulation of the sensory systems at all, and not only lack of contact with people. Thus, by having other things to keep one's mind busy, this is avoided.[1]
Still, long-term solitude is often seen as undesirable, causing loneliness or reclusion resulting from inability to establish relationships. Furthermore, it might even lead to clinical depression. However, for some people, solitude is not totally depressing. Still others (e.g. monks) regard long-term solitude as a means of spiritual enlightenment. Indeed, marooned people have been left in solitude for years without any report of psychological symptoms afterwards.
In contrast, some psychological conditions (such as schizophrenia[2]) are strongly linked to a tendency to seek solitude.
# Different types
There are two different common types of human isolation. These are known as protective isolation and source isolation. They are different in that one is voluntary, while the other is not.[citation needed]
Protective isolation is the type of isolation created in tests. This can usually be classified by the fact that one can opt out of the experiment, or the isolation. It can often be prepared for, and is generally not a negative thing. (More often than not, there is a reward for the subject's time as an experiment.)[citation needed]
Source isolation includes no benefits, and cannot be prepared for. Thus, it is usually undesirable, and is not very common.
Emotional isolation is a term used to describe a state of isolation where the individual is emotionally isolated, but may have a well functioning social network.[citation needed]
# Other uses
## As a punishment
Isolation, in the form of solitary confinement is a punishment used in many countries throughout the world for prisoners accused of serious crimes, those who may be at risk in the prison population (such as pedophiles), those who may commit suicide and those unable to participate in the prison population due to sickness or injury.
## As a treatment
In addition, psychiatric institutions may also institute full isolation or partial isolation for certain patients, particularly the violent or subversive, in order to minister to their particular needs and protect the rest of the recovering population from their influence. | https://www.wikidoc.org/index.php/Solitude | |
5941584a6de6f9853b794cfc99a7cd9b9cd73ff4 | wikidoc | Solution | Solution
# Overview
In chemistry, a solution is a homogeneous mixture composed of two or more substances. In such a mixture, a solute is dissolved in another substance, known as a solvent. A common example is a solid, such as salt or sugar, dissolved in water, a liquid. Gases may dissolve in liquids, for example, carbon dioxide or oxygen in water. Liquids may dissolve in other liquids. Gases can combine with other gases to form mixtures, rather than solutions. All solutions are characterized by interactions between the solvent phase and solute molecules or ions that result in a net decrease in free energy. Under such a definition, gases typically cannot function as solvents, since in the gas phase interactions between molecules are minimal due to the large distances between the molecules. This lack of interaction is the reason gases can expand freely and the presence of these interactions is the reason liquids do not expand.
Examples of solid solutions are alloys, certain minerals and polymers containing plasticizers. The ability of one compound to dissolve in another compound is called solubility. The physical properties of compounds such as melting point and boiling point change when other compounds are added. Together they are called colligative properties. There are several ways to quantify the amount of one compound dissolved in the other compounds collectively called concentration. Examples include molarity, molality, and parts per million (ppm).
Solutions should be distinguished from non-homogeneous mixtures such as colloids and suspensions.
# Types of solutions
Many types of solutions exist, as solids, liquids and gases can be both solvent and solute, in any combination:
# Solvents
Liquid solvents can be broadly classified into polar and non-polar solvents. A common measure of the polarity of a solvent is the dielectric constant. The most widely used polar solvent is water, with a dielectric constant of 78.5. Ethanol, with a dielectric constant of 24.3, has intermediate polarity. An example of a non-polar solvent is hexane, which has a dielectric constant of 1.9. Generally polar or ionic compounds will only dissolve in polar solvents. A simple test for the polarity of a liquid solvent is to rub a plastic rod, to induce static electricity. Then hold this charged rod close to a running stream of the solvent. If the path of the solvent deviates when the rod is held close to it, it is a polar solvent. Certain molecules have polar and non-polar regions, for example sodium dodecyl sulfate. This class of molecules (called amphipathic molecules) includes surfactants like soaps and emulsifiers, as they have the ability to stabilize emulsions by aligning themselves on the interface between the non-polar and polar liquids, with their polar ends in the polar liquid and their non-polar ends in the non-polar liquid.
# Solvation
During solvation, especially when the solvent is polar, a structure forms around it, which allows the solute-solvent interaction to remain stable.
When no more of a solute can be dissolved into a solvent, the solution is said to be saturated. However, the point at which a solution can become saturated can change significantly with different environmental factors, such as temperature, pressure, and contamination. For some solute-solvent combinations a supersaturated solution can be prepared by raising the solubility (for example by increasing the temperature) to dissolve more solute, and then lowering it (for example by cooling).
Usually, the greater the temperature of the solvent, the more of a given solid solute it can dissolve. However, most gases and some compounds exhibit solubility that deacrease with increased temperature. Such behavior is a result of an exothermic enthalpy of solution. Some surfactants exhibit this behaviour. The solubility of liquids in liquids is generally less temperature-sensitive than that of solids or gases.
# Ideal solutions
The properties of an ideal solution can be calculated by the linear combination of the properties of its components.
If both solute and solvent exist in equal quantities (such as in a 50% ethanol, 50% water solution), the concepts of "solute" and "solvent" become less relevant, but the substance that is more often used as a solvent is normally designated as the solvent (in this example, water). | Solution
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In chemistry, a solution is a homogeneous mixture composed of two or more substances. In such a mixture, a solute is dissolved in another substance, known as a solvent. A common example is a solid, such as salt or sugar, dissolved in water, a liquid. Gases may dissolve in liquids, for example, carbon dioxide or oxygen in water. Liquids may dissolve in other liquids. Gases can combine with other gases to form mixtures, rather than solutions.[1] All solutions are characterized by interactions between the solvent phase and solute molecules or ions that result in a net decrease in free energy. Under such a definition, gases typically cannot function as solvents, since in the gas phase interactions between molecules are minimal due to the large distances between the molecules. This lack of interaction is the reason gases can expand freely and the presence of these interactions is the reason liquids do not expand.
Examples of solid solutions are alloys, certain minerals and polymers containing plasticizers. The ability of one compound to dissolve in another compound is called solubility. The physical properties of compounds such as melting point and boiling point change when other compounds are added. Together they are called colligative properties. There are several ways to quantify the amount of one compound dissolved in the other compounds collectively called concentration. Examples include molarity, molality, and parts per million (ppm).
Solutions should be distinguished from non-homogeneous mixtures such as colloids and suspensions.
# Types of solutions
Many types of solutions exist, as solids, liquids and gases can be both solvent and solute, in any combination:
# Solvents
Liquid solvents can be broadly classified into polar and non-polar solvents. A common measure of the polarity of a solvent is the dielectric constant. The most widely used polar solvent is water, with a dielectric constant of 78.5. Ethanol, with a dielectric constant of 24.3, has intermediate polarity. An example of a non-polar solvent is hexane, which has a dielectric constant of 1.9. Generally polar or ionic compounds will only dissolve in polar solvents. A simple test for the polarity of a liquid solvent is to rub a plastic rod, to induce static electricity. Then hold this charged rod close to a running stream of the solvent. If the path of the solvent deviates when the rod is held close to it, it is a polar solvent. Certain molecules have polar and non-polar regions, for example sodium dodecyl sulfate. This class of molecules (called amphipathic molecules) includes surfactants like soaps and emulsifiers, as they have the ability to stabilize emulsions by aligning themselves on the interface between the non-polar and polar liquids, with their polar ends in the polar liquid and their non-polar ends in the non-polar liquid.
# Solvation
During solvation, especially when the solvent is polar, a structure forms around it, which allows the solute-solvent interaction to remain stable.
When no more of a solute can be dissolved into a solvent, the solution is said to be saturated. However, the point at which a solution can become saturated can change significantly with different environmental factors, such as temperature, pressure, and contamination. For some solute-solvent combinations a supersaturated solution can be prepared by raising the solubility (for example by increasing the temperature) to dissolve more solute, and then lowering it (for example by cooling).
Usually, the greater the temperature of the solvent, the more of a given solid solute it can dissolve. However, most gases and some compounds exhibit solubility that deacrease with increased temperature. Such behavior is a result of an exothermic enthalpy of solution. Some surfactants exhibit this behaviour. The solubility of liquids in liquids is generally less temperature-sensitive than that of solids or gases.
# Ideal solutions
The properties of an ideal solution can be calculated by the linear combination of the properties of its components.
If both solute and solvent exist in equal quantities (such as in a 50% ethanol, 50% water solution), the concepts of "solute" and "solvent" become less relevant, but the substance that is more often used as a solvent is normally designated as the solvent (in this example, water). | https://www.wikidoc.org/index.php/Solute | |
f74dd19c01e7e64eecfb5cfa6ff8c166290511fd | wikidoc | Sorbitol | Sorbitol
# Overview
Sorbitol, also known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Most sorbitol is made from corn syrup, but it is also found in apples, pears, peaches, and prunes. It is converted to fructose by Sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2. While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.
# Uses
## Sweetener
Sorbitol is a sugar substitute. It may be listed under the inactive ingredients listed for some foods and products. Its INS number and E number is 420. Sorbitol has approximately 60% the sweetness of sucrose (table sugar).
Sorbitol is referred to as a nutritive sweetener because it provides dietary energy: 2.6 kilocalories (11 kilojoules) per gram versus the average 4 kilocalories (17 kilojoules) for carbohydrates. It is often used in diet foods (including diet drinks and ice cream), mints, cough syrups, and sugar-free chewing gum.
It also occurs naturally in many stone fruits and berries from trees of the genus Sorbus.
## Laxative
Sorbitol can be used as a non-stimulant laxative via an oral suspension or enema. As with other sugar alcohols, gastrointestinal distress may result when food products that contain sorbitol are consumed. Sorbitol exerts its laxative effect by drawing water into the large intestine, thereby stimulating bowel movements. Sorbitol has been determined safe for use by the elderly, although it is not recommended without consultation with a clinician. Sorbitol is found in some dried fruits and may contribute to the laxative effects of prunes. Sorbitol was discovered initially in the fresh juice of mountain ash berries in 1872. It is found in the fruits of apples, plums, pears, cherries, dates, peaches, and apricots.
## Medical applications
Sorbitol is used in bacterial culture media to distinguish the pathogenic Escherichia coli O157:H7 from most other strains of E. coli, as it is usually incapable of fermenting sorbitol, but 93% of known E. coli strains are capable of doing so.
A treatment using sorbitol and ion-exchange resin sodium polystyrene sulfonate (tradename Kayexalate), helps remove excess potassium ions when in a hyperkalaemic state. The resin exchanges sodium ions for potassium ions in the bowel, while sorbitol helps to eliminate it. In 2010 the U.S. FDA issued a warning of increased risk for GI necrosis with this combination.
## Health care, food, and cosmetic uses
Sorbitol often is used in modern cosmetics as a humectant and thickener. Sorbitol often is used in mouthwash and toothpaste. Some transparent gels can be made only with sorbitol, as it has a refractive index sufficiently high for transparent formulations. It is also used frequently in "sugar free" chewing gum.
Sorbitol is used as a cryoprotectant additive (mixed with sucrose and sodium polyphosphates) in the manufacture of surimi, a highly refined fish paste most commonly produced from Alaska pollock (Theragra chalcogramma). It is also used as a humectant in some cigarettes.
Sorbitol sometimes is used as a sweetener and humectant in cookies and other foods that are not identified as "dietary" items.
## Miscellaneous uses
A mixture of sorbitol and potassium nitrate has found some success as an amateur solid rocket fuel.
Sorbitol is identified as a potential key chemical intermediate for production of fuels from biomass resources. Carbohydrate fractions in biomass such as cellulose undergo sequential hydrolysis and hydrogenation in the presence of metal catalysts to produce sorbitol. Complete reduction of sorbitol opens the way to alkanes, such as hexane, which can be used as a biofuel. Hydrogen required for this reaction can be produced by aqueous phase reforming of sorbitol.
The above chemical reaction is exothermic; 1.5 moles of sorbitol generate approximately 1 mole of hexane. When hydrogen is co-fed, no carbon dioxide is produced.
It is also added after electroporation of yeasts in transformation protocols, allowing the cells to recover by raising the osmolarity of the medium.
# Medical importance
Aldose reductase is the first enzyme in the sorbitol-aldose reductase pathway responsible for the reduction of glucose to sorbitol, as well as the reduction of galactose to galactitol. Too much sorbitol trapped in retinal cells, the cells of the lens, and the Schwann cells that myelinate peripheral nerves can damage these cells, leading to retinopathy, cataracts and peripheral neuropathy, respectively. Aldose reductase inhibitors, which are substances that prevent or slow the action of aldose reductase, are currently being investigated as a way to prevent or delay these complications, which frequently occur in the setting of long-term hyperglycemia that accompanies poorly controlled diabetes. It is thought that these agents may help to prevent the accumulation of intracellular sorbitol that leads to cellular damage in diabetics.
# Adverse medical effects
Sorbitol may aggravate irritable bowel syndrome and similar gastrointestinal conditions, resulting in severe abdominal pain for those affected, even from small amounts ingested.
It has been noted that the sorbitol added to SPS (sodium polystyrene sulfonate, used in the treatment of hyperkalemia) can cause complications in the GI tract, including bleeding, perforated colonic ulcers, ischemic colitis and colonic necrosis, particularly in patients with uremia. The authors of the paper in question cite a study on rats (both non-uremic and uremic) in which all uremic rats died on a sorbitol enema regimen, whilst uremic rats on non-sorbitol regimens - even with SPS included - showed no signs of colonic damage. In humans, it is suggested that the risk factors for sorbitol-induced damage include "... immunosuppression, hypovolemia, postoperative setting, hypotension after hemodialysis, and peripheral vascular disease." They conclude that SPS-sorbitol should be used with caution, and that "Physicians need to be aware of SPS-sorbitol GI side effects while managing hyperkalemia."
# Overdose effects
Ingesting large amounts of sorbitol can lead to abdominal pain, flatulence, and mild to severe diarrhea. Sorbitol ingestion of 20 grams (0.7 oz) per day as sugar-free gum has led to severe diarrhea leading to unintended weight loss of 11 kilograms (24 lb) in eight months, in a woman originally weighing 52 kilograms (115 lb); another patient required hospitalization after habitually consuming 30 grams (1 oz) per day.
# Compendial status
- European Pharmacopoeia 6.1
- British Pharmacopoeia 2009 | Sorbitol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sorbitol, also known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Most sorbitol is made from corn syrup, but it is also found in apples, pears, peaches, and prunes.[1] It is converted to fructose by Sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2.[2] While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.
# Uses
## Sweetener
Sorbitol is a sugar substitute. It may be listed under the inactive ingredients listed for some foods and products. Its INS number and E number is 420. Sorbitol has approximately 60% the sweetness of sucrose (table sugar).[3]
Sorbitol is referred to as a nutritive sweetener because it provides dietary energy: 2.6 kilocalories (11 kilojoules) per gram versus the average 4 kilocalories (17 kilojoules) for carbohydrates. It is often used in diet foods (including diet drinks and ice cream), mints, cough syrups, and sugar-free chewing gum.[4]
It also occurs naturally in many stone fruits and berries from trees of the genus Sorbus.[5]
## Laxative
Sorbitol can be used as a non-stimulant laxative via an oral suspension or enema. As with other sugar alcohols, gastrointestinal distress may result when food products that contain sorbitol are consumed. Sorbitol exerts its laxative effect by drawing water into the large intestine, thereby stimulating bowel movements.[6] Sorbitol has been determined safe for use by the elderly, although it is not recommended without consultation with a clinician.[7] Sorbitol is found in some dried fruits and may contribute to the laxative effects of prunes.[8] Sorbitol was discovered initially in the fresh juice of mountain ash berries in 1872.[9] It is found in the fruits of apples, plums, pears, cherries, dates, peaches, and apricots.
## Medical applications
Sorbitol is used in bacterial culture media to distinguish the pathogenic Escherichia coli O157:H7 from most other strains of E. coli, as it is usually incapable of fermenting sorbitol, but 93% of known E. coli strains are capable of doing so.[10]
A treatment using sorbitol and ion-exchange resin sodium polystyrene sulfonate (tradename Kayexalate), helps remove excess potassium ions when in a hyperkalaemic state.[11] The resin exchanges sodium ions for potassium ions in the bowel, while sorbitol helps to eliminate it. In 2010 the U.S. FDA issued a warning of increased risk for GI necrosis with this combination.[12]
## Health care, food, and cosmetic uses
Sorbitol often is used in modern cosmetics as a humectant and thickener.[13] Sorbitol often is used in mouthwash and toothpaste. Some transparent gels can be made only with sorbitol, as it has a refractive index sufficiently high for transparent formulations. It is also used frequently in "sugar free" chewing gum.
Sorbitol is used as a cryoprotectant additive (mixed with sucrose and sodium polyphosphates) in the manufacture of surimi, a highly refined fish paste most commonly produced from Alaska pollock (Theragra chalcogramma).[citation needed] It is also used as a humectant in some cigarettes.[14]
Sorbitol sometimes is used as a sweetener and humectant in cookies and other foods that are not identified as "dietary" items.
## Miscellaneous uses
A mixture of sorbitol and potassium nitrate has found some success as an amateur solid rocket fuel.[15]
Sorbitol is identified as a potential key chemical intermediate[16] for production of fuels from biomass resources. Carbohydrate fractions in biomass such as cellulose undergo sequential hydrolysis and hydrogenation in the presence of metal catalysts to produce sorbitol.[17] Complete reduction of sorbitol opens the way to alkanes, such as hexane, which can be used as a biofuel. Hydrogen required for this reaction can be produced by aqueous phase reforming of sorbitol.[18]
The above chemical reaction is exothermic; 1.5 moles of sorbitol generate approximately 1 mole of hexane. When hydrogen is co-fed, no carbon dioxide is produced.
It is also added after electroporation of yeasts in transformation protocols, allowing the cells to recover by raising the osmolarity of the medium.
# Medical importance
Aldose reductase is the first enzyme in the sorbitol-aldose reductase pathway[19] responsible for the reduction of glucose to sorbitol, as well as the reduction of galactose to galactitol. Too much sorbitol trapped in retinal cells, the cells of the lens, and the Schwann cells that myelinate peripheral nerves can damage these cells, leading to retinopathy, cataracts and peripheral neuropathy, respectively. Aldose reductase inhibitors, which are substances that prevent or slow the action of aldose reductase, are currently being investigated as a way to prevent or delay these complications, which frequently occur in the setting of long-term hyperglycemia that accompanies poorly controlled diabetes. It is thought that these agents may help to prevent the accumulation of intracellular sorbitol that leads to cellular damage in diabetics.[20]
# Adverse medical effects
Sorbitol may aggravate irritable bowel syndrome[21] and similar gastrointestinal conditions, resulting in severe abdominal pain for those affected, even from small amounts ingested.
It has been noted that the sorbitol added to SPS (sodium polystyrene sulfonate, used in the treatment of hyperkalemia) can cause complications in the GI tract, including bleeding, perforated colonic ulcers, ischemic colitis and colonic necrosis, particularly in patients with uremia. The authors of the paper in question cite a study on rats (both non-uremic and uremic) in which all uremic rats died on a sorbitol enema regimen, whilst uremic rats on non-sorbitol regimens - even with SPS included - showed no signs of colonic damage. In humans, it is suggested that the risk factors for sorbitol-induced damage include "... immunosuppression, hypovolemia, postoperative setting, hypotension after hemodialysis, and peripheral vascular disease." They conclude that SPS-sorbitol should be used with caution, and that "Physicians need to be aware of SPS-sorbitol GI side effects while managing hyperkalemia." [22]
# Overdose effects
Ingesting large amounts of sorbitol can lead to abdominal pain, flatulence, and mild to severe diarrhea.[23] Sorbitol ingestion of 20 grams (0.7 oz) per day as sugar-free gum has led to severe diarrhea leading to unintended weight loss of 11 kilograms (24 lb) in eight months, in a woman originally weighing 52 kilograms (115 lb); another patient required hospitalization after habitually consuming 30 grams (1 oz) per day.[24]
# Compendial status
- European Pharmacopoeia[25] 6.1[26]
- British Pharmacopoeia 2009[27] | https://www.wikidoc.org/index.php/Sorbitol | |
abf6bca75a5cf8bef45ece2626caaf7c39c1c6a7 | wikidoc | Sourwood | Sourwood
Sourwood or Sorrel Tree (Oxydendrum arboreum) is the sole species in the genus Oxydendrum DC, in the family Ericaceae. It is native to eastern North America, from southern Pennsylvania south to northwest Florida and west to southern Illinois; it is most common in the lower chain of the Appalachian Mountains.
It is a small tree or large shrub, growing to 10-20 m tall with a trunk up to 50 cm diameter. The leaves are spirally arranged, deciduous, 8-20 cm long and 4-9 cm broad, with a finely serrated margin; they are dark green in summer but turn vivid red in fall. The flowers are white, bell-shaped, 6-9 mm long, produced on 15-25 cm long panicles. The fruit is a small woody capsule. The roots are shallow, and the tree grows best when there is little root competition; it also requires acidic soils for successful growth. The leaves can be chewed (but should not be swallowed) to help alleviate a dry feeling mouth. As the name of the tree implies, the effect is similar to chewing a sour piece of gum.
# Description
- Bark: Gray with a reddish tinge, deeply furrowed and scaly. Branchlets at first light yellow green, later reddish brown.
- Wood: Reddish brown, sapwood paler; heavy, hard, close-grained, will take a high polish. Sp. gr., 0.7458, weight of cu. ft., 46.48.
- Winter buds: Axillary, minute, dark red, partly immersed in the bark. Inner scales enlarge when spring growth begins.
- Leaves: Alternate, four to seven inches long, one and a half to two and a half inches wide, oblong to ablanceolate, wedge-shaped at base, serrate, acute or acuminate. Feather-veined, midrib conspicuous. They come out of the bud revolute, bronze green and shining, smooth, when full grown are dark green, shining above, pale and glaucous below. In autumn they turn bright scarlet. Petioles long and slender, stipules wanting. Heavily laden with acid.
- Flowers: June, July. Perfect, cream-white, borne in terminal panicles of secund racemes seven to eight inches long; rachis and short pedicels downy.
- Calyx: Five-parted, persistent; lobes valvate in bud.
- Corolla: Ovoid-cylindric, narrowed at the throat, cream-white, five-toothed.
- Stamens: Ten, inserted on the corolla; filaments wider than the anthers; anthers two-celled; cells opening by long chinks.
- Pistil: Ovary superior, ovoid, five-celled; style columnar; stigma simple; disk ten-toothed, ovules many.
- Fruit: Capsule, downy, five-valved, five-angled, tipped by the persistent style, the pedicels curving.
# Cultivation and uses
The Sourwood is perfectly hardy at the north and a worthy ornamental tree in lawns and parks. Its late bloom makes it desirable and its autumnal coloring is particularly beautiful and brilliant. The leaves are heavily charged with acid, and to some extent have the poise of those of the peach.
It is renowned for nectar, and for the honey which is produced from it. Juice from its blooms are used to make sourwood jelly.
The shoots were used by the Cherokee and the Catawba to make arrowshafts. | Sourwood
Sourwood or Sorrel Tree (Oxydendrum arboreum) is the sole species in the genus Oxydendrum DC, in the family Ericaceae. It is native to eastern North America, from southern Pennsylvania south to northwest Florida and west to southern Illinois; it is most common in the lower chain of the Appalachian Mountains.
It is a small tree or large shrub, growing to 10-20 m tall with a trunk up to 50 cm diameter. The leaves are spirally arranged, deciduous, 8-20 cm long and 4-9 cm broad, with a finely serrated margin; they are dark green in summer but turn vivid red in fall. The flowers are white, bell-shaped, 6-9 mm long, produced on 15-25 cm long panicles. The fruit is a small woody capsule. The roots are shallow, and the tree grows best when there is little root competition; it also requires acidic soils for successful growth. The leaves can be chewed (but should not be swallowed) to help alleviate a dry feeling mouth. As the name of the tree implies, the effect is similar to chewing a sour piece of gum.
# Description
- Bark: Gray with a reddish tinge, deeply furrowed and scaly. Branchlets at first light yellow green, later reddish brown.
- Wood: Reddish brown, sapwood paler; heavy, hard, close-grained, will take a high polish. Sp. gr., 0.7458, weight of cu. ft., 46.48.
- Winter buds: Axillary, minute, dark red, partly immersed in the bark. Inner scales enlarge when spring growth begins.
- Leaves: Alternate, four to seven inches long, one and a half to two and a half inches wide, oblong to ablanceolate, wedge-shaped at base, serrate, acute or acuminate. Feather-veined, midrib conspicuous. They come out of the bud revolute, bronze green and shining, smooth, when full grown are dark green, shining above, pale and glaucous below. In autumn they turn bright scarlet. Petioles long and slender, stipules wanting. Heavily laden with acid.
- Flowers: June, July. Perfect, cream-white, borne in terminal panicles of secund racemes seven to eight inches long; rachis and short pedicels downy.
- Calyx: Five-parted, persistent; lobes valvate in bud.
- Corolla: Ovoid-cylindric, narrowed at the throat, cream-white, five-toothed.
- Stamens: Ten, inserted on the corolla; filaments wider than the anthers; anthers two-celled; cells opening by long chinks.
- Pistil: Ovary superior, ovoid, five-celled; style columnar; stigma simple; disk ten-toothed, ovules many.
- Fruit: Capsule, downy, five-valved, five-angled, tipped by the persistent style, the pedicels curving.[1]
# Cultivation and uses
The Sourwood is perfectly hardy at the north and a worthy ornamental tree in lawns and parks. Its late bloom makes it desirable and its autumnal coloring is particularly beautiful and brilliant. The leaves are heavily charged with acid, and to some extent have the poise of those of the peach.[1]
It is renowned for nectar, and for the honey which is produced from it. Juice from its blooms are used to make sourwood jelly.
The shoots were used by the Cherokee and the Catawba to make arrowshafts.
# External links
- Oxydendrum arboreum images at bioimages.vanderbilt.edu | https://www.wikidoc.org/index.php/Sourwood | |
1b434af63d768334b8bbcf7d6967adc222f83912 | wikidoc | Soy milk | Soy milk
Soy milk (also called soya milk or soybean milk) and sometimes referred to as soy drink/beverage and even soy latte) is a beverage made from soybeans originating from China. In Asia, the drink is common among the general population and is often served as a meal. In the West, it has gained popularity as a milk substitute for those who practice veganism or who are lactose intolerant.
# Origins
Soy milk may possibly have originated in China, a region where soybean was native and used as food long before the existence of written records. Later on, the soybean and soybean foods were transplanted to Japan. Soybean milk is reputed to have been discovered and developed by Liu An of the Han Dynasty in China about 164 BC. Liu An is also credited with the development of "Doufu" (soybean curd) in China which 900 years later spread to Japan where it is known as "tofu".
Traditional soy milk, a stable emulsion of oil, water and protein, is simply an aqueous extract of whole soybeans. The liquid is produced by soaking dry soybeans, and grinding them with water. Soy milk contains about the same proportion of protein as cow's milk~ around 3.5%; also 2% fat, 2.9% carbohydrate and 0.5% ash. Soy milk can be made at home with traditional kitchen tools or with a soy milk machine.
# Nomenclature
The Chinese term for soy milk is "豆漿" (Pinyin: dòu jiāng; lit. bean + a thick liquid). In Western nations, soy milk products packaged for Chinese-speaking consumers may be labeled "豆奶" (Pinyin: dòu nǎi; lit. "bean milk"). However, there is a product in China that is called dòu nǎi (豆奶) which is a dry miscible powder made of both cow and soy milk. The Japanese term for soy milk is tōnyū (豆乳; "bean milk").
Soy milk is commonly available in vanilla and chocolate flavors as well as its original unflavored form. Plain soy milk is also commonly sweetened, though unsweetened varieties are available.
In many countries, this product may not be sold under the name milk since it is not a dairy product, hence the name soy drink.
# Prevalence
Soy milk has developed a cachet in premium coffee blends from Western restaurant chains such as Starbucks.
In Japan soy milk is much less popular than cow's milk, and the consumption of soy milk per capita is far less than that in the U.S. However, the consumption of cow's milk began decreasing around 1995 and that of soy milk began to grow. It is, however, almost always available at Japanese tofu shops and supermarkets.
Soy milk has increased in popularity in the West as a substitute for cow's milk. In some Western nations where veganism has made inroads, it is available upon request at some cafés and coffee franchises as a cow's milk substitute, sometimes at an extra cost.
# Health
## Claims of health benefits
Soy milk is nutritionally close to cow's milk, though most soy milk commercially available today is enriched with added vitamins such as vitamin B12. It naturally has about the same amount of protein (but not the same proteins) as cow milk. Natural soy milk contains little digestible calcium as it is bound to the bean's pulp, which is insoluble in a human. To counter this, many manufacturers enrich their products with calcium carbonate available to human digestion. Unlike milk it has little saturated fat and no cholesterol, which many consider to be a benefit. Lower fat varieties, however, contain less protein than cow's milk.
Soy milk is promoted as a healthy alternative to cow's milk for reasons including:
- Source of lecithin and vitamin E
- Lacks casein
- Safe for people with lactose intolerance or milk allergy
- Polyunsaturated and monounsaturated fats are good for the heart.
- Contains isoflavones, organic chemicals that may possibly be beneficial to health.
In 1995 the New England Journal of Medicine (Vol.333, No. 5) published a report from the University of Kentucky entitled "Meta-Analysis of the Effects of Soy Protein Intake on Serum Lipids." It was financed by the PTI division of DuPont, The Solae Co of St. Louis. This meta-analysis concluded that soy protein is correlated with significant decreases in serum cholesterol, low density lipoprotein (LDL, bad cholesterol), and triglyceride concentrations. However, high density lipoprotein (HDL, good cholesterol), did not increase. Soy phytoestrogens (isoflavones:genistein and daidzein) absorbed onto the soy protein were suggested as the agent reducing serum cholesterol levels. On the basis of this research PTI, in 1998, filed a petition with FDA for a health claim that soy protein may reduce cholesterol and the risk of heart disease. The FDA granted this health claim for soy: "25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease." One serving of soy milk (1 cup or 240 mL), for instance, contains 6 or 7 grams of soy protein.
In January, 2006 an American Heart Association review (in the journal Circulation) of a decade-long study of soy protein benefits cast doubt on the FDA-allowed "Heart Healthy" claim for soy protein. The panel also found that soy isoflavones do not reduce post menopause "hot flashes" in women, nor do isoflavones help prevent cancers of the breast, uterus, or prostate. Among the conclusions the authors state, "In contrast, soy products such as tofu, soy butter, soy nuts, or some soy burgers should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat. Using these and other soy foods to replace foods high in animal protein that contain saturated fat and cholesterol may confer benefits to cardiovascular health."
## Claims of negative health effects
However, the soy industry has also received similar criticism for reasons including:
- High levels of phytic acid, which binds to important nutrients like calcium, magnesium, iron, and zinc, during digestion.
- High levels of very weak estrogen-like phytoestrogens, soy isoflavones: genistein and daidzein.
- Hemagglutinin content: Soybean hemagglutinins are glycoproteins that cause red blood cells to agglutinate or clump together. Hemagglutinins, also found in peas, are concentrated in the whey protein fraction of soy milk. Hemagglutinating activity of raw soybeans is readily destroyed by moist heat treatment. This is similar to a substance found in flu viruses, although it is rather unlikely to be harmful unless the soy milk is taken intravenously.
- Processing of soybeans, includes genetic modification, to reduce lipoxygenase and thus rancidity and beany flavor, high-alkaline processing may result in lysinoalanine production as seen in caseinate or heated milk processes, nitrosamine formation from very high heat processing may occur, just as nitrates in processed meats such as bologna and hot dogs, react with gastric amino acids to form nitrosamines. Soy contains small amounts of goitrogens, as do cruciferous vegetables such as broccoli.
- Excessive consumption of soy is also linked to potential thyroid damage.
Although in general soy milk is not suitable for babies or infants, there exist baby formulas based on soy protein, i.e. soy milk, that are used primarily in the case of lactose intolerant children, those allergic to cow's milk or parental preference for a vegetarian or vegan diet. Farley's Soya Infant Formula is approved by the Vegan Society in the UK. These formulas are commonly named "soy milk", but contain extra carbohydrates, fat, vitamins and minerals. However care must be taken that children with "Soy protein intolerance" are not fed soy milk.
# Preparation
Soy milk can be made from whole soybeans or full-fat soy flour. The dry beans are soaked in water overnight or for a minimum of 3 hours or more depending on the temperature of the water. The rehydrated beans then undergo wet grinding with enough added water to give the desired solids content to the final product. The ratio of water to beans on a weight basis should be about 10:1. The resulting slurry or purée is brought to a boil in order to improve its nutritional value by heat inactivating soybean trypsin inhibitor, improve its flavor and to sterilize the product. Heating at or near the boiling point is continued for a period of time, 15-20 minutes, followed by the removal of an insoluble residue (soy pulp or okara) by filtration.
There is a simple yet profound difference between traditional Chinese and Japanese soy milk processing: the Chinese method boils the filtrate (soy milk) after a cold filtration, while the Japanese method boils the slurry first, followed by hot filtration of the slurry. The latter method results in a higher yield of soy milk but requires the use of an anti-foaming agent or natural defoamer during the boiling step. Bringing filtered soy milk to a boil avoids the dangerous problem of foaming. It is generally opaque, white or off-white in color, and approximately the same consistency as cow's milk.
For all raw soybean protein products heat is necessary to destroy the activity of the protease inhibitors naturally present in the soybean. The pancreas naturally secretes proteases to digest a protein meal. Eating raw soybeans on a regular basis causes the pancreas to hypersecrete, leading to benign tumors of the pancreas (just like exercise causes muscles to develop(hypertrophy). This is why the above heating to properly prepare soymilk is essential.
When soybeans absorb water, the endogenous enzyme, Lipoxygenase (LOX), EC 1.13.11.12 linoleate:oxidoreductase, catalyzes a reaction between polyunsaturated fatty acids and oxygen {hydroperoxidation}. LOX initiates the formation of free radicals, which can then attack other cell components. Soybean seeds are the richest known sources of LOXs. It is thought to be a defensive mechanism by the soybean against fungal invasion.
In 1967, experiments at Cornell University and the New York State Agricultural Experiment Station at Geneva, NY led to the discovery that rancid, paint-like, off-flavors of traditional soy milk can be prevented from forming by a rapid hydration grinding process of dehulled beans at temperatures above 80 °C. The quick moist heat treatment inactivates the LOX enzyme before it can have a significant negative effect on flavor. All modern bland soy milks have been heat treated in this manner to destroy LOX.
Normal mature soybeans actually contain three LOX isozymes (SBL-1, SBL-2, and SBL-3) important for undesirable flavor development. One or more of these isozymes have recently (1998) been removed genetically from soybeans yielding soy milk with less cooked beany aroma and flavor and less astringency. An example of a triple LOX-free soybean is the American soybean named "Laura".
The University of Illinois has developed a soy milk that makes use of the entire soybean. What would normally constitute "insolubles" are ground so small by homogenization as to be in permanent suspension.
Commercial products labeled "soy drink" in the West are often derivatives of soy milk containing more water or added ingredients.
# Cooking
Soy milk is found in many vegan and vegetarian food products and can be used as a replacement for cow's milk in most recipes. Such substitution has a low impact on foods like pancakes, but there is a noticeable difference when making foods such as macaroni and cheese or quiche.
"Sweet" and "salty" soy milk are both traditional Chinese breakfast foods, usually accompanied by breads like mantou (steamed rolls), youtiao (deep-fried dough), and shaobing (sesame flatbread). The soy milk is typically sweetened by adding cane sugar or, sometimes, simple syrup. "Salty" soy milk is made with a combination of chopped pickled mustard greens (榨菜), dried shrimp and, for curdling, vinegar, garnished with youtiao croutons, chopped scallion (spring onions), cilantro (coriander), meat floss (肉鬆; ròu sōng), or shallot as well as sesame oil, soy sauce, chili oil or salt to taste.
Soy milk is used in many kinds of Japanese Cooking, such as in making yuba as well as sometimes a base soup for nabemono.
Tofu is produced from soy milk by further steps of curdling and then draining.
Soy milk is also used in making soy yogurt.
# Ecological impact
Using soybeans to make milk instead of raising cows is said to have ecological advantages, as the amount of soy that could be grown using the same amount of land would feed more people than if used to raise cows . This is debated as grazing land for animals is very different from land used to farm, and requires fewer pesticides. However, cows require much more energy in order to produce milk, since the farmer must feed the animal, which consumes 90 pounds of food and 25 to 50 gallons of water a day, while a soy bean needs merely water and land . Because the soybean plant is a legume, it also replenishes the nitrogen content of the soil in which it is grown.
In Brazil the explosion of soybean cultivation has led to losing large tracts of forest land leading to ecological damage , ; however, as noted in the articles, these cleared forests are planted with soy intended for animal agricultural enterprises--not human consumption: "The report, published today, follows a 7,000km chain that starts with the clearing of virgin forest by farmers and leads directly to Chicken McNuggets being sold in British and European fast food restaurants."
It was an American soil scientist, Dr. Andrew McClung, who first devised a method to grow soybeans in the Cerrado region of Brazil. He was rewarded with the 2006 World Food Prize. | Soy milk
Soy milk (also called soya milk or soybean milk) and sometimes referred to as soy drink/beverage and even soy latte) is a beverage made from soybeans originating from China. In Asia, the drink is common among the general population and is often served as a meal. In the West, it has gained popularity as a milk substitute for those who practice veganism or who are lactose intolerant.
# Origins
Soy milk may possibly have originated in China,[1] a region where soybean was native and used as food long before the existence of written records[citation needed]. Later on, the soybean and soybean foods were transplanted to Japan. Soybean milk is reputed to have been discovered and developed by Liu An of the Han Dynasty in China about 164 BC. Liu An is also credited with the development of "Doufu" (soybean curd) in China which 900 years later spread to Japan where it is known as "tofu".
Traditional soy milk, a stable emulsion of oil, water and protein, is simply an aqueous extract of whole soybeans. The liquid is produced by soaking dry soybeans, and grinding them with water. Soy milk contains about the same proportion of protein as cow's milk~ around 3.5%; also 2% fat, 2.9% carbohydrate and 0.5% ash. Soy milk can be made at home with traditional kitchen tools or with a soy milk machine.
# Nomenclature
The Chinese term for soy milk is "豆漿" (Pinyin: dòu jiāng; lit. bean + a thick liquid). In Western nations, soy milk products packaged for Chinese-speaking consumers may be labeled "豆奶" (Pinyin: dòu nǎi; lit. "bean milk"). However, there is a product in China that is called dòu nǎi (豆奶) which is a dry miscible powder made of both cow and soy milk. The Japanese term for soy milk is tōnyū (豆乳; "bean milk").
Soy milk is commonly available in vanilla and chocolate flavors as well as its original unflavored form. Plain soy milk is also commonly sweetened, though unsweetened varieties are available.
In many countries, this product may not be sold under the name milk since it is not a dairy product, hence the name soy drink.
# Prevalence
Soy milk has developed a cachet in premium coffee blends from Western restaurant chains such as Starbucks.
In Japan soy milk is much less popular than cow's milk, and the consumption of soy milk per capita is far less than that in the U.S. However, the consumption of cow's milk began decreasing around 1995 and that of soy milk began to grow[citation needed]. It is, however, almost always available at Japanese tofu shops and supermarkets[citation needed].
Soy milk has increased in popularity in the West as a substitute for cow's milk. In some Western nations where veganism has made inroads, it is available upon request at some cafés and coffee franchises as a cow's milk substitute, sometimes at an extra cost.
# Health
## Claims of health benefits
Template:Seealso
Soy milk is nutritionally close to cow's milk, though most soy milk commercially available today is enriched with added vitamins such as vitamin B12. It naturally has about the same amount of protein (but not the same proteins) as cow milk. Natural soy milk contains little digestible calcium as it is bound to the bean's pulp, which is insoluble in a human. To counter this, many manufacturers enrich their products with calcium carbonate available to human digestion. Unlike milk it has little saturated fat and no cholesterol, which many consider to be a benefit. Lower fat varieties, however, contain less protein than cow's milk.
Soy milk is promoted as a healthy alternative to cow's milk for reasons including:
- Source of lecithin and vitamin E
- Lacks casein
- Safe for people with lactose intolerance or milk allergy
- Polyunsaturated and monounsaturated fats are good for the heart.
- Contains isoflavones, organic chemicals that may possibly be beneficial to health.
In 1995 the New England Journal of Medicine (Vol.333, No. 5) published a report from the University of Kentucky entitled "Meta-Analysis of the Effects of Soy Protein Intake on Serum Lipids." It was financed by the PTI division of DuPont, The Solae Co of St. Louis. This meta-analysis concluded that soy protein is correlated with significant decreases in serum cholesterol, low density lipoprotein (LDL, bad cholesterol), and triglyceride concentrations. However, high density lipoprotein (HDL, good cholesterol), did not increase. Soy phytoestrogens (isoflavones:genistein and daidzein) absorbed onto the soy protein were suggested as the agent reducing serum cholesterol levels.[2] On the basis of this research PTI, in 1998, filed a petition with FDA for a health claim that soy protein may reduce cholesterol and the risk of heart disease. The FDA granted this health claim for soy: "25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease." One serving of soy milk (1 cup or 240 mL), for instance, contains 6 or 7 grams of soy protein.
In January, 2006 an American Heart Association review (in the journal Circulation) of a decade-long study of soy protein benefits cast doubt on the FDA-allowed "Heart Healthy" claim for soy protein.[3] The panel also found that soy isoflavones do not reduce post menopause "hot flashes" in women, nor do isoflavones help prevent cancers of the breast, uterus, or prostate. Among the conclusions the authors state, "In contrast, soy products such as tofu, soy butter, soy nuts, or some soy burgers should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat. Using these and other soy foods to replace foods high in animal protein that contain saturated fat and cholesterol may confer benefits to cardiovascular health."[4]
## Claims of negative health effects
However, the soy industry has also received similar criticism [2][3] for reasons including:
- High levels of phytic acid, which binds to important nutrients like calcium, magnesium, iron[5], and zinc, during digestion.
- High levels of very weak estrogen-like phytoestrogens, soy isoflavones: genistein and daidzein.
- Hemagglutinin content: Soybean hemagglutinins are glycoproteins that cause red blood cells to agglutinate or clump together. Hemagglutinins, also found in peas, are concentrated in the whey protein fraction of soy milk. Hemagglutinating activity of raw soybeans is readily destroyed by moist heat treatment. This is similar to a substance found in flu viruses, although it is rather unlikely to be harmful unless the soy milk is taken intravenously.
- Processing of soybeans, includes genetic modification, to reduce lipoxygenase and thus rancidity and beany flavor, high-alkaline processing may result in lysinoalanine production as seen in caseinate or heated milk processes, nitrosamine formation from very high heat processing may occur, just as nitrates in processed meats such as bologna and hot dogs, react with gastric amino acids to form nitrosamines. Soy contains small amounts of goitrogens, as do cruciferous vegetables such as broccoli.
- Excessive consumption of soy is also linked to potential thyroid damage.[6]
Although in general soy milk is not suitable for babies or infants, there exist baby formulas based on soy protein, i.e. soy milk, that are used primarily in the case of lactose intolerant children, those allergic to cow's milk or parental preference for a vegetarian or vegan diet. Farley's Soya Infant Formula is approved by the Vegan Society in the UK. These formulas are commonly named "soy milk", but contain extra carbohydrates, fat, vitamins and minerals. However care must be taken that children with "Soy protein intolerance" are not fed soy milk.
# Preparation
Soy milk can be made from whole soybeans or full-fat soy flour. The dry beans are soaked in water overnight or for a minimum of 3 hours or more depending on the temperature of the water. The rehydrated beans then undergo wet grinding with enough added water to give the desired solids content to the final product. The ratio of water to beans on a weight basis should be about 10:1. The resulting slurry or purée is brought to a boil in order to improve its nutritional value by heat inactivating soybean trypsin inhibitor, improve its flavor and to sterilize the product. Heating at or near the boiling point is continued for a period of time, 15-20 minutes, followed by the removal of an insoluble residue (soy pulp or okara) by filtration.
There is a simple yet profound difference between traditional Chinese and Japanese soy milk processing: the Chinese method boils the filtrate (soy milk) after a cold filtration, while the Japanese method boils the slurry first, followed by hot filtration of the slurry. The latter method results in a higher yield of soy milk but requires the use of an anti-foaming agent or natural defoamer during the boiling step. Bringing filtered soy milk to a boil avoids the dangerous problem of foaming. It is generally opaque, white or off-white in color, and approximately the same consistency as cow's milk.
For all raw soybean protein products heat is necessary to destroy the activity of the protease inhibitors naturally present in the soybean. The pancreas naturally secretes proteases to digest a protein meal. Eating raw soybeans on a regular basis causes the pancreas to hypersecrete, leading to benign tumors of the pancreas (just like exercise causes muscles to develop(hypertrophy). This is why the above heating to properly prepare soymilk is essential.
When soybeans absorb water, the endogenous enzyme, Lipoxygenase (LOX), EC 1.13.11.12 linoleate:oxidoreductase, catalyzes a reaction between polyunsaturated fatty acids and oxygen {hydroperoxidation}. LOX initiates the formation of free radicals, which can then attack other cell components. Soybean seeds are the richest known sources of LOXs. It is thought to be a defensive mechanism by the soybean against fungal invasion.
In 1967, experiments at Cornell University and the New York State Agricultural Experiment Station at Geneva, NY led to the discovery that rancid, paint-like, off-flavors of traditional soy milk can be prevented from forming by a rapid hydration grinding process of dehulled beans at temperatures above 80 °C. The quick moist heat treatment inactivates the LOX enzyme before it can have a significant negative effect on flavor. All modern bland soy milks have been heat treated in this manner to destroy LOX.
Normal mature soybeans actually contain three LOX isozymes (SBL-1, SBL-2, and SBL-3) important for undesirable flavor development. One or more of these isozymes have recently (1998) been removed genetically from soybeans yielding soy milk with less cooked beany aroma and flavor and less astringency. An example of a triple LOX-free soybean is the American soybean named "Laura".
The University of Illinois has developed a soy milk that makes use of the entire soybean. What would normally constitute "insolubles" are ground so small by homogenization as to be in permanent suspension.
Commercial products labeled "soy drink" in the West are often derivatives of soy milk containing more water or added ingredients.
# Cooking
Soy milk is found in many vegan and vegetarian food products and can be used as a replacement for cow's milk in most recipes. Such substitution has a low impact on foods like pancakes, but there is a noticeable difference when making foods such as macaroni and cheese or quiche.
"Sweet" and "salty" soy milk are both traditional Chinese breakfast foods, usually accompanied by breads like mantou (steamed rolls), youtiao (deep-fried dough), and shaobing (sesame flatbread). The soy milk is typically sweetened by adding cane sugar or, sometimes, simple syrup. "Salty" soy milk is made with a combination of chopped pickled mustard greens (榨菜), dried shrimp and, for curdling, vinegar, garnished with youtiao croutons, chopped scallion (spring onions), cilantro (coriander), meat floss (肉鬆; ròu sōng), or shallot as well as sesame oil, soy sauce, chili oil or salt to taste.
Soy milk is used in many kinds of Japanese Cooking, such as in making yuba as well as sometimes a base soup for nabemono.
Tofu is produced from soy milk by further steps of curdling and then draining.
Soy milk is also used in making soy yogurt.
# Ecological impact
Using soybeans to make milk instead of raising cows is said to have ecological advantages, as the amount of soy that could be grown using the same amount of land would feed more people than if used to raise cows [7]. This is debated as grazing land for animals is very different from land used to farm, and requires fewer pesticides. However, cows require much more energy in order to produce milk, since the farmer must feed the animal, which consumes 90 pounds of food and 25 to 50 gallons of water a day, while a soy bean needs merely water and land [8]. Because the soybean plant is a legume, it also replenishes the nitrogen content of the soil in which it is grown.
In Brazil the explosion of soybean cultivation has led to losing large tracts of forest land leading to ecological damage [4], [5]; however, as noted in the articles, these cleared forests are planted with soy intended for animal agricultural enterprises--not human consumption: "The report, published today, follows a 7,000km chain that starts with the clearing of virgin forest by farmers and leads directly to Chicken McNuggets being sold in British and European fast food restaurants."
It was an American soil scientist, Dr. Andrew McClung, who first devised a method to grow soybeans in the Cerrado region of Brazil. He was rewarded with the 2006 World Food Prize. [6] | https://www.wikidoc.org/index.php/Soy_milk | |
da2d6660df80356c5d7c2e0370f1b86e8bf0596c | wikidoc | Spagyric | Spagyric
Spagyric, sometimes called herbal alchemy is the production of herbal medicine by alchemical procedures. These procedures involve fermentation, distillation and the extraction of mineral components from the ash of the marc. Paracelsus stated that the true purpose of Alchemy was not for the vulgar purpose of gold making, but rather for the production of medicines. The term ‘Spagyria’ has been used by Paracelsus in his book 'Liber Paragranum', deriving from the Greek words 'spao' and 'ageiro', the essential meaning of which is to 'separate and to combine'.
He formulated that nature in itself was 'raw and unfinished' and man had the God-given task to evolve things to a higher level. As an example: The 'raw' medicinal plant would be separated into the basic components he termed 'mercurius', 'sulphur' and 'sal' and thereby cleaned of nonessential components. 'Mercurius', 'sulphur' and 'sal' were then recombined forming the medicine.
In nowadays terms this would be the extraction of the essential oils with vapor gaining the 'sulphur'. Then fermentation of the remaining plant and distilling the alcohol produced thus gaining 'mercurius'. Extraction of the mineral components from the ash of the marc which would be the 'sal'. Diluting the essential oils in the alcohol and then solving the mineral salts in it would produce the final potion.
Note that this is a simplified representation of the process which varies strongly depending on the source chosen. | Spagyric
Spagyric, sometimes called herbal alchemy is the production of herbal medicine by alchemical procedures. These procedures involve fermentation, distillation and the extraction of mineral components from the ash of the marc. Paracelsus stated that the true purpose of Alchemy was not for the vulgar purpose of gold making, but rather for the production of medicines. [1] The term ‘Spagyria’ has been used by Paracelsus in his book 'Liber Paragranum', deriving from the Greek words 'spao' and 'ageiro', the essential meaning of which is to 'separate and to combine'.
He formulated that nature in itself was 'raw and unfinished' and man had the God-given task to evolve things to a higher level. As an example: The 'raw' medicinal plant would be separated into the basic components he termed 'mercurius', 'sulphur' and 'sal' and thereby cleaned of nonessential components. 'Mercurius', 'sulphur' and 'sal' were then recombined forming the medicine.
In nowadays terms this would be the extraction of the essential oils with vapor gaining the 'sulphur'. Then fermentation of the remaining plant and distilling the alcohol produced thus gaining 'mercurius'. Extraction of the mineral components from the ash of the marc which would be the 'sal'. Diluting the essential oils in the alcohol and then solving the mineral salts in it would produce the final potion.
Note that this is a simplified representation of the process which varies strongly depending on the source chosen. | https://www.wikidoc.org/index.php/Spagyric | |
67e603b039b93b9a43f5fe91b95cef49001f33fa | wikidoc | Spectrum | Spectrum
A spectrum (plural spectra or spectrums) is a condition that is not limited to a specific set of values but can vary infinitely within a continuum. The word saw its first scientific use within the field of optics to describe the rainbow of colors in visible light when separated using a prism; it has since been applied by analogy to many fields. Thus one might talk about the spectrum of political opinion, or the spectrum of activity of a drug, or the autism spectrum. In these uses, values within a spectrum are not necessarily precisely defined numbers as in optics; exact values within the spectrum are not precisely quantifiable. Such use implies a broad range of conditions or behaviors grouped together and studied under a single title for ease of discussion.
In most modern usages of spectrum there is a unifying theme between extremes at either end. Some older usages of the word did not have a unifying theme, but they led to modern ones through a sequence of events set out below. Modern usages in mathematics did evolve from a unifying theme, but this may be difficult to recognize.
# Origins
In Latin spectrum means "image" or "apparition", including the meaning "spectre". Spectral evidence is testimony about what was done by spectres of persons not present physically, or hearsay evidence about what ghosts or apparitions of Satan said. It was used to convict a number of persons of witchcraft at Salem, Massachusetts in the late 17th century.
# Modern meaning in the physical sciences
In the 17th century the word spectrum was introduced into optics, referring to the range of colors observed when white light was dispersed through a prism. Soon the term referred to a plot of light intensity or power as a function of frequency or wavelength, also known as a spectral density.
The term spectrum was soon applied to other waves, such as sound waves, and now applies to any signal that can be decomposed into frequency components. A spectrum is a usually 2-dimensional plot, of a compound signal, depicting the components by another measure. Sometimes, the word spectrum refers to the compound signal itself, such as the "spectrum of visible light", a reference to those electromagnetic waves which are visible to the human eye. Looking at light through a prism separates visible light into its colors according to wavelength. It separates them according to its dispersion relation and a grating separates according to the grating equation and if massive particles are measured often their speed is measured. To get a spectrum, the measured function has to be transformed in their independent variable to frequencies and the dependent variable has to be reduced in regions, where the independent variable is stretched. For this imagine that the spectrum of pulse with a finite number of particles is measured on a film or a CCD. Assuming no particles are lost, any nonlinearity (compared to frequency) on the spectral separation concentrates particles at some points of the film. The same is true for taking a spectrum by scanning a monochromator with a fixed slit width. Violet at one end has the shortest wavelength and red at the other end has the longest wavelength of visible light. The colors in order are violet, blue, green, yellow, orange, red. As the wavelengths get bigger below the red visible light they become infrared, microwave, and radio. As the wavelengths get smaller above violet light, they become ultra-violet, x-ray, and gamma ray. | Spectrum
A spectrum (plural spectra or spectrums[1]) is a condition that is not limited to a specific set of values but can vary infinitely within a continuum. The word saw its first scientific use within the field of optics to describe the rainbow of colors in visible light when separated using a prism; it has since been applied by analogy to many fields. Thus one might talk about the spectrum of political opinion, or the spectrum of activity of a drug, or the autism spectrum. In these uses, values within a spectrum are not necessarily precisely defined numbers as in optics; exact values within the spectrum are not precisely quantifiable. Such use implies a broad range of conditions or behaviors grouped together and studied under a single title for ease of discussion.
In most modern usages of spectrum there is a unifying theme between extremes at either end. Some older usages of the word did not have a unifying theme, but they led to modern ones through a sequence of events set out below. Modern usages in mathematics did evolve from a unifying theme, but this may be difficult to recognize.
# Origins
In Latin spectrum means "image" or "apparition", including the meaning "spectre". Spectral evidence is testimony about what was done by spectres of persons not present physically, or hearsay evidence about what ghosts or apparitions of Satan said. It was used to convict a number of persons of witchcraft at Salem, Massachusetts in the late 17th century.
# Modern meaning in the physical sciences
In the 17th century the word spectrum was introduced into optics, referring to the range of colors observed when white light was dispersed through a prism. Soon the term referred to a plot of light intensity or power as a function of frequency or wavelength, also known as a spectral density.
The term spectrum was soon applied to other waves, such as sound waves, and now applies to any signal that can be decomposed into frequency components. A spectrum is a usually 2-dimensional plot, of a compound signal, depicting the components by another measure. Sometimes, the word spectrum refers to the compound signal itself, such as the "spectrum of visible light", a reference to those electromagnetic waves which are visible to the human eye. Looking at light through a prism separates visible light into its colors according to wavelength. It separates them according to its dispersion relation and a grating separates according to the grating equation and if massive particles are measured often their speed is measured. To get a spectrum, the measured function has to be transformed in their independent variable to frequencies and the dependent variable has to be reduced in regions, where the independent variable is stretched. For this imagine that the spectrum of pulse with a finite number of particles is measured on a film or a CCD. Assuming no particles are lost, any nonlinearity (compared to frequency) on the spectral separation concentrates particles at some points of the film. The same is true for taking a spectrum by scanning a monochromator with a fixed slit width. Violet at one end has the shortest wavelength and red at the other end has the longest wavelength of visible light. The colors in order are violet, blue, green, yellow, orange, red. As the wavelengths get bigger below the red visible light they become infrared, microwave, and radio. As the wavelengths get smaller above violet light, they become ultra-violet, x-ray, and gamma ray. | https://www.wikidoc.org/index.php/Spectrum | |
ad6a4b22fe94be32ec47ca99f3ce1e35308888cf | wikidoc | Speculum | Speculum
# Overview
A speculum is a medical tool for investigating body cavities, with a form dependent on the body cavity for which it is designed. In old texts, the speculum may also be referred to as a diopter or dioptra.
Vaginal specula were used by the Romans, and speculum artifacts have been found in Pompeii. A vaginal speculum, developed by J. Marion Sims, consists of a hollow cylinder with a rounded end that is divided into two hinged parts, somewhat like the beak of a duck. The speculum is inserted into the vagina to dilate it for examination of the vagina and cervix.
A specialized form of vaginal speculum is the weighted speculum, which consists of a broad half tube which is bent at about a 90 degree angle, with the channel of the tube on the exterior side of the angle. One end of the tube has a roughly spherical metal weight surrounding the channel of the speculum. A weighted speculum is placed in the vagina during vaginal surgery with the patient in the lithotomy position. The weight holds the speculum in place and frees the surgeon's hands for other tasks.
Vaginal specula are also used for anal surgery, although several other forms of anal specula exist. One common form, the sigmoidoscope, resembles a tube that has a removable bullet shaped insert. When the speculum is inserted into the rectum, the insert dilates the rectum to the diameter of the tube. The insert is then removed, leaving the tube to allow examination of the rectum. This style of anal speculum is one of the oldest designs for surgical instruments still in use, with examples dating back many centuries.
Ear specula resemble a funnel, and come in a variety of sizes.
Nasal specula have two relatively flat blades with handle. The instrument is hinged so that when the handles are squeezed together the blades spread laterally, allowing examination.
All specula were formerly made of metal, and sterilized after use. However, many, especially those used in Emergency Departments and Doctor's offices, are now made of plastic, and are sterile, disposable, single-use items. Those used in surgical suites are still commonly made of metal.
Vaginal and anal specula are also sometimes used as sex toys.
Contrary to some previously-held opinions, the speculum does not cause damage to the vaginal opening, as many gynecological teachers will attest. In very few states in the United States, vaginal specula are illegal for personal use, but since there was a popular cervical self-examination component to the second-wave feminist movement, many states are either much more lenient or have completely relinquished restrictions on speculum use. However, distributors still face specific guidelines about which specula may or may not be sold.
# Notes
- ↑ The Compact Edition of the Oxford English Dictionary, Oxford University Press, 1971 - see entry for diopter
- ↑ Cecilia Mettler. History of Medicine. Text "publisher - The Blakiston Co (1947)" ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | Speculum
# Overview
A speculum is a medical tool for investigating body cavities, with a form dependent on the body cavity for which it is designed. In old texts, the speculum may also be referred to as a diopter or dioptra.[1]
Vaginal specula were used by the Romans, and speculum artifacts have been found in Pompeii.[2] A vaginal speculum, developed by J. Marion Sims, consists of a hollow cylinder with a rounded end that is divided into two hinged parts, somewhat like the beak of a duck. The speculum is inserted into the vagina to dilate it for examination of the vagina and cervix.
A specialized form of vaginal speculum is the weighted speculum, which consists of a broad half tube which is bent at about a 90 degree angle, with the channel of the tube on the exterior side of the angle. One end of the tube has a roughly spherical metal weight surrounding the channel of the speculum. A weighted speculum is placed in the vagina during vaginal surgery with the patient in the lithotomy position. The weight holds the speculum in place and frees the surgeon's hands for other tasks.
Vaginal specula are also used for anal surgery, although several other forms of anal specula exist. One common form, the sigmoidoscope, resembles a tube that has a removable bullet shaped insert. When the speculum is inserted into the rectum, the insert dilates the rectum to the diameter of the tube. The insert is then removed, leaving the tube to allow examination of the rectum. This style of anal speculum is one of the oldest designs for surgical instruments still in use, with examples dating back many centuries.
Ear specula resemble a funnel, and come in a variety of sizes.
Nasal specula have two relatively flat blades with handle. The instrument is hinged so that when the handles are squeezed together the blades spread laterally, allowing examination.
All specula were formerly made of metal, and sterilized after use. However, many, especially those used in Emergency Departments and Doctor's offices, are now made of plastic, and are sterile, disposable, single-use items. Those used in surgical suites are still commonly made of metal.
Vaginal and anal specula are also sometimes used as sex toys.
Contrary to some previously-held opinions, the speculum does not cause damage to the vaginal opening, as many gynecological teachers will attest. In very few states in the United States, vaginal specula are illegal for personal use, but since there was a popular cervical self-examination component to the second-wave feminist movement, many states are either much more lenient or have completely relinquished restrictions on speculum use. However, distributors still face specific guidelines about which specula may or may not be sold.
# Notes
- ↑ The Compact Edition of the Oxford English Dictionary, Oxford University Press, 1971 - see entry for diopter
- ↑ Cecilia Mettler. History of Medicine. Text "publisher - The Blakiston Co (1947)" ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/Speculum | |
00061b3b379113565fbf2c53968d1b2973e8477c | wikidoc | Spinosad | Spinosad
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Spinosad is a Dermatological Agent that is FDA approved for the treatment of head lice. Common adverse reactions include application site erythema and ocular erythema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Spinosad Topical Suspension is indicated for the topical treatment of head lice infestation in patients four (4) years of age and older.
- Spinosad Topical Suspension should be used in the context of an overall lice management program:
- Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding and towels.
- Wash personal care items such as combs, brushes and hair clips in hot water
- A fine-tooth comb or special nit comb may be used to remove dead lice and nits.
### Dosage
- For topical use only. Spinosad Topical Suspension is not for oral, ophthalmic, or intravaginal use.
- Shake bottle well. Apply sufficient Spinosad Topical Suspension to cover dry scalp, then apply to dry hair. Depending on hair length, apply up to 120 mL (one bottle) to adequately cover scalp and hair. Leave on for 10 minutes, then thoroughly rinse off Spinosad Topical Suspension with warm water. If live lice are seen 7 days after the first treatment, a second treatment should be applied. Avoid contact with eyes.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Spinosad in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Spinosad in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Spinosad Topical Suspension is indicated for the topical treatment of head lice infestation in patients four (4) years of age and older.
- Spinosad Topical Suspension should be used in the context of an overall lice management program:
- Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding and towels.
- Wash personal care items such as combs, brushes and hair clips in hot water
- A fine-tooth comb or special nit comb may be used to remove dead lice and nits.
### Dosage
- For topical use only. Spinosad Topical Suspension is not for oral, ophthalmic, or intravaginal use.
Shake bottle well. Apply sufficient Spinosad Topical Suspension to cover dry scalp, then apply to dry hair. Depending on hair length, apply up to 120 mL (one bottle) to adequately cover scalp and hair. Leave on for 10 minutes, then thoroughly rinse off Spinosad Topical Suspension with warm water. If live lice are seen 7 days after the first treatment, a second treatment should be applied. Avoid contact with eyes.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Spinosad in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Spinosad in pediatric patients.
# Contraindications
- None
# Warnings
- Spinosad Topical Suspension contains benzyl alcohol and is not recommended for use in neonates and infants below the age of 6 months. Systemic exposure to benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
- Spinosad Topical Suspension was studied in two randomized, active-controlled trials (N=552) in subjects with head lice; the results are presented in Table 1.
- Other less common reactions (less than 1% but more than 0.1%) were application site dryness, application site exfoliation, alopecia, and dry skin.
- Systemic safety was not assessed in pediatric subjects under 4 years of age as laboratory parameters were not monitored in these controlled studies.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Spinosad in the drug label.
# Drug Interactions
There is limited information regarding Spinosad Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies with Spinosad Topical Suspension in pregnant women. Studies in humans did not assess for the absorption of benzyl alcohol contained in Spinosad Topical Suspension. Reproduction studies conducted in rats and rabbits were negative for teratogenic effects. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- No comparisons of animal exposure with human exposure are provided in this labeling due to the low systemic exposure noted in the clinical pharmacokinetic study which did not allow for the determination of human AUC values that could be used for this calculation.
- Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 10, 50 and 200 mg/kg/day spinosad were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No teratogenic effects were noted at any dose. Maternal toxicity occurred at 200 mg/kg/day. Oral doses of 2.5, 10, and 50 mg/kg/day spinosad were administered during the period of organogenesis (gestational days 7 – 19) to pregnant female rabbits. No teratogenic effects were noted at any dose. Maternal toxicity occurred at 50 mg/kg/day.
- A two-generation dietary reproduction study was conducted in rats. Oral doses of 3, 10, and 100 mg/kg/day spinosad were administered to male and female rats from 10-12 weeks prior to mating and throughout mating, parturition, and lactation. No reproductive/developmental toxicity was noted at doses up to 10 mg/kg/day. In the presence of maternal toxicity, increased dystocia in parturition, decreased gestation survival, decreased litter size, decreased pup body weight, and decreased neonatal survival occurred at a dose of 100 mg/kg/day.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Spinosad in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Spinosad during labor and delivery.
### Nursing Mothers
- Spinosad, the active ingredient in Spinosad Topical Suspension is not systemically absorbed; and therefore, will not be present in human milk. However, Spinosad Topical Suspension contains benzyl alcohol, which may be systemically absorbed through the skin, and the amount of benzyl alcohol excreted in human milk with use of Spinosad Topical Suspension is unknown. Caution should be exercised when Spinosad Topical Suspension is administered to a lactating woman. A lactating woman may choose to pump and discard breast milk for 8 hours (5 half-lives of benzyl alcohol) after use to avoid infant ingestion of benzyl alcohol.
### Pediatric Use
- The safety and effectiveness of Spinosad Topical Suspension have been established in pediatric patients 4 years of age and older with active head lice infestation.
- Safety in pediatric patients below the age of 4 years has not been established. Spinosad Topical Suspension is not recommended in pediatric patients below the age of 6 months because of the potential for increased systemic absorption due to a high ratio of skin surface area to body mass and the potential for an immature skin barrier.
- Spinosad Topical Suspension contains benzyl alcohol which has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
- The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity
### Geriatic Use
Clinical studies of Spinosad Topical Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Spinosad with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Spinosad with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Spinosad in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Spinosad in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Spinosad in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Spinosad in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- topical
### Monitoring
There is limited information regarding Monitoring of Spinosad in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Spinosad in the drug label.
# Overdosage
If oral ingestion occurs, seek medical advice immediately.
# Pharmacology
## Mechanism of Action
- Spinosad causes neuronal excitation in insects. After periods of hyperexcitation, lice become paralyzed and die.
## Structure
- Spinosad Topical Suspension, is a slightly opaque, light orange colored, viscous topical suspension.
- Spinosad, the active ingredient, is derived from the fermentation of a soil actinomycete bacterium, Saccharopolyspora spinosa.
- Spinosad is a mixture of spinosyn A and spinosyn D in a ratio of approximately 5 to 1 (spinosyn A to spinosyn D).
- Spinosyn A: The chemical name is: 1H-as-Indacenooxacyclododecin-7,a5-dione, 2-(6-deoxy-2,3,4-tri-O-methyl-alpha- L-mannopyranosyl)oxy]-13-2R,5S,6R)-5-(dimethylamino) tetrahydro-6-methyl-2H-pyran-2-yloxy-9-ethyl- 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-14-metyl-, (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-
- Spinosyn D: The chemical name is: 1H-as-Indaceno3,2- doxacyclododecin-7,15-dione, 2-(6-deoxy-2,3,4-tri-O-methyl-alpha- L-mannopyranosyl)oxy-13-2R,5S,6R)-5-(dimethylamino) tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl- 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-dimetyl-, (2S,3aSR,5aS,5bS,9S,13S,14R,16aS,16bS)-
- Spinosad Topical Suspension contains 9 mg spinosad per gram in a viscous, slightly opaque, light orange colored vehicle consisting of Water, Isopropyl Alcohol, Benzyl Alcohol, Hexylene Glycol, Propylene Glycol, Cetearyl Alcohol, Stearalkonium Chloride, Ceteareth-20, Hydroxyethyl Cellulose, Butylated Hydroxytoluene, FD&C Yellow #6.
## Pharmacodynamics
The pharmacodynamics of Spinosad Topical Suspension has not been studied.
## Pharmacokinetics
- An open-label, single-center study was conducted over a period of seven days to determine the pharmacokinetic profile of spinosad 1.8% in pediatric subjects with head lice infestation. Fourteen (14) subjects, 4 – 15 years of age, with head lice were enrolled into the study. All subjects applied a single topical (scalp) treatment of spinosad 1.8% for 10 minutes, after which the test article was washed off, and subjects underwent plasma sampling. Plasma samples were analyzed by a validated LC/MS/MS method. Results demonstrated that spinosad was below the limit of quantitation (3ng/mL) in all samples. The bioavailability of benzyl alcohol from Spinosad Topical Suspension is unknown as plasma concentrations of benzyl alcohol were not determined in these subjects.
## Nonclinical Toxicology
- In an oral (diet) mouse carcinogenicity study, spinosad was administered to CD-1 mice at doses of 0.0025, 0.008, and 0.036% in the diet (approximately 3.4, 11.4, and 50.9 mg/kg/day for males and 4.2, 13.8, and 67.0 mg/kg/day for females) for 18 months. No treatment-related tumors were noted in the mouse carcinogenicity study up to the highest doses evaluated in this study of 50.9 mg/kg/day in male mice and 13.8 mg/kg/day in female mice. Female mice treated with a dose of 67.0 mg/kg/day were not evaluated in this study due to high mortality.
- In an oral (diet) rat carcinogenicity study, spinosad was administered to Fischer 344 rats at doses of 0.005, 0.02, 0.05, and 0.1% in the diet (approximately 2.4, 9.5, 24.1 and 49.4 mg/kg/day for males and 3.0, 12.0, 30.1 and 62.8 mg/kg/day for females) for 24 months. No treatment-related tumors were noted in the rat carcinogenicity study in male or female rats up to the highest doses evaluated in this study of 24.1 mg/kg/day in male rats and 30.1 mg/kg/day in female rats. Rats in the highest dose group in this study were not evaluated due to high mortality.
- Spinosad demonstrated no evidence of mutagenic or clastogenic potential based on the results of four in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, and rat hepatocyte unscheduled DNA synthesis assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay).
- Oral administration of spinosad (in diet) to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 10 mg/kg/day
# Clinical Studies
- Two multicenter, randomized, investigator-blind, activecontrolled studies were conducted in 1038 subjects 6 months of age and older with head lice infestation. A total of 552 subjects were treated with Spinosad Topical Suspension. For the evaluation of efficacy, the youngest subject from each household was considered to be the primary subject of the household, and other members in the household were enrolled in the study as secondary subjects, and evaluated for all safety parameters.
- In Study 1, 91 primary subjects were randomized to Spinosad Topical Suspension, and 89 primary subjects were randomized to permethrin 1%. In Study 2, 83 and 84 primary subjects were randomized to Spinosad Topical Suspension and permethrin 1%, respectively.
- In both studies, all subjects who were treated on Day 0 returned for efficacy evaluation at Day 7. Subjects with live lice present at Day 7 received a second treatment. Subjects who were lice free on Day 7 were to return on Day 14 for evaluation. Subjects with live lice and who received a second treatment were to return on Days 14 and 21.
- Efficacy was assessed as the proportion of primary subjects who were free of live lice 14 days after the final treatment. Table 2 contains the proportion of primary subjects who were free of live lice in each of the two trials.
# How Supplied
- Spinosad Topical Suspension, 0.9% is a slightly opaque, light orange colored, viscous liquid, supplied in 4 oz (120 mL) high density polyetheylene (HDPE) bottles. NDC 28595-570-04
## Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Keep out of reach of children
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 120 ML BOTTLE CARTON
### Ingredients and Appearance
# Patient Counseling Information
The patient should be instructed as follows:
- Shake bottle well immediately prior to use
- Use Spinosad Topical Suspension only on dry scalp and dry scalp hair.
- Do not swallow.
- Avoid contact with eyes. If Spinosad Topical Suspension gets in or near the eyes, rinse thoroughly with water.
- Wash hands after applying Spinosad Topical Suspension
- Use Spinosad Topical Suspension on children only under direct supervision of an adult.
- If pregnant or breastfeeding, consult a physician before use.
### PATIENT INFORMATION
PATIENT INSTRUCTIONS FOR USE
# Precautions with Alcohol
- Alcohol-Spinosad interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SPINOSAD®
# Look-Alike Drug Names
- There is limited information regarding look alike drug names.
# Drug Shortage Status
# Price | Spinosad
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Spinosad is a Dermatological Agent that is FDA approved for the treatment of head lice. Common adverse reactions include application site erythema and ocular erythema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Spinosad Topical Suspension is indicated for the topical treatment of head lice infestation in patients four (4) years of age and older.
- Spinosad Topical Suspension should be used in the context of an overall lice management program:
- Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding and towels.
- Wash personal care items such as combs, brushes and hair clips in hot water
- A fine-tooth comb or special nit comb may be used to remove dead lice and nits.
### Dosage
- For topical use only. Spinosad Topical Suspension is not for oral, ophthalmic, or intravaginal use.
- Shake bottle well. Apply sufficient Spinosad Topical Suspension to cover dry scalp, then apply to dry hair. Depending on hair length, apply up to 120 mL (one bottle) to adequately cover scalp and hair. Leave on for 10 minutes, then thoroughly rinse off Spinosad Topical Suspension with warm water. If live lice are seen 7 days after the first treatment, a second treatment should be applied. Avoid contact with eyes.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Spinosad in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Spinosad in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Spinosad Topical Suspension is indicated for the topical treatment of head lice infestation in patients four (4) years of age and older.
- Spinosad Topical Suspension should be used in the context of an overall lice management program:
- Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding and towels.
- Wash personal care items such as combs, brushes and hair clips in hot water
- A fine-tooth comb or special nit comb may be used to remove dead lice and nits.
### Dosage
- For topical use only. Spinosad Topical Suspension is not for oral, ophthalmic, or intravaginal use.
Shake bottle well. Apply sufficient Spinosad Topical Suspension to cover dry scalp, then apply to dry hair. Depending on hair length, apply up to 120 mL (one bottle) to adequately cover scalp and hair. Leave on for 10 minutes, then thoroughly rinse off Spinosad Topical Suspension with warm water. If live lice are seen 7 days after the first treatment, a second treatment should be applied. Avoid contact with eyes.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Spinosad in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Spinosad in pediatric patients.
# Contraindications
- None
# Warnings
- Spinosad Topical Suspension contains benzyl alcohol and is not recommended for use in neonates and infants below the age of 6 months. Systemic exposure to benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
- Spinosad Topical Suspension was studied in two randomized, active-controlled trials (N=552) in subjects with head lice; the results are presented in Table 1.
- Other less common reactions (less than 1% but more than 0.1%) were application site dryness, application site exfoliation, alopecia, and dry skin.
- Systemic safety was not assessed in pediatric subjects under 4 years of age as laboratory parameters were not monitored in these controlled studies.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Spinosad in the drug label.
# Drug Interactions
There is limited information regarding Spinosad Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies with Spinosad Topical Suspension in pregnant women. Studies in humans did not assess for the absorption of benzyl alcohol contained in Spinosad Topical Suspension. Reproduction studies conducted in rats and rabbits were negative for teratogenic effects. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- No comparisons of animal exposure with human exposure are provided in this labeling due to the low systemic exposure noted in the clinical pharmacokinetic study which did not allow for the determination of human AUC values that could be used for this calculation.
- Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 10, 50 and 200 mg/kg/day spinosad were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No teratogenic effects were noted at any dose. Maternal toxicity occurred at 200 mg/kg/day. Oral doses of 2.5, 10, and 50 mg/kg/day spinosad were administered during the period of organogenesis (gestational days 7 – 19) to pregnant female rabbits. No teratogenic effects were noted at any dose. Maternal toxicity occurred at 50 mg/kg/day.
- A two-generation dietary reproduction study was conducted in rats. Oral doses of 3, 10, and 100 mg/kg/day spinosad were administered to male and female rats from 10-12 weeks prior to mating and throughout mating, parturition, and lactation. No reproductive/developmental toxicity was noted at doses up to 10 mg/kg/day. In the presence of maternal toxicity, increased dystocia in parturition, decreased gestation survival, decreased litter size, decreased pup body weight, and decreased neonatal survival occurred at a dose of 100 mg/kg/day.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Spinosad in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Spinosad during labor and delivery.
### Nursing Mothers
- Spinosad, the active ingredient in Spinosad Topical Suspension is not systemically absorbed; and therefore, will not be present in human milk. However, Spinosad Topical Suspension contains benzyl alcohol, which may be systemically absorbed through the skin, and the amount of benzyl alcohol excreted in human milk with use of Spinosad Topical Suspension is unknown. Caution should be exercised when Spinosad Topical Suspension is administered to a lactating woman. A lactating woman may choose to pump and discard breast milk for 8 hours (5 half-lives of benzyl alcohol) after use to avoid infant ingestion of benzyl alcohol.
### Pediatric Use
- The safety and effectiveness of Spinosad Topical Suspension have been established in pediatric patients 4 years of age and older with active head lice infestation.
- Safety in pediatric patients below the age of 4 years has not been established. Spinosad Topical Suspension is not recommended in pediatric patients below the age of 6 months because of the potential for increased systemic absorption due to a high ratio of skin surface area to body mass and the potential for an immature skin barrier.
- Spinosad Topical Suspension contains benzyl alcohol which has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
- The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity
### Geriatic Use
Clinical studies of Spinosad Topical Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Spinosad with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Spinosad with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Spinosad in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Spinosad in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Spinosad in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Spinosad in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- topical
### Monitoring
There is limited information regarding Monitoring of Spinosad in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Spinosad in the drug label.
# Overdosage
If oral ingestion occurs, seek medical advice immediately.
# Pharmacology
## Mechanism of Action
- Spinosad causes neuronal excitation in insects. After periods of hyperexcitation, lice become paralyzed and die.
## Structure
- Spinosad Topical Suspension, is a slightly opaque, light orange colored, viscous topical suspension.
- Spinosad, the active ingredient, is derived from the fermentation of a soil actinomycete bacterium, Saccharopolyspora spinosa.
- Spinosad is a mixture of spinosyn A and spinosyn D in a ratio of approximately 5 to 1 (spinosyn A to spinosyn D).
- Spinosyn A: The chemical name is: 1H-as-Indaceno[3,2- d]oxacyclododecin-7,a5-dione, 2-(6-deoxy-2,3,4-tri-O-methyl-alpha- L-mannopyranosyl)oxy]-13-2R,5S,6R)-5-(dimethylamino) tetrahydro-6-methyl-2H-pyran-2-yloxy-9-ethyl- 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-14-metyl-, (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-
- Spinosyn D: The chemical name is: 1H-as-Indaceno3,2- doxacyclododecin-7,15-dione, 2-(6-deoxy-2,3,4-tri-O-methyl-alpha- L-mannopyranosyl)oxy-13-2R,5S,6R)-5-(dimethylamino) tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl- 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-dimetyl-, (2S,3aSR,5aS,5bS,9S,13S,14R,16aS,16bS)-
- Spinosad Topical Suspension contains 9 mg spinosad per gram in a viscous, slightly opaque, light orange colored vehicle consisting of Water, Isopropyl Alcohol, Benzyl Alcohol, Hexylene Glycol, Propylene Glycol, Cetearyl Alcohol, Stearalkonium Chloride, Ceteareth-20, Hydroxyethyl Cellulose, Butylated Hydroxytoluene, FD&C Yellow #6.
## Pharmacodynamics
The pharmacodynamics of Spinosad Topical Suspension has not been studied.
## Pharmacokinetics
- An open-label, single-center study was conducted over a period of seven days to determine the pharmacokinetic profile of spinosad 1.8% in pediatric subjects with head lice infestation. Fourteen (14) subjects, 4 – 15 years of age, with head lice were enrolled into the study. All subjects applied a single topical (scalp) treatment of spinosad 1.8% for 10 minutes, after which the test article was washed off, and subjects underwent plasma sampling. Plasma samples were analyzed by a validated LC/MS/MS method. Results demonstrated that spinosad was below the limit of quantitation (3ng/mL) in all samples. The bioavailability of benzyl alcohol from Spinosad Topical Suspension is unknown as plasma concentrations of benzyl alcohol were not determined in these subjects.
## Nonclinical Toxicology
- In an oral (diet) mouse carcinogenicity study, spinosad was administered to CD-1 mice at doses of 0.0025, 0.008, and 0.036% in the diet (approximately 3.4, 11.4, and 50.9 mg/kg/day for males and 4.2, 13.8, and 67.0 mg/kg/day for females) for 18 months. No treatment-related tumors were noted in the mouse carcinogenicity study up to the highest doses evaluated in this study of 50.9 mg/kg/day in male mice and 13.8 mg/kg/day in female mice. Female mice treated with a dose of 67.0 mg/kg/day were not evaluated in this study due to high mortality.
- In an oral (diet) rat carcinogenicity study, spinosad was administered to Fischer 344 rats at doses of 0.005, 0.02, 0.05, and 0.1% in the diet (approximately 2.4, 9.5, 24.1 and 49.4 mg/kg/day for males and 3.0, 12.0, 30.1 and 62.8 mg/kg/day for females) for 24 months. No treatment-related tumors were noted in the rat carcinogenicity study in male or female rats up to the highest doses evaluated in this study of 24.1 mg/kg/day in male rats and 30.1 mg/kg/day in female rats. Rats in the highest dose group in this study were not evaluated due to high mortality.
- Spinosad demonstrated no evidence of mutagenic or clastogenic potential based on the results of four in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, and rat hepatocyte unscheduled DNA synthesis assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay).
- Oral administration of spinosad (in diet) to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 10 mg/kg/day
# Clinical Studies
- Two multicenter, randomized, investigator-blind, activecontrolled studies were conducted in 1038 subjects 6 months of age and older with head lice infestation. A total of 552 subjects were treated with Spinosad Topical Suspension. For the evaluation of efficacy, the youngest subject from each household was considered to be the primary subject of the household, and other members in the household were enrolled in the study as secondary subjects, and evaluated for all safety parameters.
- In Study 1, 91 primary subjects were randomized to Spinosad Topical Suspension, and 89 primary subjects were randomized to permethrin 1%. In Study 2, 83 and 84 primary subjects were randomized to Spinosad Topical Suspension and permethrin 1%, respectively.
- In both studies, all subjects who were treated on Day 0 returned for efficacy evaluation at Day 7. Subjects with live lice present at Day 7 received a second treatment. Subjects who were lice free on Day 7 were to return on Day 14 for evaluation. Subjects with live lice and who received a second treatment were to return on Days 14 and 21.
- Efficacy was assessed as the proportion of primary subjects who were free of live lice 14 days after the final treatment. Table 2 contains the proportion of primary subjects who were free of live lice in each of the two trials.
# How Supplied
- Spinosad Topical Suspension, 0.9% is a slightly opaque, light orange colored, viscous liquid, supplied in 4 oz (120 mL) high density polyetheylene (HDPE) bottles. NDC 28595-570-04
## Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Keep out of reach of children
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 120 ML BOTTLE CARTON
### Ingredients and Appearance
# Patient Counseling Information
The patient should be instructed as follows:
- Shake bottle well immediately prior to use
- Use Spinosad Topical Suspension only on dry scalp and dry scalp hair.
- Do not swallow.
- Avoid contact with eyes. If Spinosad Topical Suspension gets in or near the eyes, rinse thoroughly with water.
- Wash hands after applying Spinosad Topical Suspension
- Use Spinosad Topical Suspension on children only under direct supervision of an adult.
- If pregnant or breastfeeding, consult a physician before use.
### PATIENT INFORMATION
PATIENT INSTRUCTIONS FOR USE
# Precautions with Alcohol
- Alcohol-Spinosad interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SPINOSAD®[1]
# Look-Alike Drug Names
- There is limited information regarding look alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Spinosad | |
1e5997fdfc499613518b05127a19a8b893e28def | wikidoc | Spiracle | Spiracle
Spiracles are small openings on the surface of some animals that usually lead to respiratory systems.
In elasmobranchs (sharks and rays), a spiracle is found behind each eye, and is often used to pump water through the gills while the animal is at rest (Fouts, 2003). A spiracle is also found in primitive bony fishes as the bichir.
# Spiracles in insects
In insects and some more advanced spiders, spiracles on their exoskeleton allow air to enter trachea (Solomon et.al., 2002). However, the two groups differ in how the tracheae function; in insects, the tracheal tubes primarily deliver oxygen directly to the animals' tissues. The spiracles can be opened and closed in an efficient manner to reduce water loss. This is done by contracting closer muscles surrounding the spiracle. In order to open, the muscle relaxes. The closer muscle is controlled by the central nervous system but can also react to localized chemical stimuli. Several aquatic insects have similar or alternative closing methods to prevent water from entering the trachea. In spiders, however, the oxygen diffuses into the hemolymph (Foelix, 1996). A similar diffusion effect also occurs in some insect caterpillars. In these latter groups, then, the respiration is more reminiscent of lungs (in spiders and other arachnids, they have structures called book lungs, in fact). | Spiracle
Spiracles are small openings on the surface of some animals that usually lead to respiratory systems.
In elasmobranchs (sharks and rays), a spiracle is found behind each eye, and is often used to pump water through the gills while the animal is at rest (Fouts, 2003). A spiracle is also found in primitive bony fishes as the bichir.
# Spiracles in insects
In insects and some more advanced spiders, spiracles on their exoskeleton allow air to enter trachea (Solomon et.al., 2002). However, the two groups differ in how the tracheae function; in insects, the tracheal tubes primarily deliver oxygen directly to the animals' tissues. The spiracles can be opened and closed in an efficient manner to reduce water loss. This is done by contracting closer muscles surrounding the spiracle. In order to open, the muscle relaxes. The closer muscle is controlled by the central nervous system but can also react to localized chemical stimuli. Several aquatic insects have similar or alternative closing methods to prevent water from entering the trachea. In spiders, however, the oxygen diffuses into the hemolymph (Foelix, 1996). A similar diffusion effect also occurs in some insect caterpillars. In these latter groups, then, the respiration is more reminiscent of lungs (in spiders and other arachnids, they have structures called book lungs, in fact). | https://www.wikidoc.org/index.php/Spiracle | |
dcd791df198e7a718c79436360572ec9ba0c2375 | wikidoc | Squalene | Squalene
# Overview
Squalene is a natural organic compound originally obtained for commercial purposes primarily from shark liver oil, though there are botanic sources as well, including amaranth seed, rice bran, wheat germ, and olives. All higher organisms produce squalene, including humans. It is a hydrocarbon and a triterpene.
# Role in steroid synthesis
Squalene is the biochemical precursor to the whole family of steroids Oxidation (via squalene monooxygenase) of one of the terminal double bonds of squalene yields 2,3-squalene oxide which undergoes enzyme-catalyzed cyclization to afford lanosterol, which is then elaborated into cholesterol and other steroids.
# Shark squalene
Squalene is a low density compound often stored in the bodies of cartilaginous fishes such as sharks, which lack a swim bladder and must therefore reduce their body density with fats and oils. Squalene, which is stored mainly in the shark's liver, is lighter than water with a specific gravity of 0.855. Environmental and other concerns over shark hunting have motivated its extraction from vegetable sources instead.
Recently it has become a trend for sharks to be hunted to process their livers for the purpose of making squalene health capsules. However, there is little clinical evidence to prove that, taken internally, squalene does anything to increase an individual's quality of life.
A study linking squalene, as experimental vaccine adjuvant, to individuals with the clinical signs of Gulf War syndrome was published in 2002. The published findings strongly suggest that the squalene contaminated vaccines could be responsible for the Gulf
War Syndrome symptoms seen in the study group, and recommended that a large scale epidemiological study be performed to verify or correct this. Despite repeated assurances that the vaccine was safe and necessary, a U.S. Federal Judge ruled that there was good cause to believe it was harmful, and he ordered the Pentagon to stop administering it in October 2004.
# Use as a moisturizer
Squalene is used in cosmetics as a natural moisturizer. It penetrates the skin quickly, does not leave a greasy feeling on the skin and blends well with other oils and vitamins.
# Biosynthesis
- Two molecules of farnesyl pyrophosphate condense with reduction by NADPH to form squalene - by squalene synthase; | Squalene
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Squalene is a natural organic compound originally obtained for commercial purposes primarily from shark liver oil, though there are botanic sources as well, including amaranth seed, rice bran, wheat germ, and olives. All higher organisms produce squalene, including humans. It is a hydrocarbon and a triterpene.
# Role in steroid synthesis
Squalene is the biochemical precursor to the whole family of steroids[1] Oxidation (via squalene monooxygenase) of one of the terminal double bonds of squalene yields 2,3-squalene oxide which undergoes enzyme-catalyzed cyclization to afford lanosterol, which is then elaborated into cholesterol and other steroids.
# Shark squalene
Squalene is a low density compound often stored in the bodies of cartilaginous fishes such as sharks, which lack a swim bladder and must therefore reduce their body density with fats and oils. Squalene, which is stored mainly in the shark's liver, is lighter than water with a specific gravity of 0.855. Environmental and other concerns over shark hunting have motivated its extraction from vegetable sources instead.[2]
Recently it has become a trend for sharks to be hunted to process their livers for the purpose of making squalene health capsules. However, there is little clinical evidence to prove that, taken internally, squalene does anything to increase an individual's quality of life.
A study linking squalene, as experimental vaccine adjuvant, to individuals with the clinical signs of Gulf War syndrome was published in 2002. The published findings strongly suggest that the squalene contaminated vaccines could be responsible for the Gulf
War Syndrome symptoms seen in the study group, and recommended that a large scale epidemiological study be performed to verify or correct this.[3] Despite repeated assurances that the vaccine was safe and necessary, a U.S. Federal Judge ruled that there was good cause to believe it was harmful, and he ordered the Pentagon to stop administering it in October 2004. [4]
# Use as a moisturizer
Squalene is used in cosmetics as a natural moisturizer. It penetrates the skin quickly, does not leave a greasy feeling on the skin and blends well with other oils and vitamins.
# Biosynthesis
- Two molecules of farnesyl pyrophosphate condense with reduction by NADPH to form squalene - by squalene synthase; | https://www.wikidoc.org/index.php/Squalene | |
d3e0163202dd67be875522819411ca8febbccbb1 | wikidoc | Staining | Staining
# Overview
Staining is a biochemical technique of adding a class-specific (DNA, proteins, lipids, carbohydrates) dye to a substrate to qualify or quantify the presence of a specific compound. It is similar to fluorescent tagging.
Stains and dyes are frequently used in biology and medicine to highlight structures in biological tissues for viewing, often with the aid of different microscopes. Stains may be used to define and examine bulk tissues (highlighting, for example, muscle fibers or connective tissue), cell populations (classifying different blood cells, for instance), or organelles within individual cells.
Biological staining is also used to mark cells in flow cytometry, and to flag proteins or nucleic acids in gel electrophoresis.
# In vitro staining
In vitro staining involves colouring cells or structures that are no longer living. Certain stains are often to reveal more details and features than a single stain alone. Combined with specific protocols for fixation and sample preparation, scientists and physicians can use these standard techniques as consistent, repeatable diagnostic tools. A counterstain is stain that makes cells or structures more visible, when not completely visible with the principal stain. For example, crystal violet stains only Gram-positive bacteria in Gram staining. A safranin counterstain is applied which stains all cells, allowing the identification of Gram-negative bacteria as well.
## Preparation
The preparatory steps involved depend on the type of analysis planned; some or all of the following procedures may be required.
Permeabilization involves treatment of cells with (usually) a mild surfactant. This treatment will dissolve the cell membranes, and allow larger dye molecules access to the cell's interior.
Fixation–which may itself consist of several steps–aims to preserve the shape of the cells or tissue involved as much as possible. Sometimes heat is used to kill, adhere, and alter the specimen so it will accept stains. Most chemical fixatives (chemicals causing fixation) generate chemical bonds between proteins and other substances within the sample, increasing their rigidity. Common fixative include formaldehyde, ethanol, methanol, and/or picric acid. Pieces of tissue may be embedded in paraffin wax to increase their mechanical strength and stability and to make them easier to cut into thin slices.
Mounting usually involves attaching the samples to a glass microscope slide for observation and analysis. In some cases, cells may be grown directly on a slide. For samples of loose cells (as with a blood smear or a pap smear) the sample can be directly applied to a slide. For larger pieces of tissue, thin sections (slices) are made using a microtome; these slices can then be mounted and inspected.
## Staining
At its simplest, the actual staining process may involve immersing the sample (before or after fixation and mounting) in dye solution, followed by rinsing and observation.
Many dyes, however, require the use of a mordant: a chemical compound which reacts with the stain to form an insoluble, coloured precipitate. When excess dye solution is washed away, the mordanted stain remains.
### Negative staining
A simple staining method for bacteria which is usually successful even when the "positive staining" methods detailed below fail, is to employ a negative stain. This can be achieved simply by smearing the sample on to the slide, followed by an application of nigrosin (indian ink). After drying, the microorganisms may be viewed in bright field microscopy as lighter inclusions well-contrasted against the dark environment surrounding them. Note: negative staining is a mild technique which may not destroy the microorganisms therefore it is unsuitable for studying pathogens.
### Gram staining
Gram staining is used to determine gram status to classify bacteria broadly. It is based on the composition of their cell wall. Gram staining uses crystal violet to stain cell walls, iodine as a mordant, and a fuchsin or safranin counterstain to mark all bacteria. Gram status is important in medicine; the presence or absence of a cell wall will change the bacterium's susceptibility to some antibiotics.
Gram-positive bacteria stain dark blue or violet. Their cell wall is typically rich with peptidoglycan and lacks the secondary membrane and lipopolysaccharide layer found in Gram-negative bacteria.
On most Gram-stained preparations, Gram-negative organisms will appear red or pink because they are counterstained;due to presence of higher lipid content, after alcohol-treatment, the porosity of the cell wall increases & hence the CVI complex (Crystal violet -Iodine) can pass through. Thus, the primary stain is not retained. Also, in contrast to most Gram-positive bacteria, Gram-negative bacteria have only a few layers of peptidoglycan and a secondary cell membrane made primarily of lipopolysaccharide.
### Haematoxylin and eosin (H&E) staining
Haematoxylin and eosin staining protocol is used frequently in histology to examine thin sections of tissue. Haematoxylin stains cell nuclei blue, while eosin stains cytoplasm, connective tissue and other extracellular substances pink or red. Eosin is strongly absorbed by red blood cells, colouring them bright red.
### Papanicolaou staining
Papanicolaou staining, or Pap staining, is a frequently used method for examining cell samples from various bodily secretions. It is frequently used to stain the Pap smear specimens. It uses a combination of haematoxylin, Orange G, eosin Y, Light Green SF yellowish, and sometimes Bismarck Brown Y.
### PAS staining
Periodic acid-Schiff staining is used to mark carbohydrates (glycogen, glycoprotein, proteoglycans). It is used to distinguish different types of glycogen storage diseases.
### Masson's trichrome
Masson's trichrome is (as the name implies) a three-colour staining protocol. The recipe has evolved from Masson's original technique for different specific applications, but all are well-suited to distinguish cells from surrounding connective tissue. Most recipes will produce red keratin and muscle fibers, blue or green staining of collagen and bone, light red or pink staining of cytoplasm, and black cell nuclei.
### Romanowsky stains
The Romanowsky stains are all based on a combination of eosinate (chemically reduced eosin) and methylene blue (sometimes with its oxidation products azure A and azure B). Common variants include Wright's stain, Jenner's stain, Leishman stain and Giemsa stain.
All are used to examine blood or bone marrow samples. They are preferred over H&E for inspection of blood cells because different types of leukocytes (white blood cells) can be readily distinguished. All are also suited to examination of blood to detect blood-borne parasites like malaria.
### Silver staining
Silver staining is the use of silver to stain histologic sections. This kind of staining is important especially to show proteins (for example type III collagen) and DNA. It is used to show both substances inside and outside cells. Silver staining is also used in temperature gradient gel electrophoresis.
Some cells are argentaffin. These reduce silver solution to metallic silver after formalin fixation. This method was discovered by Italian Camillo Golgi, by using a reaction between silver nitrate and potassium dichromate, thus precipitating silver chromate in some cells (see Golgi's method). Other cells are argyrophilic. These reduce silver solution to metallic silver after being exposed to the stain that contains a reductant, for example hydroquinone or formalin.
before silver staining we must clean all the glass ware with acid wash by 10% Hcl this will leads to give good result.
### Sudan staining
Sudan staining is the use of Sudan dyes to stain sudanophilic substances, usually lipids. Sudan III, Sudan IV, Oil Red O, and Sudan Black B are often used. Sudan staining is often used to determine the level of fecal fat to diagnose steatorrhea.
# In vivo staining
In vivo staining is the process of dyeing living tissues—in vivo means "in life" (compare with in vitro staining). By causing certain cells or structures to take on contrasting color(s), their form (morphology) or position within a cell or tissue can be readily seen and studied. The usual purpose is to reveal cytological details that might otherwise not be apparent; however, staining can also reveal where certain chemicals or specific chemical reactions are taking place within cells or tissues.
Often these stains are called vital stains. They are introduced to the organism while the cells are still living. However, these stains are eventually toxic to the organism, some more so than others. To achieve desired effects, the stains are used in very dilute solutions ranging from 1:5,000 to 1:500,000 (Howey, 2000). Note that many stains may be used in both living and fixed cells.
# Basic biological stains
Different stains react or concentrate in different parts of a cell or tissue, and these properties are used to advantage to reveal specific parts or areas. Some of the most common biological stains are listed below. Unless otherwise marked, all of these dyes may be used with fixed cells and tissues; vital dyes (suitable for use with living organisms) are noted.
## Acridine orange
Acridine orange (AO) is a nucleic acid selective fluorescent cationic dye useful for cell cycle determination. It is cell-permeable, and interacts with DNA and RNA by intercalation or electrostatic attractions. When bound to DNA, it is very similar spectrally to fluorescein.
## Bismarck brown
Bismarck brown (also Bismarck brown Y or Manchester brown) imparts a yellow colour to acid mucins. Bismarck brown may be used with live cells.
## Carmine
Carmine is an intensely red dye which may be used to stain glycogen, while Carmine alum is a nuclear stain. Carmine stains require the use of a mordant, usually aluminum.
## Coomassie blue
Coomassie blue (also brilliant blue) nonspecifically stains proteins a strong blue colour. It is often used in gel electrophoresis.
## Crystal violet
Crystal violet, when combined with a suitable mordant, stains cell walls purple. Crystal violet is an important component in Gram staining.
## DAPI
DAPI is a fluorescent nuclear stain, excited by ultraviolet light and showing strong blue fluorescence when bound to DNA. DAPI is not visible with regular transmission microscopy. It may be used in living or fixed cells.
## Eosin
Eosin is most often used as a counterstain to haematoxylin, imparting a pink or red colour to cytoplasmic material, cell membranes, and some extracellular structures. It also imparts a strong red colour to red blood cells. Eosin may also be used as a counterstain in some variants of Gram staining, and in many other protocols. There are actually two very closely related compounds commonly referred to as eosin. Most often used is eosin Y (also known as eosin Y ws or eosin yellowish); it has a very slightly yellowish cast. The other eosin compound is eosin B (eosin bluish or imperial red); it has a very faint bluish cast. The two dyes are interchangeable, and the use of one or the other is more a matter of preference and tradition.
## Ethidium bromide
Ethidium bromide intercalates and stains DNA, providing a fluorescent red-orange stain. Although it will not stain healthy cells, it can be used to identify cells that are in the final stages of apoptosis - such cells have much more permeable membranes. Consequently, ethidium bromide is often used as a marker for apoptosis in cells populations and to locate bands of DNA in gel electrophoresis. The stain may also be used in conjunction with acridine orange (AO) in viable cell counting. This EB/AO combined stain causes live cells to fluoresce green whilst apoptotic cells retain the distinctive red-orange fluorescence.
## Fuchsin
Fuchsin may be used to stain collagen, smooth muscle, or mitochondria.
Acid fuchsin is commonly used in Masson's trichrome and van Gieson's picro-fuchsin, and was used in an older method to stain mitochondria.
## Haematoxylin
Haematoxylin (hematoxylin in North America) is a nuclear stain. Used with a mordant, haematoxylin stains nuclei blue-violet or brown. It is most often used with eosin in H&E (haematoxylin and eosin) staining—one of the most common procedures in histology.
## Hoechst stains
Hoechst is a bis-benzimidazole derivative compound which binds to the minor groove of DNA. Often used in fluorescence microscopy for DNA staining, Hoechst stains appear yellow when dissolved in aqueous solutions and emit blue light under UV excitation. There are two major types of Hoechst: Hoechst 33258 and Hoechst 33342. The two compounds are functionally similar, but with a little difference in structure. Hoechst 33258 contains a terminal hydroxyl group and is thus more soluble in aqueous solution, however this characteristics reduces its ability to penetrate the plasma membrane. Hoechst 33342 contains a ethyl substitution on the terminal hydroxyl group (i.e. an ethylether group) making it more hydrophobic for easier plasma membrane passage.
## Iodine
Iodine is used in chemistry as an indicator for starch. When starch is mixed with iodine in solution, an intensely dark blue color develops, representing a starch/iodine complex. Starch is a substance common to most plant cells and so a weak iodine solution will stain starch present in the cells. Iodine is one component in the staining technique known as Gram staining, used in microbiology.
Lugol's solution or Lugol's iodine (IKI) is a brown solution that turns black in the presence of starches and can be used as a cell stain, making the cell nuclei more visible.
## Malachite green
Malachite green (also known as diamond green B or victoria green B) can be used as a blue-green counterstain to safranin in the Gimenez staining technique for bacteria. It also can be used to directly stain spores.
## Methyl green
Methyl green is chemically related to crystal violet, sporting an extra methyl or ethyl group.
## Methylene blue
Methylene blue is used to stain animal cells, such as human cheek cells, to make their nuclei more observable.
## Neutral red
Neutral red (or toluylene red) stains nuclei red. It is usually used as a counterstain in combination with other dyes.
## Nile blue
Nile blue (or Nile blue A) stains nuclei blue. It may be used with living cells.
## Nile red
Nile red (also known as Nile blue oxazone) is formed by boiling Nile blue with sulfuric acid. This produces a mix of Nile red and Nile blue. Nile red is a lipophilic stain; it will accumulate in lipid globules inside cells, staining them red. Nile red can be used with living cells.
## Osmium tetroxide
Osmium tetroxide is used in optical microscopy to stain lipids. It dissolves in fats, and is reduced by organic materials to elemental osmium, an easily visible black substance.
## Rhodamine
Rhodamine is a protein specific fluorescent stain commonly used in fluorescence microscopy.
## Safranin
Safranin (or Safranin O) is a nuclear stain. It produces red nuclei, and is used primarily as a counterstain. Safranin may also be used to give a yellow colour to collagen.
# Electron microscopy
Similar to light microscopy, stains can be used to selectively highlight cellular structures in transmission electron microscopy. Electron-dense compounds of heavy metals are typically used. For example, phosphotungstic acid is a common negative stain for viruses, nerves, polysaccharides, and other biological tissue materials.
Other chemicals used in electron microscopy staining include ammonium molybdate, cadmium iodide, carbohydrazide, ferric chloride, hexamine, indium trichloride, lanthanum nitrate, lead acetate, lead citrate, lead(II) nitrate, osmium tetroxide, periodic acid, phosphomolybdic acid, potassium ferricyanide, potassium ferrocyanide, Ruthenium Red, silver nitrate, sodium chloroaurate, thallium nitrate, thiosemicarbazide, uranyl acetate, uranyl nitrate, and vanadyl sulfate. | Staining
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Staining is a biochemical technique of adding a class-specific (DNA, proteins, lipids, carbohydrates) dye to a substrate to qualify or quantify the presence of a specific compound. It is similar to fluorescent tagging.
Stains and dyes are frequently used in biology and medicine to highlight structures in biological tissues for viewing, often with the aid of different microscopes. Stains may be used to define and examine bulk tissues (highlighting, for example, muscle fibers or connective tissue), cell populations (classifying different blood cells, for instance), or organelles within individual cells.
Biological staining is also used to mark cells in flow cytometry, and to flag proteins or nucleic acids in gel electrophoresis.
# In vitro staining
In vitro staining involves colouring cells or structures that are no longer living. Certain stains are often to reveal more details and features than a single stain alone. Combined with specific protocols for fixation and sample preparation, scientists and physicians can use these standard techniques as consistent, repeatable diagnostic tools. A counterstain is stain that makes cells or structures more visible, when not completely visible with the principal stain. For example, crystal violet stains only Gram-positive bacteria in Gram staining. A safranin counterstain is applied which stains all cells, allowing the identification of Gram-negative bacteria as well.
## Preparation
The preparatory steps involved depend on the type of analysis planned; some or all of the following procedures may be required.
Permeabilization involves treatment of cells with (usually) a mild surfactant. This treatment will dissolve the cell membranes, and allow larger dye molecules access to the cell's interior.
Fixation–which may itself consist of several steps–aims to preserve the shape of the cells or tissue involved as much as possible. Sometimes heat is used to kill, adhere, and alter the specimen so it will accept stains. Most chemical fixatives (chemicals causing fixation) generate chemical bonds between proteins and other substances within the sample, increasing their rigidity. Common fixative include formaldehyde, ethanol, methanol, and/or picric acid. Pieces of tissue may be embedded in paraffin wax to increase their mechanical strength and stability and to make them easier to cut into thin slices.
Mounting usually involves attaching the samples to a glass microscope slide for observation and analysis. In some cases, cells may be grown directly on a slide. For samples of loose cells (as with a blood smear or a pap smear) the sample can be directly applied to a slide. For larger pieces of tissue, thin sections (slices) are made using a microtome; these slices can then be mounted and inspected.
## Staining
At its simplest, the actual staining process may involve immersing the sample (before or after fixation and mounting) in dye solution, followed by rinsing and observation.
Many dyes, however, require the use of a mordant: a chemical compound which reacts with the stain to form an insoluble, coloured precipitate. When excess dye solution is washed away, the mordanted stain remains.
### Negative staining
A simple staining method for bacteria which is usually successful even when the "positive staining" methods detailed below fail, is to employ a negative stain. This can be achieved simply by smearing the sample on to the slide, followed by an application of nigrosin (indian ink). After drying, the microorganisms may be viewed in bright field microscopy as lighter inclusions well-contrasted against the dark environment surrounding them. Note: negative staining is a mild technique which may not destroy the microorganisms therefore it is unsuitable for studying pathogens.
### Gram staining
Gram staining is used to determine gram status to classify bacteria broadly. It is based on the composition of their cell wall. Gram staining uses crystal violet to stain cell walls, iodine as a mordant, and a fuchsin or safranin counterstain to mark all bacteria. Gram status is important in medicine; the presence or absence of a cell wall will change the bacterium's susceptibility to some antibiotics.
Gram-positive bacteria stain dark blue or violet. Their cell wall is typically rich with peptidoglycan and lacks the secondary membrane and lipopolysaccharide layer found in Gram-negative bacteria.
On most Gram-stained preparations, Gram-negative organisms will appear red or pink because they are counterstained;due to presence of higher lipid content, after alcohol-treatment, the porosity of the cell wall increases & hence the CVI complex (Crystal violet -Iodine) can pass through. Thus, the primary stain is not retained. Also, in contrast to most Gram-positive bacteria, Gram-negative bacteria have only a few layers of peptidoglycan and a secondary cell membrane made primarily of lipopolysaccharide.
### Haematoxylin and eosin (H&E) staining
Haematoxylin and eosin staining protocol is used frequently in histology to examine thin sections of tissue. Haematoxylin stains cell nuclei blue, while eosin stains cytoplasm, connective tissue and other extracellular substances pink or red. Eosin is strongly absorbed by red blood cells, colouring them bright red.
### Papanicolaou staining
Papanicolaou staining, or Pap staining, is a frequently used method for examining cell samples from various bodily secretions. It is frequently used to stain the Pap smear specimens. It uses a combination of haematoxylin, Orange G, eosin Y, Light Green SF yellowish, and sometimes Bismarck Brown Y.
### PAS staining
Periodic acid-Schiff staining is used to mark carbohydrates (glycogen, glycoprotein, proteoglycans). It is used to distinguish different types of glycogen storage diseases.
### Masson's trichrome
Masson's trichrome is (as the name implies) a three-colour staining protocol. The recipe has evolved from Masson's original technique for different specific applications, but all are well-suited to distinguish cells from surrounding connective tissue. Most recipes will produce red keratin and muscle fibers, blue or green staining of collagen and bone, light red or pink staining of cytoplasm, and black cell nuclei.
### Romanowsky stains
The Romanowsky stains are all based on a combination of eosinate (chemically reduced eosin) and methylene blue (sometimes with its oxidation products azure A and azure B). Common variants include Wright's stain, Jenner's stain, Leishman stain and Giemsa stain.
All are used to examine blood or bone marrow samples. They are preferred over H&E for inspection of blood cells because different types of leukocytes (white blood cells) can be readily distinguished. All are also suited to examination of blood to detect blood-borne parasites like malaria.
### Silver staining
Silver staining is the use of silver to stain histologic sections. This kind of staining is important especially to show proteins (for example type III collagen) and DNA. It is used to show both substances inside and outside cells. Silver staining is also used in temperature gradient gel electrophoresis.
Some cells are argentaffin. These reduce silver solution to metallic silver after formalin fixation. This method was discovered by Italian Camillo Golgi, by using a reaction between silver nitrate and potassium dichromate, thus precipitating silver chromate in some cells (see Golgi's method). Other cells are argyrophilic. These reduce silver solution to metallic silver after being exposed to the stain that contains a reductant, for example hydroquinone or formalin.
before silver staining we must clean all the glass ware with acid wash by 10% Hcl this will leads to give good result.
### Sudan staining
Sudan staining is the use of Sudan dyes to stain sudanophilic substances, usually lipids. Sudan III, Sudan IV, Oil Red O, and Sudan Black B are often used. Sudan staining is often used to determine the level of fecal fat to diagnose steatorrhea.
# In vivo staining
In vivo staining is the process of dyeing living tissues—in vivo means "in life" (compare with in vitro staining). By causing certain cells or structures to take on contrasting color(s), their form (morphology) or position within a cell or tissue can be readily seen and studied. The usual purpose is to reveal cytological details that might otherwise not be apparent; however, staining can also reveal where certain chemicals or specific chemical reactions are taking place within cells or tissues.
Often these stains are called vital stains. They are introduced to the organism while the cells are still living. However, these stains are eventually toxic to the organism, some more so than others. To achieve desired effects, the stains are used in very dilute solutions ranging from 1:5,000 to 1:500,000 (Howey, 2000). Note that many stains may be used in both living and fixed cells.
# Basic biological stains
Different stains react or concentrate in different parts of a cell or tissue, and these properties are used to advantage to reveal specific parts or areas. Some of the most common biological stains are listed below. Unless otherwise marked, all of these dyes may be used with fixed cells and tissues; vital dyes (suitable for use with living organisms) are noted.
## Acridine orange
Acridine orange (AO) is a nucleic acid selective fluorescent cationic dye useful for cell cycle determination. It is cell-permeable, and interacts with DNA and RNA by intercalation or electrostatic attractions. When bound to DNA, it is very similar spectrally to fluorescein.
## Bismarck brown
Bismarck brown (also Bismarck brown Y or Manchester brown) imparts a yellow colour to acid mucins. Bismarck brown may be used with live cells.
## Carmine
Carmine is an intensely red dye which may be used to stain glycogen, while Carmine alum is a nuclear stain. Carmine stains require the use of a mordant, usually aluminum.
## Coomassie blue
Coomassie blue (also brilliant blue) nonspecifically stains proteins a strong blue colour. It is often used in gel electrophoresis.
## Crystal violet
Crystal violet, when combined with a suitable mordant, stains cell walls purple. Crystal violet is an important component in Gram staining.
## DAPI
DAPI is a fluorescent nuclear stain, excited by ultraviolet light and showing strong blue fluorescence when bound to DNA. DAPI is not visible with regular transmission microscopy. It may be used in living or fixed cells.
## Eosin
Eosin is most often used as a counterstain to haematoxylin, imparting a pink or red colour to cytoplasmic material, cell membranes, and some extracellular structures. It also imparts a strong red colour to red blood cells. Eosin may also be used as a counterstain in some variants of Gram staining, and in many other protocols. There are actually two very closely related compounds commonly referred to as eosin. Most often used is eosin Y (also known as eosin Y ws or eosin yellowish); it has a very slightly yellowish cast. The other eosin compound is eosin B (eosin bluish or imperial red); it has a very faint bluish cast. The two dyes are interchangeable, and the use of one or the other is more a matter of preference and tradition.
## Ethidium bromide
Ethidium bromide intercalates and stains DNA, providing a fluorescent red-orange stain. Although it will not stain healthy cells, it can be used to identify cells that are in the final stages of apoptosis - such cells have much more permeable membranes. Consequently, ethidium bromide is often used as a marker for apoptosis in cells populations and to locate bands of DNA in gel electrophoresis. The stain may also be used in conjunction with acridine orange (AO) in viable cell counting. This EB/AO combined stain causes live cells to fluoresce green whilst apoptotic cells retain the distinctive red-orange fluorescence.
## Fuchsin
Fuchsin may be used to stain collagen, smooth muscle, or mitochondria.
Acid fuchsin is commonly used in Masson's trichrome and van Gieson's picro-fuchsin, and was used in an older method to stain mitochondria.
## Haematoxylin
Haematoxylin (hematoxylin in North America) is a nuclear stain. Used with a mordant, haematoxylin stains nuclei blue-violet or brown. It is most often used with eosin in H&E (haematoxylin and eosin) staining—one of the most common procedures in histology.
## Hoechst stains
Hoechst is a bis-benzimidazole derivative compound which binds to the minor groove of DNA. Often used in fluorescence microscopy for DNA staining, Hoechst stains appear yellow when dissolved in aqueous solutions and emit blue light under UV excitation. There are two major types of Hoechst: Hoechst 33258 and Hoechst 33342. The two compounds are functionally similar, but with a little difference in structure. Hoechst 33258 contains a terminal hydroxyl group and is thus more soluble in aqueous solution, however this characteristics reduces its ability to penetrate the plasma membrane. Hoechst 33342 contains a ethyl substitution on the terminal hydroxyl group (i.e. an ethylether group) making it more hydrophobic for easier plasma membrane passage.
## Iodine
Iodine is used in chemistry as an indicator for starch. When starch is mixed with iodine in solution, an intensely dark blue color develops, representing a starch/iodine complex. Starch is a substance common to most plant cells and so a weak iodine solution will stain starch present in the cells. Iodine is one component in the staining technique known as Gram staining, used in microbiology.
Lugol's solution or Lugol's iodine (IKI) is a brown solution that turns black in the presence of starches and can be used as a cell stain, making the cell nuclei more visible.
## Malachite green
Malachite green (also known as diamond green B or victoria green B) can be used as a blue-green counterstain to safranin in the Gimenez staining technique for bacteria. It also can be used to directly stain spores.
## Methyl green
Methyl green is chemically related to crystal violet, sporting an extra methyl or ethyl group.
## Methylene blue
Methylene blue is used to stain animal cells, such as human cheek cells, to make their nuclei more observable.
## Neutral red
Neutral red (or toluylene red) stains nuclei red. It is usually used as a counterstain in combination with other dyes.
## Nile blue
Nile blue (or Nile blue A) stains nuclei blue. It may be used with living cells.
## Nile red
Nile red (also known as Nile blue oxazone) is formed by boiling Nile blue with sulfuric acid. This produces a mix of Nile red and Nile blue. Nile red is a lipophilic stain; it will accumulate in lipid globules inside cells, staining them red. Nile red can be used with living cells.
## Osmium tetroxide
Osmium tetroxide is used in optical microscopy to stain lipids. It dissolves in fats, and is reduced by organic materials to elemental osmium, an easily visible black substance.
## Rhodamine
Rhodamine is a protein specific fluorescent stain commonly used in fluorescence microscopy.
## Safranin
Safranin (or Safranin O) is a nuclear stain. It produces red nuclei, and is used primarily as a counterstain. Safranin may also be used to give a yellow colour to collagen.
# Electron microscopy
Similar to light microscopy, stains can be used to selectively highlight cellular structures in transmission electron microscopy. Electron-dense compounds of heavy metals are typically used. For example, phosphotungstic acid is a common negative stain for viruses, nerves, polysaccharides, and other biological tissue materials.
Other chemicals used in electron microscopy staining include ammonium molybdate, cadmium iodide, carbohydrazide, ferric chloride, hexamine, indium trichloride, lanthanum nitrate, lead acetate, lead citrate, lead(II) nitrate, osmium tetroxide, periodic acid, phosphomolybdic acid, potassium ferricyanide, potassium ferrocyanide, Ruthenium Red, silver nitrate, sodium chloroaurate, thallium nitrate, thiosemicarbazide, uranyl acetate, uranyl nitrate, and vanadyl sulfate. [2] | https://www.wikidoc.org/index.php/Stain_(biology) | |
c36ad92d0fc29485225e24a4fb7c7ec870c929b6 | wikidoc | Standard | Standard
A technical standard is an established norm or requirement. It is usually a formal document that establishes uniform engineering or technical criteria, methods, processes and practices.
A technical standard can also be a controlled artifact or similar formal means used for calibration. Reference Standards and certified reference materials have an assigned value by direct comparison with a reference base. A primary standard is usually under jurisdication of a national standards body. Secondary, tertiary, check standards and standard materials may be used for reference in a metrology system.
This article discusses formal technical standards. A custom, convention, company product, corporate standard, etc which becomes generally accepted and dominant is often called a de facto standard.
A technical standard can be developed privately or unilaterally, for example by a corporation, regulatory body, military, etc. Standards can also be developed by groups such as trade unions, and trade associations. Standards organizations usually have more diverse input and usually develop voluntary standards: these might become mandatory if adopted by a government, business contract, etc.
The standardization process may be by edict or may involve the formal consensus of technical experts.
# Types of Standards
The primary types of technical standards are:
- A standard specification is an explicit set of requirements for an item, material, component, system or service. It is often used to formalize the technical aspects of a procurement agreement or contract. For example, there may be a specification for a turbine blade for a jet engine which defines the exact material and performance requirements.
- A standard Goal
- A standard test method describes a definitive procedure which produces a test result. It may involve making a careful personal observation or conducting a highly technical measurement. For example, a physical property of a material is often affected by the precise method of testing: any reference to the property should therefore reference the test method used.
- A standard procedure (or standard practice) gives a set of instructions for performing operations or functions. For example, there are detailed standard operating procedures for operation of a nuclear power plant.
- A standard guide is general information or options which do not require a specific course of action.
- A standard definition is formally established terminology.
# Enforcement
Many standards are written as voluntary standards. Interested parties may participate in the development voluntarily and the use of the finished standard is voluntary. The standards organization usually does not have any way to impose their use or to enforce compliance. People and organizations may choose to use or not to use a published voluntary standard.
Some standards are written to be mandatory standards. A defense standard is mandatory in relation to that use: It may be voluntarily referenced by a different organization. A standard written and published by a government regulator is mandatory for that use. (A standard which is enforced by law is sometimes called a de jure standard.) A corporation may write its own standard for its mandatory use.
The use of some voluntary standards may sometimes become mandatory.
- A voluntary standard may be referenced or adopted by a government or regulatory body. Its use becomes mandatory within the scope of its legal reference. Enforcement is by the regulator or government body which chose to reference the standard.
- A voluntary standard may be referenced or adopted by a private organization or become part of a legal contract. The voluntary standard becomes mandatory within the scope of that usage or contract.
- A voluntary standard sometimes may sometimse become so common and dominant that its use becomes expected.. Enforcement of a de facto standard is usually by free market forces.
# Availability
Standards may be:
- Public documents available on the internet, public library, etc. (Some technical standards may be found at a major central library or at the library of a good technical university.)
- Published documents which are available for purchase.
- Private documents owned by an organization or corporation. These are used and circulated as they determine necessary or useful.
- Documents open for public use but with intellectual property (copyright, etc) associated with them.
- Closed or controlled documents which contain trade secrets or classified information.
# Geographic levels
When a geographically defined community needs to solve a community-wide coordination problem, it can adopt an existing standard, or produce a new one.
The main geographic levels are:
- National standard: by National standards organizations.
- Regional standard: see standards of the Regional standards organizations. For example, CEN standards.
- International standard: see International standards organizations Example, ISO and ASTM International.
National/Regional/International standards is one way of overcoming technical barriers in inter-local or inter-regional commerce caused by differences among technical regulations and standards developed independently and separately by each local, local standards organisation, or local company. Technical barriers arise when different groups come together, each with a large user base, doing some well established thing that between them is mutually incompatible. Establishing national/regional/international standards is one way of preventing or overcoming this problem.
# Usage
The existence of a published standard does not imply that it is always useful or correct. For example, if an item complies with a certain standard, there is not necessarily assurance that it is fit for any particular use. The people who use the item or service (engineers, trade unions, etc) or specify it (building codes, government, industry, etc) have the responsibility to consider the available standards, specify the correct one, enforce compliance, and use the item correctly. Validation of suitability is necessary.
Standards often get reviewed, revised and updated. It is critical that the most current version of a published standard be used. The originator or standard writing body often has the current versions listed on its web site. | Standard
Template:Otheruses4
A technical standard is an established norm or requirement. It is usually a formal document that establishes uniform engineering or technical criteria, methods, processes and practices.
A technical standard can also be a controlled artifact or similar formal means used for calibration. Reference Standards and certified reference materials have an assigned value by direct comparison with a reference base. A primary standard is usually under jurisdication of a national standards body. Secondary, tertiary, check standards and standard materials may be used for reference in a metrology system.
This article discusses formal technical standards. A custom, convention, company product, corporate standard, etc which becomes generally accepted and dominant is often called a de facto standard.
A technical standard can be developed privately or unilaterally, for example by a corporation, regulatory body, military, etc. Standards can also be developed by groups such as trade unions, and trade associations. Standards organizations usually have more diverse input and usually develop voluntary standards: these might become mandatory if adopted by a government, business contract, etc.
The standardization process may be by edict or may involve the formal consensus [1] of technical experts.
# Types of Standards
The primary types of technical standards are:
- A standard specification is an explicit set of requirements for an item, material, component, system or service. It is often used to formalize the technical aspects of a procurement agreement or contract. For example, there may be a specification for a turbine blade for a jet engine which defines the exact material and performance requirements.
- A standard Goal
- A standard test method describes a definitive procedure which produces a test result. It may involve making a careful personal observation or conducting a highly technical measurement. For example, a physical property of a material is often affected by the precise method of testing: any reference to the property should therefore reference the test method used.
- A standard procedure (or standard practice) gives a set of instructions for performing operations or functions. For example, there are detailed standard operating procedures for operation of a nuclear power plant.
- A standard guide is general information or options which do not require a specific course of action.
- A standard definition is formally established terminology.
# Enforcement
Many standards are written as voluntary standards. Interested parties may participate in the development voluntarily and the use of the finished standard is voluntary. The standards organization usually does not have any way to impose their use or to enforce compliance. [2] People and organizations may choose to use or not to use a published voluntary standard.
Some standards are written to be mandatory standards. A defense standard is mandatory in relation to that use: It may be voluntarily referenced by a different organization. A standard written and published by a government regulator is mandatory for that use. (A standard which is enforced by law is sometimes called a de jure standard.) A corporation may write its own standard for its mandatory use.
The use of some voluntary standards may sometimes become mandatory.
- A voluntary standard may be referenced or adopted by a government or regulatory body. Its use becomes mandatory within the scope of its legal reference. Enforcement is by the regulator or government body which chose to reference the standard. [3] [4]
- A voluntary standard may be referenced or adopted by a private organization or become part of a legal contract. The voluntary standard becomes mandatory within the scope of that usage or contract. [5]
- A voluntary standard sometimes may sometimse become so common and dominant that its use becomes expected.. Enforcement of a de facto standard is usually by free market forces.
# Availability
Standards may be:
- Public documents available on the internet, public library, etc. (Some technical standards may be found at a major central library or at the library of a good technical university.)
- Published documents which are available for purchase.
- Private documents owned by an organization or corporation. These are used and circulated as they determine necessary or useful.
- Documents open for public use but with intellectual property (copyright, etc) associated with them. [6]
- Closed or controlled documents which contain trade secrets or classified information.
# Geographic levels
When a geographically defined community needs to solve a community-wide coordination problem, it can adopt an existing standard, or produce a new one.
The main geographic levels are:
- National standard: by National standards organizations.
- Regional standard: see standards of the Regional standards organizations. For example, CEN standards.
- International standard: see International standards organizations Example, ISO and ASTM International.
National/Regional/International standards is one way of overcoming technical barriers in inter-local or inter-regional commerce caused by differences among technical regulations and standards developed independently and separately by each local, local standards organisation, or local company. Technical barriers arise when different groups come together, each with a large user base, doing some well established thing that between them is mutually incompatible. Establishing national/regional/international standards is one way of preventing or overcoming this problem.
# Usage
The existence of a published standard does not imply that it is always useful or correct. For example, if an item complies with a certain standard, there is not necessarily assurance that it is fit for any particular use. The people who use the item or service (engineers, trade unions, etc) or specify it (building codes, government, industry, etc) have the responsibility to consider the available standards, specify the correct one, enforce compliance, and use the item correctly. Validation of suitability is necessary.
Standards often get reviewed, revised and updated. It is critical that the most current version of a published standard be used. The originator or standard writing body often has the current versions listed on its web site. | https://www.wikidoc.org/index.php/Standard | |
cd05a2050723275959489d4c56dc293bad521235 | wikidoc | Stathmin | Stathmin
Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the STMN1 gene.
Stathmin is a highly conserved 17 kDa protein that is crucial for the regulation of the cell cytoskeleton. Changes in the cytoskeleton are important because the cytoskeleton is a scaffold required for many cellular processes, such as cytoplasmic organization, cell division and cell motility. More specifically, stathmin is crucial in regulating the cell cycle. It is found solely in eukaryotes.
Its function as an important regulatory protein of microtubule dynamics has been well-characterized. Eukaryotic microtubules are one of three major components of the cell’s cytoskeleton. They are highly dynamic structures that continuously alternate between assembly and disassembly. Stathmin performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cell’s needs. Microtubules are cylindrical polymers of α,β-tubulin. Their assembly is in part determined by the concentration of free tubulin in the cytoplasm.
At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).
# Structure
Stathmin, and the related proteins SCG10 and XB3, contain a N-terminal domain (XB3 contains an additional N-terminal hydrophobic region), a 78 amino acid coiled-coil region, and a short C-terminal domain.
# Function
The function of Stathmin is to regulate the cytoskeleton of the cell. The cytoskeleton is made up of long hollow cylinders named microtubules. These microtubules are made up of alpha and beta tubulin heterodimers. The changes in cytoskeleton are known as microtubule dynamics; the addition of the tubulin subunits lead to polymerisation and their loss, depolymerisation. Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.
Additionally, Stathmin is thought to have a role in cell signaling pathway. Stathmin is a ubiquitous phosphorylated protein which makes it act as an intracellular relay for diverse regulatory pathways, functioning through a variety of second messengers.
Its phosphorylation and gene expression are regulated throughout development and in response to extracellular signals regulating cell proliferation, differentiation and function.
# Interactions
Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex. One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD). When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly. Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.
The rate of microtubule assembly is an important aspect of cell growth therefore associating regulation of stathmin with cell cycle progress. Regulation of stathmin is cell cycle dependent and controlled by the cell’s protein kinases in response to specific cell signals. Phosphorylation at four serine residues on stathmin named Ser16, Ser25, Ser38 and Ser63 causes weakened stathmin-tubulin binding. Stathmin phosphorylation increases the concentration of tubulin available in the cytoplasm for microtubule assembly. For cells to assemble the mitotic spindle necessary for initiation of the mitotic phase of the cell cycle, stathmin phosphorylation must occur. Without microtuble growth and assembly, the mitotic spindle cannot form, and the cell cycle is arrested. At cytokinesis, the last phase of the cell cycle, rapid dephosphorylation of stathmin occurs to block the cell from entering back into the cell cycle until it is ready.
# Clinical significance
Stathmin’s role in regulation of the cell cycle causes it to be an oncoprotein named oncoprotein 18 (op18). Stathmin (aka op18) can cause uncontrolled cell proliferation when mutated and not functioning properly. If stathmin is unable to bind to tubulin, it allows for constant microtubule assembly and therefore constant mitotic spindle assembly. With no regulation of the mitotic spindle, the cell cycle is capable of cycling uncontrollably resulting in the unregulated cell growth characteristic of cancer cells.
# Role in social behaviour
Mice without stathmin have deficiency in innate and learned fear. Stathmin−/− females do not assess threats well, leading to lack of innate parental care and adult social interactions. They lack motivation for retrieving pups and are unable to choose a safe location for nest-building. However, they have an enhancement in social interactions. | Stathmin
Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the STMN1 gene.
Stathmin is a highly conserved 17 kDa protein that is crucial for the regulation of the cell cytoskeleton. Changes in the cytoskeleton are important because the cytoskeleton is a scaffold required for many cellular processes, such as cytoplasmic organization, cell division and cell motility.[1] More specifically, stathmin is crucial in regulating the cell cycle.[2] It is found solely in eukaryotes.
Its function as an important regulatory protein of microtubule dynamics has been well-characterized.[3] Eukaryotic microtubules are one of three major components of the cell’s cytoskeleton. They are highly dynamic structures that continuously alternate between assembly and disassembly. Stathmin performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cell’s needs. Microtubules are cylindrical polymers of α,β-tubulin. Their assembly is in part determined by the concentration of free tubulin in the cytoplasm.[4]
At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).[3][5]
# Structure
Stathmin, and the related proteins SCG10 and XB3, contain a N-terminal domain (XB3 contains an additional N-terminal hydrophobic region), a 78 amino acid coiled-coil region, and a short C-terminal domain.
# Function
The function of Stathmin is to regulate the cytoskeleton of the cell. The cytoskeleton is made up of long hollow cylinders named microtubules. These microtubules are made up of alpha and beta tubulin heterodimers. The changes in cytoskeleton are known as microtubule dynamics; the addition of the tubulin subunits lead to polymerisation and their loss, depolymerisation.[1] Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.[2]
Additionally, Stathmin is thought to have a role in cell signaling pathway. Stathmin is a ubiquitous phosphorylated protein which makes it act as an intracellular relay for diverse regulatory pathways,[6] functioning through a variety of second messengers.
Its phosphorylation and gene expression are regulated throughout development [7] and in response to extracellular signals regulating cell proliferation, differentiation and function.[8]
# Interactions
Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex.[3] One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD).[5] When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly.[3] Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.[9]
The rate of microtubule assembly is an important aspect of cell growth therefore associating regulation of stathmin with cell cycle progress. Regulation of stathmin is cell cycle dependent and controlled by the cell’s protein kinases in response to specific cell signals.[5] Phosphorylation at four serine residues on stathmin named Ser16, Ser25, Ser38 and Ser63 causes weakened stathmin-tubulin binding. Stathmin phosphorylation increases the concentration of tubulin available in the cytoplasm for microtubule assembly. For cells to assemble the mitotic spindle necessary for initiation of the mitotic phase of the cell cycle, stathmin phosphorylation must occur. Without microtuble growth and assembly, the mitotic spindle cannot form, and the cell cycle is arrested. At cytokinesis, the last phase of the cell cycle, rapid dephosphorylation of stathmin occurs to block the cell from entering back into the cell cycle until it is ready.[5]
# Clinical significance
Stathmin’s role in regulation of the cell cycle causes it to be an oncoprotein named oncoprotein 18 (op18). Stathmin (aka op18) can cause uncontrolled cell proliferation when mutated and not functioning properly. If stathmin is unable to bind to tubulin, it allows for constant microtubule assembly and therefore constant mitotic spindle assembly. With no regulation of the mitotic spindle, the cell cycle is capable of cycling uncontrollably resulting in the unregulated cell growth characteristic of cancer cells.[5]
# Role in social behaviour
Mice without stathmin have deficiency in innate and learned fear. Stathmin−/− females do not assess threats well, leading to lack of innate parental care and adult social interactions. They lack motivation for retrieving pups and are unable to choose a safe location for nest-building. However, they have an enhancement in social interactions.[10] | https://www.wikidoc.org/index.php/Stathmin | |
8b4f8892abce5166f7ad8e73a3311024c498278c | wikidoc | Steapsin | Steapsin
Steapsin belongs to the class of digestive enzymes called lipases found in the pancreatic juice that catalyzes the hydrolysis of triglycerides (main constituent in vegetable oils and animal fat) to fatty acids and glycerol. When food travels through the oral cavity and down the esophagus into the stomach, enzymes such as pepsin are released where it cleaves large proteins into smaller peptide fragments so further digestion and absorption can occur in the duodenum, the tube that connects the stomach to the small intestine. Fats are minimally digested in the stomach by gastric lipases but most digestion occurs in the small intestine.
# Function
The lipase steapsin is secreted from the pancreas to break down triglycerides to liberate the fatty acids and glycerol. The free fatty acids can then be absorbed to the liver and kidneys where it may be converted to glyceraldehyde 3-phosphate, a constituent in the process of glycolysis to ultimately generate energy in the form of ATP via the citric acid cycle. Fatty acids that are not used for energy can then be allowed to cross the intestinal barrier to be repackaged into fatty tissue.
# Characterization
Previous studies have shown some physical characteristics of steapsin. Throughout this experiment, steapsin was found to be inherently unstable and will degrade naturally.
# Method
To quantify the activity of steapsin in vitro, olive oil was used as the fat (triglycerides) to be broken down. Steapsin was added and various experiments were conducted which thus digested olive oil to form glycerol and free fatty acids. The free fatty acid formation caused the mixture to turn acidic, thus phenolphthalein indicator was added and the mixture was titrated against 0.1M NaOH. Therefore, the steapsin activity correlates to the amount of NaOH added, and subsequent experiments can be quantified and compared this way. To simulate the factors of the stomach, all experiments were carried out at 40 C.
# pH stability
Under basic (done by adding 0.12 M sodium carbonate until pH 11) and neutral conditions, steapsin activity decreased by 10% per hour. Under acidic conditions, it was discovered that only a small quantity of free hydrochloric acid (approximately 0.02M) was required to diminish the lipolytic activity of steapsin by 80% in the first hour. This suggests that steapsin is inactivated by acid and is present in the small intestines and not the stomach.
# Temperature
After steapsin was subject to separate time course experiments heated to various temperatures, the lowest rate at which steapsin activity degraded was at 37C.
- 37 C – 8% degradation per hour
- 40 C – 10% degradation per hour
- 50 C – 99% degradation per hour
- 60 C – 99% degradation in 10 minutes
# Inhibitors
# Trypsin
Trypsin protease (enzyme that digests protein) and functions as a steapsin inhibitor. Trypsin is produced in the pancreas and secreted as trypsinogen, an inactive precursor of trypsin. The reason for this is to prevent trypsin from acting upon the pancreas. Upon entering the duodenum, enteropeptidase is secreted which activates trypsin. Since trypsin is classified as a protease, its function in the gastric tract is to act as a steapsin suppressor by digesting steapsin.
# Anti-inhibitors
# Egg Albumen
Egg albumen (egg whites) acts as a trypsin inhibitor because egg whites are full of protein which allows trypsin to act upon the egg whites instead of steapsin. This allows the trypsin to be neutralized and allows steapsin's activity to remain unchanged.
# Conclusions
When eating greasy foods:
- Eat protein (e.g. egg whites, lean meat) to allow steapsin to remain active for a longer period to break down triglycerides.
- Remember to expend the energy from these fatty acids to prevent it from being incorporated into adipose tissue. | Steapsin
Steapsin belongs to the class of digestive enzymes called lipases found in the pancreatic juice that catalyzes the hydrolysis of triglycerides (main constituent in vegetable oils and animal fat) to fatty acids and glycerol. When food travels through the oral cavity and down the esophagus into the stomach, enzymes such as pepsin are released where it cleaves large proteins into smaller peptide fragments so further digestion and absorption can occur in the duodenum, the tube that connects the stomach to the small intestine. Fats are minimally digested in the stomach by gastric lipases but most digestion occurs in the small intestine.
# Function
The lipase steapsin is secreted from the pancreas to break down triglycerides to liberate the fatty acids and glycerol. The free fatty acids can then be absorbed to the liver and kidneys where it may be converted to glyceraldehyde 3-phosphate, a constituent in the process of glycolysis to ultimately generate energy in the form of ATP via the citric acid cycle. Fatty acids that are not used for energy can then be allowed to cross the intestinal barrier to be repackaged into fatty tissue.
# Characterization
Previous studies have shown some physical characteristics of steapsin. Throughout this experiment, steapsin was found to be inherently unstable and will degrade naturally.
# Method
To quantify the activity of steapsin in vitro, olive oil was used as the fat (triglycerides) to be broken down. Steapsin was added and various experiments were conducted which thus digested olive oil to form glycerol and free fatty acids. The free fatty acid formation caused the mixture to turn acidic, thus phenolphthalein indicator was added and the mixture was titrated against 0.1M NaOH. Therefore, the steapsin activity correlates to the amount of NaOH added, and subsequent experiments can be quantified and compared this way. To simulate the factors of the stomach, all experiments were carried out at 40 C.
# pH stability
Under basic (done by adding 0.12 M sodium carbonate until pH 11) and neutral conditions, steapsin activity decreased by 10% per hour. Under acidic conditions, it was discovered that only a small quantity of free hydrochloric acid (approximately 0.02M) was required to diminish the lipolytic activity of steapsin by 80% in the first hour. This suggests that steapsin is inactivated by acid and is present in the small intestines and not the stomach.
# Temperature
After steapsin was subject to separate time course experiments heated to various temperatures, the lowest rate at which steapsin activity degraded was at 37C.
• 37 C – 8% degradation per hour
• 40 C – 10% degradation per hour
• 50 C – 99% degradation per hour
• 60 C – 99% degradation in 10 minutes
# Inhibitors
# Trypsin
Trypsin protease (enzyme that digests protein) and functions as a steapsin inhibitor. Trypsin is produced in the pancreas and secreted as trypsinogen, an inactive precursor of trypsin. The reason for this is to prevent trypsin from acting upon the pancreas. Upon entering the duodenum, enteropeptidase is secreted which activates trypsin. Since trypsin is classified as a protease, its function in the gastric tract is to act as a steapsin suppressor by digesting steapsin.
# Anti-inhibitors
# Egg Albumen
Egg albumen (egg whites) acts as a trypsin inhibitor because egg whites are full of protein which allows trypsin to act upon the egg whites instead of steapsin. This allows the trypsin to be neutralized and allows steapsin's activity to remain unchanged.
# Conclusions
When eating greasy foods:
- Eat protein (e.g. egg whites, lean meat) to allow steapsin to remain active for a longer period to break down triglycerides.
- Remember to expend the energy from these fatty acids to prevent it from being incorporated into adipose tissue.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Steapsin | |
b9e1d5509bfbcf6c09ff89c4f6a86158b1cf9b9a | wikidoc | Stenosis | Stenosis
# Overview
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure. It is also sometimes called a "stricture" (as in urethral stricture).
Stenoses of the vascular type are often associated with a noise (bruit) resulting from turbulent flow over the narrowed blood vessel. This bruit can be made audible by a stethoscope. Other, more reliable methods of diagnosing a stenosis are imaging methods including ultrasound, Magnetic Resonance Imaging/Magnetic Resonance Angiography, Computed Tomography/CT-Angiography which display anatomic imaging (i.e. the visible narrowing of a vessel) and/or flow phenomena (signs of the movement of the bodily fluid through the bodily structure).
# Causes
- atherosclerosis causes stenotic lesions in arteries.
- birth defects
- ischemia
- infection
- neoplasm
- inflammation
- iatrogenic, e.g. secondary to radiation therapy
# Types
The resulting syndrome depends on the structure affected.
Examples of vascular stenotic lesions include:
- Intermittent claudication (peripheral artery stenosis)
- Angina (coronary artery stenosis)
- Carotid artery stenosis which predispose to (strokes and transient ischaemic episodes)
- Renal artery stenosis
Stenoses/strictures of other bodily structures/organs include:
- Pyloric stenosis (gastric outflow obstruction)
- Obstructive jaundice (biliary tract stenosis)
- Bowel obstruction
- Phimosis
- Hydrocephalus
- Stenosing tenosynovitis
- Spinal stenosis
- Subglottic stenosis (SGS) | Stenosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure. It is also sometimes called a "stricture" (as in urethral stricture).
Stenoses of the vascular type are often associated with a noise (bruit) resulting from turbulent flow over the narrowed blood vessel. This bruit can be made audible by a stethoscope. Other, more reliable methods of diagnosing a stenosis are imaging methods including ultrasound, Magnetic Resonance Imaging/Magnetic Resonance Angiography, Computed Tomography/CT-Angiography which display anatomic imaging (i.e. the visible narrowing of a vessel) and/or flow phenomena (signs of the movement of the bodily fluid through the bodily structure).
# Causes
- atherosclerosis causes stenotic lesions in arteries.
- birth defects
- ischemia
- infection
- neoplasm
- inflammation
- iatrogenic, e.g. secondary to radiation therapy
# Types
The resulting syndrome depends on the structure affected.
Examples of vascular stenotic lesions include:
- Intermittent claudication (peripheral artery stenosis)
- Angina (coronary artery stenosis)
- Carotid artery stenosis which predispose to (strokes and transient ischaemic episodes)
- Renal artery stenosis
Stenoses/strictures of other bodily structures/organs include:
- Pyloric stenosis (gastric outflow obstruction)
- Obstructive jaundice (biliary tract stenosis)
- Bowel obstruction
- Phimosis
- Hydrocephalus
- Stenosing tenosynovitis
- Spinal stenosis
- Subglottic stenosis (SGS) | https://www.wikidoc.org/index.php/Stenosed | |
f2015df7ad95f3812946c80afa2af551e495f480 | wikidoc | Sterolin | Sterolin
ABCG5 and ABCG8 genes encode for two proteins sterolin-1 and -2, respectively. Sterolin-1 and –2 are two ‘half’ adenosine triphosphate binding (ATP) cassette (ABC) transporters which found to be indispensable for the regulation of sterol absorption and excretion. Mutations in either genes result in a lipid disorder, sitosterolemia.
# Locus of the genes
The molecular mechanisms regulating the absorption of dietary sterols in the body are poorly understood, and as sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols, studies have focused on the molecular basis of sitosterolemia to shed light on important principles concerning intestinal sterol absorption as well as cholesterol secretion into bile.
In 1998, sitosterolemia (STSL) locus has been mapped to the short arm of human chromosome 2 (2p21) after studying 10 well-characterized families with this disorder. Subsequently, the STSL locus has been further localized to a less than 2 centimorgans (cM) region.
In 2001, The STSL locus was found to be comprises two genes, ABCG5 and ABCG8, encoding 2 members of the ABC-transporter family, named sterolin-1 and sterolin-2, respectively, Sterolin-2, discovered after sterolin-1, is located <400 base pair (bp) upstream of sterolin-1 in the opposite orientation.
# Structure of the encoded proteins
Typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. However, the ABCG or White subfamily with its five fully characterized human members consists of half-size ABC proteins which probably dimerize to form active membrane transporters. In our case, it is suggested that ABCG5 and ABCG8 form a heterodimer . Among the half-size molecules, ABCG proteins have a peculiar domain organization characterized by a nucleotide-binding domain at the N-terminus followed by six transmembrane-spanning domains.
# Function
Under normal circumstances, a western diet contains almost equal amounts of cholesterol and noncholesterol sterols(such as plant sterols sitosterol, campesterol,and brassicasterol). However, only about 55% of total dietary cholesterol is absorbed and retained while almost none of the noncholesterol sterols are retained since the small amount of dietary non-cholesterols that do enter the body are rapidly excreted by the liver into bile, almost unchanged.
Sterolins are likely involved both in the selective transport of dietary cholesterol in and out of enterocytes and in selective sterol excretion by the liver into bile, as evidenced by the consequences when it is deficient or over expressed. The exact mechanism(s) whereby ABCG5/ABCG8 exert their effects on sterol metabolism has not yet been clarified. But it is suggested that the ABCG5/ABCG8 heterodimer shuttles cholesterol from the inner leaflet of the canalicular membrane through a chamber formed by the two half-transporters. Following ATP binding and hydrolysis, the complex undergoes a conformational change, flipping a cholesterol molecule into the outer membrane leaflet in a configuration that favors its release into the canalicular space.
Based on the clinical defects in sitosterolemia, ABCG5/ABCG8 are expressed in the liver and/or the intestine. 5 These genes respond to environmental dietary sterols, although whether they are also increased by high phytosterols has yet to be determined.
It is worth to mention that other gene products play a role in dietary-cholesterol transport (such as ABCA1).
# Disorders involving ABCG5 and ABCG8 genes
Mutations in both alleles of either ABCG5 or ABCG8 in the human results in sitosterolemia. Sitosterolemia (also known as phytosterolemia) is a rare autosomal recessively inherited lipid metabolic disorder characterized by the presence of tendon xanthomas, premature coronary artery disease and atherosclerotic disease, hemolytic episodes, arthralgias and arthritis. The hallmark of sitosterolemia is diagnostically elevated levels of plant sterols in the plasma. | Sterolin
ABCG5 and ABCG8 genes encode for two proteins sterolin-1 and -2, respectively. Sterolin-1 and –2 are two ‘half’ adenosine triphosphate binding (ATP) cassette (ABC) transporters which found to be indispensable for the regulation of sterol absorption and excretion. Mutations in either genes result in a lipid disorder, sitosterolemia.
# Locus of the genes
The molecular mechanisms regulating the absorption of dietary sterols in the body are poorly understood, and as sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols, studies have focused on the molecular basis of sitosterolemia to shed light on important principles concerning intestinal sterol absorption as well as cholesterol secretion into bile.
In 1998, sitosterolemia (STSL) locus has been mapped to the short arm of human chromosome 2 (2p21) after studying 10 well-characterized families with this disorder. Subsequently, the STSL locus has been further localized to a less than 2 centimorgans (cM) region.
In 2001, The STSL locus was found to be comprises two genes, ABCG5 and ABCG8, encoding 2 members of the ABC-transporter family, named sterolin-1 and sterolin-2, respectively, Sterolin-2, discovered after sterolin-1, is located <400 base pair (bp) upstream of sterolin-1 in the opposite orientation.
# Structure of the encoded proteins
Typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. However, the ABCG or White subfamily with its five fully characterized human members consists of half-size ABC proteins which probably dimerize to form active membrane transporters. In our case, it is suggested that ABCG5 and ABCG8 form a heterodimer . Among the half-size molecules, ABCG proteins have a peculiar domain organization characterized by a nucleotide-binding domain at the N-terminus followed by six transmembrane-spanning domains.
# Function
Under normal circumstances, a western diet contains almost equal amounts of cholesterol and noncholesterol sterols(such as plant sterols sitosterol, campesterol,and brassicasterol). However, only about 55% of total dietary cholesterol is absorbed and retained while almost none of the noncholesterol sterols are retained since the small amount of dietary non-cholesterols that do enter the body are rapidly excreted by the liver into bile, almost unchanged.
Sterolins are likely involved both in the selective transport of dietary cholesterol in and out of enterocytes and in selective sterol excretion by the liver into bile, as evidenced by the consequences when it is deficient or over expressed. The exact mechanism(s) whereby ABCG5/ABCG8 exert their effects on sterol metabolism has not yet been clarified. But it is suggested that the ABCG5/ABCG8 heterodimer shuttles cholesterol from the inner leaflet of the canalicular membrane through a chamber formed by the two half-transporters. Following ATP binding and hydrolysis, the complex undergoes a conformational change, flipping a cholesterol molecule into the outer membrane leaflet in a configuration that favors its release into the canalicular space.
Based on the clinical defects in sitosterolemia, ABCG5/ABCG8 are expressed in the liver and/or the intestine. 5 These genes respond to environmental dietary sterols, although whether they are also increased by high phytosterols has yet to be determined.
It is worth to mention that other gene products play a role in dietary-cholesterol transport (such as ABCA1).
# Disorders involving ABCG5 and ABCG8 genes
Mutations in both alleles of either ABCG5 or ABCG8 in the human results in sitosterolemia. Sitosterolemia (also known as phytosterolemia) is a rare autosomal recessively inherited lipid metabolic disorder characterized by the presence of tendon xanthomas, premature coronary artery disease and atherosclerotic disease, hemolytic episodes, arthralgias and arthritis. The hallmark of sitosterolemia is diagnostically elevated levels of plant sterols in the plasma. | https://www.wikidoc.org/index.php/Sterolin | |
aa11f37d211bb5ac1a06d3a12328716567e1037a | wikidoc | Stilbene | Stilbene
# Overview
Officially known as trans-1,2-diphenylethylene, aka, stilbene, or more specifically, (E)-stilbene, is the alkene, ethene with two phenyl groups on either carbon of the parent chain. The name was derived from the Greek word stilbos, which means shining. It should also be noted, there is also a (Z)-stilbene which is sterically hindered and less stable because of it. Also notice that (Z)-stilbene has a melting point of 5°C to 6°C, while the melting point of (E)-stilbene is in the 125°C area, this illustrates the significant differences between the two. Because (E)-stilbene is so much more common than (Z)-stilbene, this page will focus only on (E)-stilbene.
Its risk and safety phrases are:
- Template:R22 — harmful if swallowed
- Template:R37 — irritating to respiratory system
- Template:R38 — irritating to skin
- Template:R62 — possible risk of impaired fertility
- Template:S22 — do not breathe dust
- Template:S26A — in case of contact with eyes, rinse immediately with water and seek medical advice
- Template:S36 — wear suitable protective clothing
- Template:S37 — wear suitable gloves
- Template:S45 — in case of accident or if you feel unwell seek medical advice immediately, and show the label if possible
# Uses of Stilbene
Stilbene is used in manufacture of dyes and optical brighteners, and also as a phosphor and a scintillator.
Stilbene is one of the gain mediums used in dye lasers.
Many stilbene derivates (stilbenoids) are present naturally in plants. An example is resveratrol and its cousin, pterostilbene.
# Stilbene Reactions
## Halogenation of Stilbene
Simple hydrocarbons are relatively unreactive. In order to form more complex molecules, it is generally necessary to introduce more reactive functional groups. Alkenes (olefins) containing the carbon-carbon double bond may be halogenated to form alkyl halides, which are more capable of undergoing further chemical reactions.
An example of halogenation is the bromination of (E)-stilbene. Bromine is somewhat of a special case due in no small part, to its relatively enormous size compared to carbon. Since elemental bromine (Br2) is volatile and highly corrosive, pyridinium tribromide is commonly used to generate Br2 in situ.
## Green halogenation
To green this reaction, the pyridinium tribromide in situ generation of Br2 is replaced with hydrobromic acid, which is oxidized by hydrogen peroxide(H2O2).
In either case the halogenation of stilbene is as follows; as seen in the first reaction, the Br-Br bond attracts the attention of the π-bonding electrons (π-bonds being e- dense and Br being very electronegative), this leads to a weakening and eventual break (heat, plays a crucial role in driving the break forward) of the π-bond. Once the π-bond has been broken, its electrons are transferred to Br2, causing the Br-Br bond to be severed when the bonding electrons are transferred to the other bromine. At this stage there is the positively charged intermediate and the loose bromine ion (Br-), coming from the opposite direction as the Br2, the Br- loosens one of the C-Br Bonds, leaving the final brominated product.
It doesn't matter which stilbene is used for this reaction, (E)-stilbene and (Z)-stilbene will both produce 1,2-dibromo-1,2-diphenylethane. However, bromination of the (Z) isomer results in a racemic mixture of dl stilbene dibromide, while the bromination of an (E) isomer results in a majority meso-stilbene dibromide along with minor amounts of the dl enantiomers. The minor dl product in the bromination of (E)-stilbene is a result of resonance in the bromonium bridge intermediate, where a positive charge is located on one of the two bridge carbons, thus allowing for a syn-addition of a bromine anion.
## Photochemical reaction
trans-stilbene isomerizes to cis-stilbene under the influence of light. The reverse path can be induced by heat or light.
# More Information
## Spectra
- IR Spectra
- Mass Spectra
- HNMR Spectra
- CNMR Spectra | Stilbene
# Overview
Officially known as trans-1,2-diphenylethylene, aka, stilbene, or more specifically, (E)-stilbene, is the alkene, ethene with two phenyl groups on either carbon of the parent chain. The name was derived from the Greek word stilbos, which means shining. It should also be noted, there is also a (Z)-stilbene which is sterically hindered and less stable because of it. Also notice that (Z)-stilbene has a melting point of 5°C to 6°C, while the melting point of (E)-stilbene is in the 125°C area, this illustrates the significant differences between the two. Because (E)-stilbene is so much more common than (Z)-stilbene, this page will focus only on (E)-stilbene.
Its risk and safety phrases are:
- Template:R22 — harmful if swallowed
- Template:R37 — irritating to respiratory system
- Template:R38 — irritating to skin
- Template:R62 — possible risk of impaired fertility
- Template:S22 — do not breathe dust
- Template:S26A — in case of contact with eyes, rinse immediately with water and seek medical advice
- Template:S36 — wear suitable protective clothing
- Template:S37 — wear suitable gloves
- Template:S45 — in case of accident or if you feel unwell seek medical advice immediately, and show the label if possible
# Uses of Stilbene
Stilbene is used in manufacture of dyes and optical brighteners, and also as a phosphor and a scintillator.
Stilbene is one of the gain mediums used in dye lasers.
Many stilbene derivates (stilbenoids) are present naturally in plants. An example is resveratrol and its cousin, pterostilbene.
# Stilbene Reactions
## Halogenation of Stilbene
Simple hydrocarbons are relatively unreactive. In order to form more complex molecules, it is generally necessary to introduce more reactive functional groups. Alkenes (olefins) containing the carbon-carbon double bond may be halogenated to form alkyl halides, which are more capable of undergoing further chemical reactions.
An example of halogenation is the bromination of (E)-stilbene. Bromine is somewhat of a special case due in no small part, to its relatively enormous size compared to carbon. Since elemental bromine (Br2) is volatile and highly corrosive, pyridinium tribromide is commonly used to generate Br2 in situ.
## Green halogenation
To green this reaction, the pyridinium tribromide in situ generation of Br2 is replaced with hydrobromic acid, which is oxidized by hydrogen peroxide(H2O2).
In either case the halogenation of stilbene is as follows; as seen in the first reaction, the Br-Br bond attracts the attention of the π-bonding electrons (π-bonds being e- dense and Br being very electronegative), this leads to a weakening and eventual break (heat, plays a crucial role in driving the break forward) of the π-bond. Once the π-bond has been broken, its electrons are transferred to Br2, causing the Br-Br bond to be severed when the bonding electrons are transferred to the other bromine. At this stage there is the positively charged intermediate and the loose bromine ion (Br-), coming from the opposite direction as the Br2, the Br- loosens one of the C-Br Bonds, leaving the final brominated product.
It doesn't matter which stilbene is used for this reaction, (E)-stilbene and (Z)-stilbene will both produce 1,2-dibromo-1,2-diphenylethane. However, bromination of the (Z) isomer results in a racemic mixture of dl stilbene dibromide, while the bromination of an (E) isomer results in a majority meso-stilbene dibromide along with minor amounts of the dl enantiomers. The minor dl product in the bromination of (E)-stilbene is a result of resonance in the bromonium bridge intermediate, where a positive charge is located on one of the two bridge carbons, thus allowing for a syn-addition of a bromine anion.
## Photochemical reaction
trans-stilbene isomerizes to cis-stilbene under the influence of light. The reverse path can be induced by heat or light.
# More Information
## Spectra
- IR Spectra
- Mass Spectra
- HNMR Spectra
- CNMR Spectra | https://www.wikidoc.org/index.php/Stilbene | |
428dd3096df9b54eaf494d3f8348a3603e11da73 | wikidoc | Stimming | Stimming
Stimming is a jargon term for a particular form of stereotypy, a repetitive body movement (often done unconsciously) that self-stimulates one or more senses in a regulated manner. It is shorthand for self-stimulation, and a stereotypy is referred to as stimming under the hypothesis that it has a function related to sensory input. Stereotypy is one of the symptoms listed by the DSM IV for autism and is observed in about 10% of non-autistic young children. Many people with autism do not exhibit stereotypy. Common forms of stereotypy among people with autism include hand flapping, body spinning or rocking, lining up or spinning toys or other objects, echolalia, perseveration, and repeating rote phrases.
There are many theories about the function of stimming, and the reasons for its increased incidence in autistic people. For hyposensitive people, it may provide needed nervous system arousal, releasing beta-endorphins. For hypersensitive people, it may provide a "norming" effect, allowing the person to control a specific part of their sensorium, and is thus a soothing behavior.
Sometimes self-injury is viewed as a form of stimming. Usually, self-injury is very different from stimming, but people with decreased pain sensitivity may injure themselves because they like the feel of it, similar to other stims. For example, they might like the way their hand feels in the mouth when they bite themselves, while not feeling the pain of the bite. Or they might like pressure on their forehead and bang their head without it hurting, even if they are risking brain damage. | Stimming
Stimming is a jargon term for a particular form of stereotypy, a repetitive body movement (often done unconsciously) that self-stimulates one or more senses in a regulated manner. It is shorthand for self-stimulation, and a stereotypy is referred to as stimming under the hypothesis that it has a function related to sensory input.[1] Stereotypy is one of the symptoms listed by the DSM IV for autism and is observed in about 10% of non-autistic young children. Many people with autism do not exhibit stereotypy. Common forms of stereotypy among people with autism include hand flapping, body spinning or rocking, lining up or spinning toys or other objects, echolalia, perseveration, and repeating rote phrases.[2]
There are many theories about the function of stimming, and the reasons for its increased incidence in autistic people. For hyposensitive people, it may provide needed nervous system arousal, releasing beta-endorphins. For hypersensitive people, it may provide a "norming" effect, allowing the person to control a specific part of their sensorium, and is thus a soothing behavior.[3]
Sometimes self-injury is viewed as a form of stimming.[citation needed] Usually, self-injury is very different from stimming, but people with decreased pain sensitivity may injure themselves because they like the feel of it, similar to other stims.[citation needed] For example, they might like the way their hand feels in the mouth when they bite themselves, while not feeling the pain of the bite. Or they might like pressure on their forehead and bang their head without it hurting, even if they are risking brain damage. | https://www.wikidoc.org/index.php/Stimming | |
74814702c0d7fba40785b625998ff5049bdfa77c | wikidoc | Stomatin | Stomatin
Stomatin also known as human erythrocyte integral membrane protein band 7 is a protein that in humans is encoded by the STOM gene.
# Clinical significance
Stomatin is a 31 kDa integral membrane protein, named after the rare human haemolytic anaemia hereditary stomatocytosis. This gene encodes a member of a highly conserved family of integral membrane proteins. The encoded protein localizes to the cell membrane of red blood cells and other cell types, where it may regulate ion channels and transporters. Loss of localization of the encoded protein is associated with hereditary stomatocytosis, a form of hemolytic anemia.
# Function
This gene encodes a member of a highly conserved family of integral membrane proteins. The encoded protein localizes to the cell membrane of red blood cells and other cell types, where it may regulate ion channels and transporters. Loss of localization of the encoded protein is associated with hereditary stomatocytosis, a form of hemolytic anemia.
Although the wide distribution of stomatin and its constitutive expression suggest an important role for this protein in cell biology, perhaps as a “house-keeping” component, its function remains undetermined. The massive presence of stomatin in membrane-protruding folds and extensions suggests a possible structural role for this protein in the formation of these structures and/or the anchorage to the actin cytoskeleton. | Stomatin
Stomatin also known as human erythrocyte integral membrane protein band 7 is a protein that in humans is encoded by the STOM gene.[1][2]
# Clinical significance
Stomatin is a 31 kDa integral membrane protein, named after the rare human haemolytic anaemia hereditary stomatocytosis. This gene encodes a member of a highly conserved family of integral membrane proteins. The encoded protein localizes to the cell membrane of red blood cells and other cell types, where it may regulate ion channels and transporters. Loss of localization of the encoded protein is associated with hereditary stomatocytosis, a form of hemolytic anemia.[2]
# Function
This gene encodes a member of a highly conserved family of integral membrane proteins. The encoded protein localizes to the cell membrane of red blood cells and other cell types, where it may regulate ion channels and transporters. Loss of localization of the encoded protein is associated with hereditary stomatocytosis, a form of hemolytic anemia.[2]
Although the wide distribution of stomatin and its constitutive expression suggest an important role for this protein in cell biology, perhaps as a “house-keeping” component, its function remains undetermined. The massive presence of stomatin in membrane-protruding folds and extensions suggests a possible structural role for this protein in the formation of these structures and/or the anchorage to the actin cytoskeleton. | https://www.wikidoc.org/index.php/Stomatin | |
9c50582df72e527fccda5656403405030466812d | wikidoc | Stomatol | Stomatol
# Overview
Stomatol is a brand of toothpaste first sold in Sweden at the beginning of the 20th century. It was particularly notable as having been one of the first Swedish brands to recognize and to use the power of mass media. The brand was originally made by the soap manufacturer Grumme & Son, acquired 1985 by pharmaceutical company Cederroth AB. The company made extensive use of press, film and signs, both enamel and neon.
It is particularly known for the large advertisement sign which has been a prominent local landmark at Slussen in Stockholm since 1909. The Stomatol sign, made from lightbulbs, not neon tubes, was the first animated advertisement sign in Sweden (one can see the toothpaste being squeezed out of the tube). It was originally placed on the Katarinahissen elevator, but was moved in 1933 to the roof of the nearby building at Klevgränd 1 B. Technical problems have forced the electricity to be shut down between 1963 and 1972 and from 1981 until 1986.
Many Stomatol film commercials were animated. At least ten of the commercials produced in and around 1930 were drawn by Arvid Olson and Victor Bergdahl, creator of Captain Grogg.
Live action, near-feature quality ads were produced around that time by Kinocentralen and which starred popular Swedish comedic actor Thor Modéen. Modéen was well known for living a rather extravagant lifestyle, mostly paid for through his work for Stomatol.
The brand's slogan was "Stomatol - the only way to obtain healthy and strong teeth!" | Stomatol
# Overview
Stomatol is a brand of toothpaste first sold in Sweden at the beginning of the 20th century. It was particularly notable as having been one of the first Swedish brands to recognize and to use the power of mass media. The brand was originally made by the soap manufacturer Grumme & Son, acquired 1985 by pharmaceutical company Cederroth AB. The company made extensive use of press, film and signs, both enamel and neon.
It is particularly known for the large advertisement sign which has been a prominent local landmark at Slussen in Stockholm since 1909. The Stomatol sign, made from lightbulbs, not neon tubes, was the first animated advertisement sign in Sweden (one can see the toothpaste being squeezed out of the tube). It was originally placed on the Katarinahissen elevator, but was moved in 1933 to the roof of the nearby building at Klevgränd 1 B. Technical problems have forced the electricity to be shut down between 1963 and 1972 and from 1981 until 1986.
Many Stomatol film commercials were animated. At least ten of the commercials produced in and around 1930 were drawn by Arvid Olson and Victor Bergdahl, creator of Captain Grogg.
Live action, near-feature quality ads were produced around that time by Kinocentralen and which starred popular Swedish comedic actor Thor Modéen. Modéen was well known for living a rather extravagant lifestyle, mostly paid for through his work for Stomatol.
The brand's slogan was "Stomatol - the only way to obtain healthy and strong teeth!" | https://www.wikidoc.org/index.php/Stomatol | |
be650d8f71c363da59989c123b0304ee53eccd21 | wikidoc | Subacute | Subacute
Rather recent onset or somewhat rapid change.
The term "subacute" is used in contrast to acute which indicates very sudden onset or rapid change and chronic which indicates indefinite duration or virtually no change.
A chronic condition is one lasting 3 months or more, by the definition of the U.S. National Center for Health Statistics.
In ancient Greece, the "father of medicine" Hippocrates distinguished diseases that were acute (abrupt, sharp and brief) from those that were chronic. This is still a very useful distinction.
Subacute has been coined to designate the mid-ground between acute and chronic. | Subacute
Rather recent onset or somewhat rapid change.
The term "subacute" is used in contrast to acute which indicates very sudden onset or rapid change and chronic which indicates indefinite duration or virtually no change.
A chronic condition is one lasting 3 months or more, by the definition of the U.S. National Center for Health Statistics.
In ancient Greece, the "father of medicine" Hippocrates distinguished diseases that were acute (abrupt, sharp and brief) from those that were chronic. This is still a very useful distinction.
Subacute has been coined to designate the mid-ground between acute and chronic.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Subacute | |
7bf4995970b4943bfe8c2aa84d2a4084cc271920 | wikidoc | Succimer | Succimer
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Succimer is a heavy metal chelator that is FDA approved for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. Common adverse reactions include rash, diarrhea, loss of appetite, nausea, vomiting, increased liver function test.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Succimer FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Succimer in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Succimer in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Succimer is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. succimer is not indicated for prophylaxis of lead poisoning in a lead-containing environment; the use of succimer should always be accompanied by identification and removal of the source of the lead exposure.
- Start dosage at 10 mg/kg or 350 mg/m2 every eight hours for five days. Initiation of therapy at higher doses is not recommended. (See TABLE II for Dosing chart and number of capsules.) Reduce frequency of administration to 10 mg/kg or 350 mg/m2 every 12 hours (two-thirds of initial daily dosage) for an additional two weeks of therapy. A course of treatment lasts 19 days. Repeated courses may be necessary if indicated by weekly monitoring of blood lead concentration. A minimum of two weeks between courses is recommended unless blood lead levels indicate the need for more prompt treatment.
- In young pediatric patients who cannot swallow capsules, succimer can be administered by separating the capsule and sprinkling the medicated beads on a small amount of soft food or putting them in a spoon and following with fruit drink.
- Identification of the source of lead in the pediatric patient’s environment and its abatement are critical to a successful therapy outcome. Chelation therapy is not a substitute for preventing further exposure to lead and should not be used to permit continued exposure to lead.
- Patients who have received CaNa2EDTA with or without BAL may use succimer for subsequent treatment after an interval of four weeks. Data on the concomitant use of succimer with CaNa2EDTA with or without BAL are not available, and such use is not recommended.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Succimer in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Succimer in pediatric patients.
# Contraindications
- succimer should not be administered to patients with a history of allergy to the drug.
# Warnings
- Keep out of reach of pediatric patients. succimer is not a substitute for effective abatement of lead exposure.
- Mild to moderate neutropenia has been observed in some patients receiving succimer. While a causal relationship to succimer has not been definitely established, neutropenia has been reported with other drugs in the same chemical class. A complete blood count with white blood cell differential and direct platelet counts should be obtained prior to and weekly during treatment with succimer. Therapy should either be withheld or discontinued if the absolute neutrophil count (ANC) is below 1200/mcL and the patient followed closely to document recovery of the ANC to above 1500/mcL or to the patient’s baseline neutrophil count. There is limited experience with reexposure in patients who have developed neutropenia. Therefore, such patients should be rechallenged only if the benefit of succimer therapy clearly outweighs the potential risk of another episode of neutropenia and then only with careful patient monitoring.
- Patients treated with succimer should be instructed to promptly report any signs of infection. If infection is suspected, the above laboratory tests should be conducted immediately.
### Precautions
- The extent of clinical experience with succimer is limited. Therefore, patients should be carefully observed during treatment.
- Elevated blood lead levels and associated symptoms may return rapidly after discontinuation of succimer because of redistribution of lead from bone stores to soft tissues and blood. After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring.
- All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using succimer therapy in patients with compromised renal function. Limited data suggests that succimer is dialyzable, but that the lead chelates are not.
- Transient mild elevations of serum transaminases have been observed in 6-10% of patients during the course of succimer therapy. Serum transaminases should be monitored before the start of therapy and at least weekly during therapy. Patients with a history of liver disease should be monitored closely. No data are available regarding the metabolism of succimer in patients with liver disease.
- Clinical experience with repeated courses is limited. The safety of uninterrupted dosing longer than three weeks has not been established and it is not recommended.
- The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on readministration (as well as during initial courses). Patients requiring repeated courses of succimer should be monitored during each treatment course. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity affecting the oral mucosa, the external urethral meatus and the perianal area on the third, fourth and fifth courses of the drug. The reaction resolved between courses and upon discontinuation of therapy.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with succimer has been limited. Consequently, the full spectrum and incidence of adverse reactions including the possibility of hypersensitivity or idiosyncratic reactions have not been determined.
- The most common events attributable to succimer, i.e., gastrointestinal symptoms or increases in serum transaminases, have been observed in about 10% of patients . Rashes, some necessitating discontinuation of therapy, have been reported in about 4% of patients. If rash occurs, other causes (e.g. measles) should be considered before ascribing the reaction to succimer. Rechallenge with succimer may be considered if lead levels are high enough to warrant retreatment. One allergic mucocutaneous reaction has been reported on repeated administration of the drug . Mild to moderate neutropenia has been observed in some patients receiving succimer . Table I presents adverse events reported with the administration of succimer for the treatment of lead and other heavy metal intoxication.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Succimer in the drug label.
# Drug Interactions
- succimer is not known to interact with other drugs including iron supplements; interactions have not been systematically studied. Concomitant administration of succimer with other chelation therapy, such as CaNa2EDTA is not recommended.
- Drug/Laboratory Tests Interaction: Succimer may interfere with serum and urinary laboratory tests.In vitro studies have shown succimer to cause false positive results for ketones in urine using nitroprusside reagents such as Ketostix1 and falsely decreased measurements of serum uric acid and CPK.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratogenic Effects succimer has been shown to be teratogenic and fetotoxic in pregnant mice when given subcutaneously in a dose range of 410 to 1640 mg/kg/day during the period of organogenesis. In a developmental study in rats, succimer produced maternal toxicity and deaths at the dose of 720 mg/kg/day or more during organogenesis.
- The dose of 510 mg/kg/day was the highest tolerable dose in pregnant rats. Impaired development of reflexes was noted in pups of 720 mg/kg/day group dam. There are no adequate and well controlled studies in pregnant women. succimer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Succimer in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Succimer during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs and heavy metals are excreted in human milk, nursing mothers requiring succimer therapy should be discouraged from nursing their infants.
### Pediatric Use
- Safety and efficacy in pediatric patients less than 12 months of age have not been established.
### Geriatic Use
There is no FDA guidance on the use of Succimer with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Succimer with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Succimer with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Succimer in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Succimer in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Succimer in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Succimer in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Succimer in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Succimer in the drug label.
# Overdosage
- Doses of 2300 mg/kg in the rat and 2400 mg/kg in the mouse produced ataxia, convulsions, labored respiration and frequently death. No case of overdosage has been reported in humans. Limited data indicate that succimer is dialyzable. In case of acute overdosage, induction of vomiting or gastric lavage followed by administration of an activated charcoal slurry and appropriate supportive therapy are recommended.
# Pharmacology
## Mechanism of Action
- Succimer is a lead chelator; it forms water soluble chelates and, consequently, increases the urinary excretion of lead.
- Preclinical Toxicology: succimer has low acute oral toxicity, with oral median lethal doses in rodents in excess of 3.6 g/kg. In a 28-day toxicity study, dogs receiving 30 and 100 mg/kg/day had lower urinary specific gravity and an increase in renal tubular regenerative hyperplasia. No renal toxicity was noted in dogs given 50 mg/kg/day orally for 14 consecutive days. In a chronic 6-month oral toxicity study, one male dog died (out of 7) at a dose of 200 mg/kg/day attributed to associated renal toxicity. Treatment related renal tubule epithelial changes in this study were observed in dogs after chronic (6-month) exposure to 110 and 200 mg/kg/day for 17 days then to 80 and 140 mg/kg/day for the remainder of the study. These changes were dose-dependent and correlated with increased kidney weights in male and female dogs at the 10 mg/kg/day dose. Nephropathy was not observed in dogs treated at 10 mg/kg/day. Reduced platelet counts were noted in 5 of 7 dogs receiving either 80 or 140 mg/kg/day for 3 or 6 months, although group means were not statistically different from concurrent controls. Platelets had not been quantified in earlier studies. Normal megakaryocytes in the bone marrow, plus the absence of fibrin degradation products or histologic evidence for DIC, suggested an autoimmune-mediated thrombocytopenia, a finding common in dogs but not in other species. However, serum antibody tests were inconclusive. Rats dosed chronically to 500 mg/kg/day developed no evidence for nephropathy or thrombocytopenia.
## Structure
- succimer (succimer) is an orally active, heavy metal chelating agent. The chemical name for succimer ismeso 2, 3-dimercaptosuccinic acid (DMSA). Its empirical formula is C4H6O4S2 and molecular weight is 182.2. The meso-structural formula is:
- Succimer is a white crystalline powder with an unpleasant, characteristic mercaptan odor and taste.
- Each succimer opaque white capsule for oral administration contains beads coated with 100 mg of succimer and is imprinted black with succimer 100. Inactive ingredients in medicated beads are: povidone, sodium starch glycolate, starch and sucrose. Inactive ingredients in capsule are: gelatin, iron oxide, titanium dioxide and other ingredients.
## Pharmacodynamics
- Dose ranging studies were performed in 18 men with blood lead levels of 44-96 mcg/dL. Three groups of 6 patients received either 10.0, 6.7 or 3.3 mg/kg succimer orally every 8 hours for 5 days. After five days the mean blood levels of the three groups decreased 72.5%, 58.3% and 35.5% respectively. The mean urinary lead excretions in the initial 24 hours were 28.6, 18.6 and 12.3 times the pretreatment 24 hour urinary lead excretion. As the chelatable pool was reduced during therapy, urinary lead output decreased. A mean of 19 mg of lead was excreted during a five-day course of 30 mg/kg/day succimer. Clinical symptoms, such as headache and colic, and biochemical indices of lead toxicity also improved. Decrease in urinary excretion of d-aminolevulinic acid (ALA) and coproporphyrin paralleled the improvement in erythrocyte d-aminolevulinic acid dehydratase (ALA-D). Three control patients with lead poisoning of similar severity received CaNa2EDTA intravenously at a dose of 50 mg/kg/day for five days. The mean blood lead level decreased 47.4% and the mean urinary lead excretion was 21 mg in the control patients.
- Effect on Essential Minerals: In the above studies succimer had no significant effect on the urinary elimination of iron, calcium or magnesium. Zinc excretion doubled during treatment. The effect of succimer on the excretion of essential minerals was small compared to that of CaNa2EDTA, which can induce more than a ten-fold increase in urinary excretion of zinc and doubling of copper and iron excretion.
- Efficacy: A dose ranging study was performed in 15 pediatric patients aged 2 to 7 years with blood lead levels of 30-49 mcg/dL and positive CaNa2EDTA lead mobilization tests. Each group of five patients received 350, 233 or 116 mg/m2 succimer every 8 hours for 5 days. These doses corresponded to 10, 6.7 and 3.3 mg/kg. Six control patients received 1000 mg/m2/day CaNa2EDTA intravenously for 5 days. Following therapy, the mean blood lead levels decreased 78, 63 and 42% respectively in the three groups treated with succimer. The response of the 350 mg/m2 every 8 hours (10 mg/kg every 8 hours) group was significantly better than that of the other succimer treated groups as well as that of the control group, whose mean blood lead level fell 48%. No adverse reactions or changes in essential mineral excretion were reported in the succimer treated groups. In the CaNa2EDTA treated group, the cumulative amount of urinary lead excreted was slightly but significantly greater than in the succimer group. After CaNa2EDTA, the urinary excretion of copper, zinc, iron and calcium were significantly increased.
- As with other chelators, both adults and pediatric patients experienced a rebound in blood lead levels after discontinuation of succimer. In these studies, after treatment with a dose of 350 mg/m2 (10 mg/kg) every 8 hours for five days, the mean lead level rebounded and plateaued at 60-85% of pretreatment levels two weeks after therapy. The rebound plateau was somewhat higher with lower doses of succimer and with intravenous CaNa2EDTA.
- In an attempt to control rebound of blood lead levels, 19 pediatric patients, ages 1-7 years, with blood lead levels of 42-67 mcg/dL, were treated with 350 mg/m2 succimer every 8 hours for five days and then divided into three groups. One group was followed for two weeks with no further therapy, the second group was treated for two weeks with 350 mg/m2 daily, and the third with 350 mg/m2 every 12 hours. After the initial 5 days of therapy, the mean blood lead level in all subjects declined 61%. While the untreated group and the group treated with 350 mg/m2 daily experienced rebound during the ensuing two weeks, the group who received the 350 mg/m2 every 12 hours experienced no such rebound during the treatment period and less rebound following cessation of therapy.
- In another study, ten pediatric patients, ages 21 to 72 months, with blood lead levels of 30-57 mcg/dL were treated with succimer 350 mg/m2 every eight hours for five days followed by an additional 19-22 days of therapy at a dose of 350 mg/m2 every 12 hours. The mean blood lead levels decreased and remained stable at under 15 mcg/dL during the extended dosing period.
- In addition to the controlled studies, approximately 250 patients with lead poisoning have been treated with succimer either orally or parenterally in open U.S. and foreign studies with similar results reported. Succimer has been used for the treatment of lead poisoning in one patient with sickle cell anemia and in five patients with glucose-6-phosphodehydrogenase (G6PD) deficiency without adverse reactions.
- Lead Encephalopathy: Three adults with lead encephalopathy have been reported in the literature to have improved with succimer therapy. However, data are not available regarding the use of succimer for the treatment of this rare and sometimes fatal complication of lead poisoning in pediatric patients.
- Other Heavy Metal Poisoning: No controlled clinical studies have been conducted with succimer in poisoning with other heavy metals. A limited number of patients have received succimer for mercury or arsenic poisoning. These patients showed increased urinary excretion of the heavy metal and varying degrees of symptomatic improvement.
## Pharmacokinetics
- In a study performed in healthy adult volunteers, after a single dose of 14C-succimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days.
- In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis and Impairment of Fertility: succimer has not been tested for carcinogenic potential in long-term animal studies. succimer up to a dose of 510 mg/kg/day in males and 100 mg/kg/day in females did not show any adverse effect on fertility and reproductive performance. It was not mutagenic in the Ames bacterial assay and in the mammalian cell forward gene mutation assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Succimer in the drug label.
# How Supplied
- 100 mg capsules in bottle of 100 (NDC 55292-201-11).
- Store between 15°C and 25°C and avoid excessive heat.
## Storage
There is limited information regarding Succimer Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to maintain adequate fluid intake. If rash occurs, patients should consult their physician. Patients should be instructed to promptly report any indication of infection, which may be a sign of neutropenia .
- In young pediatric patients unable to swallow capsules, the contents of the capsule can be administered in a small amount of food
# Precautions with Alcohol
- Alcohol-Succimer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
# Look-Alike Drug Names
There is limited information regarding Succimer Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Succimer
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Succimer is a heavy metal chelator that is FDA approved for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. Common adverse reactions include rash, diarrhea, loss of appetite, nausea, vomiting, increased liver function test.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Succimer FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Succimer in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Succimer in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Succimer is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. succimer is not indicated for prophylaxis of lead poisoning in a lead-containing environment; the use of succimer should always be accompanied by identification and removal of the source of the lead exposure.
- Start dosage at 10 mg/kg or 350 mg/m2 every eight hours for five days. Initiation of therapy at higher doses is not recommended. (See TABLE II for Dosing chart and number of capsules.) Reduce frequency of administration to 10 mg/kg or 350 mg/m2 every 12 hours (two-thirds of initial daily dosage) for an additional two weeks of therapy. A course of treatment lasts 19 days. Repeated courses may be necessary if indicated by weekly monitoring of blood lead concentration. A minimum of two weeks between courses is recommended unless blood lead levels indicate the need for more prompt treatment.
- In young pediatric patients who cannot swallow capsules, succimer can be administered by separating the capsule and sprinkling the medicated beads on a small amount of soft food or putting them in a spoon and following with fruit drink.
- Identification of the source of lead in the pediatric patient’s environment and its abatement are critical to a successful therapy outcome. Chelation therapy is not a substitute for preventing further exposure to lead and should not be used to permit continued exposure to lead.
- Patients who have received CaNa2EDTA with or without BAL may use succimer for subsequent treatment after an interval of four weeks. Data on the concomitant use of succimer with CaNa2EDTA with or without BAL are not available, and such use is not recommended.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Succimer in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Succimer in pediatric patients.
# Contraindications
- succimer should not be administered to patients with a history of allergy to the drug.
# Warnings
- Keep out of reach of pediatric patients. succimer is not a substitute for effective abatement of lead exposure.
- Mild to moderate neutropenia has been observed in some patients receiving succimer. While a causal relationship to succimer has not been definitely established, neutropenia has been reported with other drugs in the same chemical class. A complete blood count with white blood cell differential and direct platelet counts should be obtained prior to and weekly during treatment with succimer. Therapy should either be withheld or discontinued if the absolute neutrophil count (ANC) is below 1200/mcL and the patient followed closely to document recovery of the ANC to above 1500/mcL or to the patient’s baseline neutrophil count. There is limited experience with reexposure in patients who have developed neutropenia. Therefore, such patients should be rechallenged only if the benefit of succimer therapy clearly outweighs the potential risk of another episode of neutropenia and then only with careful patient monitoring.
- Patients treated with succimer should be instructed to promptly report any signs of infection. If infection is suspected, the above laboratory tests should be conducted immediately.
### Precautions
- The extent of clinical experience with succimer is limited. Therefore, patients should be carefully observed during treatment.
- Elevated blood lead levels and associated symptoms may return rapidly after discontinuation of succimer because of redistribution of lead from bone stores to soft tissues and blood. After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring.
- All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using succimer therapy in patients with compromised renal function. Limited data suggests that succimer is dialyzable, but that the lead chelates are not.
- Transient mild elevations of serum transaminases have been observed in 6-10% of patients during the course of succimer therapy. Serum transaminases should be monitored before the start of therapy and at least weekly during therapy. Patients with a history of liver disease should be monitored closely. No data are available regarding the metabolism of succimer in patients with liver disease.
- Clinical experience with repeated courses is limited. The safety of uninterrupted dosing longer than three weeks has not been established and it is not recommended.
- The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on readministration (as well as during initial courses). Patients requiring repeated courses of succimer should be monitored during each treatment course. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity affecting the oral mucosa, the external urethral meatus and the perianal area on the third, fourth and fifth courses of the drug. The reaction resolved between courses and upon discontinuation of therapy.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with succimer has been limited. Consequently, the full spectrum and incidence of adverse reactions including the possibility of hypersensitivity or idiosyncratic reactions have not been determined.
- The most common events attributable to succimer, i.e., gastrointestinal symptoms or increases in serum transaminases, have been observed in about 10% of patients . Rashes, some necessitating discontinuation of therapy, have been reported in about 4% of patients. If rash occurs, other causes (e.g. measles) should be considered before ascribing the reaction to succimer. Rechallenge with succimer may be considered if lead levels are high enough to warrant retreatment. One allergic mucocutaneous reaction has been reported on repeated administration of the drug . Mild to moderate neutropenia has been observed in some patients receiving succimer . Table I presents adverse events reported with the administration of succimer for the treatment of lead and other heavy metal intoxication.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Succimer in the drug label.
# Drug Interactions
- succimer is not known to interact with other drugs including iron supplements; interactions have not been systematically studied. Concomitant administration of succimer with other chelation therapy, such as CaNa2EDTA is not recommended.
- Drug/Laboratory Tests Interaction: Succimer may interfere with serum and urinary laboratory tests.In vitro studies have shown succimer to cause false positive results for ketones in urine using nitroprusside reagents such as Ketostix1 and falsely decreased measurements of serum uric acid and CPK.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratogenic Effects succimer has been shown to be teratogenic and fetotoxic in pregnant mice when given subcutaneously in a dose range of 410 to 1640 mg/kg/day during the period of organogenesis. In a developmental study in rats, succimer produced maternal toxicity and deaths at the dose of 720 mg/kg/day or more during organogenesis.
- The dose of 510 mg/kg/day was the highest tolerable dose in pregnant rats. Impaired development of reflexes was noted in pups of 720 mg/kg/day group dam. There are no adequate and well controlled studies in pregnant women. succimer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Succimer in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Succimer during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs and heavy metals are excreted in human milk, nursing mothers requiring succimer therapy should be discouraged from nursing their infants.
### Pediatric Use
- Safety and efficacy in pediatric patients less than 12 months of age have not been established.
### Geriatic Use
There is no FDA guidance on the use of Succimer with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Succimer with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Succimer with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Succimer in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Succimer in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Succimer in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Succimer in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Succimer in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Succimer in the drug label.
# Overdosage
- Doses of 2300 mg/kg in the rat and 2400 mg/kg in the mouse produced ataxia, convulsions, labored respiration and frequently death. No case of overdosage has been reported in humans. Limited data indicate that succimer is dialyzable. In case of acute overdosage, induction of vomiting or gastric lavage followed by administration of an activated charcoal slurry and appropriate supportive therapy are recommended.
# Pharmacology
## Mechanism of Action
- Succimer is a lead chelator; it forms water soluble chelates and, consequently, increases the urinary excretion of lead.
- Preclinical Toxicology: succimer has low acute oral toxicity, with oral median lethal doses in rodents in excess of 3.6 g/kg. In a 28-day toxicity study, dogs receiving 30 and 100 mg/kg/day had lower urinary specific gravity and an increase in renal tubular regenerative hyperplasia. No renal toxicity was noted in dogs given 50 mg/kg/day orally for 14 consecutive days. In a chronic 6-month oral toxicity study, one male dog died (out of 7) at a dose of 200 mg/kg/day attributed to associated renal toxicity. Treatment related renal tubule epithelial changes in this study were observed in dogs after chronic (6-month) exposure to 110 and 200 mg/kg/day for 17 days then to 80 and 140 mg/kg/day for the remainder of the study. These changes were dose-dependent and correlated with increased kidney weights in male and female dogs at the 10 mg/kg/day dose. Nephropathy was not observed in dogs treated at 10 mg/kg/day. Reduced platelet counts were noted in 5 of 7 dogs receiving either 80 or 140 mg/kg/day for 3 or 6 months, although group means were not statistically different from concurrent controls. Platelets had not been quantified in earlier studies. Normal megakaryocytes in the bone marrow, plus the absence of fibrin degradation products or histologic evidence for DIC, suggested an autoimmune-mediated thrombocytopenia, a finding common in dogs but not in other species. However, serum antibody tests were inconclusive. Rats dosed chronically to 500 mg/kg/day developed no evidence for nephropathy or thrombocytopenia.
## Structure
- succimer (succimer) is an orally active, heavy metal chelating agent. The chemical name for succimer ismeso 2, 3-dimercaptosuccinic acid (DMSA). Its empirical formula is C4H6O4S2 and molecular weight is 182.2. The meso-structural formula is:
- Succimer is a white crystalline powder with an unpleasant, characteristic mercaptan odor and taste.
- Each succimer opaque white capsule for oral administration contains beads coated with 100 mg of succimer and is imprinted black with succimer 100. Inactive ingredients in medicated beads are: povidone, sodium starch glycolate, starch and sucrose. Inactive ingredients in capsule are: gelatin, iron oxide, titanium dioxide and other ingredients.
## Pharmacodynamics
- Dose ranging studies were performed in 18 men with blood lead levels of 44-96 mcg/dL. Three groups of 6 patients received either 10.0, 6.7 or 3.3 mg/kg succimer orally every 8 hours for 5 days. After five days the mean blood levels of the three groups decreased 72.5%, 58.3% and 35.5% respectively. The mean urinary lead excretions in the initial 24 hours were 28.6, 18.6 and 12.3 times the pretreatment 24 hour urinary lead excretion. As the chelatable pool was reduced during therapy, urinary lead output decreased. A mean of 19 mg of lead was excreted during a five-day course of 30 mg/kg/day succimer. Clinical symptoms, such as headache and colic, and biochemical indices of lead toxicity also improved. Decrease in urinary excretion of d-aminolevulinic acid (ALA) and coproporphyrin paralleled the improvement in erythrocyte d-aminolevulinic acid dehydratase (ALA-D). Three control patients with lead poisoning of similar severity received CaNa2EDTA intravenously at a dose of 50 mg/kg/day for five days. The mean blood lead level decreased 47.4% and the mean urinary lead excretion was 21 mg in the control patients.
- Effect on Essential Minerals: In the above studies succimer had no significant effect on the urinary elimination of iron, calcium or magnesium. Zinc excretion doubled during treatment. The effect of succimer on the excretion of essential minerals was small compared to that of CaNa2EDTA, which can induce more than a ten-fold increase in urinary excretion of zinc and doubling of copper and iron excretion.
- Efficacy: A dose ranging study was performed in 15 pediatric patients aged 2 to 7 years with blood lead levels of 30-49 mcg/dL and positive CaNa2EDTA lead mobilization tests. Each group of five patients received 350, 233 or 116 mg/m2 succimer every 8 hours for 5 days. These doses corresponded to 10, 6.7 and 3.3 mg/kg. Six control patients received 1000 mg/m2/day CaNa2EDTA intravenously for 5 days. Following therapy, the mean blood lead levels decreased 78, 63 and 42% respectively in the three groups treated with succimer. The response of the 350 mg/m2 every 8 hours (10 mg/kg every 8 hours) group was significantly better than that of the other succimer treated groups as well as that of the control group, whose mean blood lead level fell 48%. No adverse reactions or changes in essential mineral excretion were reported in the succimer treated groups. In the CaNa2EDTA treated group, the cumulative amount of urinary lead excreted was slightly but significantly greater than in the succimer group. After CaNa2EDTA, the urinary excretion of copper, zinc, iron and calcium were significantly increased.
- As with other chelators, both adults and pediatric patients experienced a rebound in blood lead levels after discontinuation of succimer. In these studies, after treatment with a dose of 350 mg/m2 (10 mg/kg) every 8 hours for five days, the mean lead level rebounded and plateaued at 60-85% of pretreatment levels two weeks after therapy. The rebound plateau was somewhat higher with lower doses of succimer and with intravenous CaNa2EDTA.
- In an attempt to control rebound of blood lead levels, 19 pediatric patients, ages 1-7 years, with blood lead levels of 42-67 mcg/dL, were treated with 350 mg/m2 succimer every 8 hours for five days and then divided into three groups. One group was followed for two weeks with no further therapy, the second group was treated for two weeks with 350 mg/m2 daily, and the third with 350 mg/m2 every 12 hours. After the initial 5 days of therapy, the mean blood lead level in all subjects declined 61%. While the untreated group and the group treated with 350 mg/m2 daily experienced rebound during the ensuing two weeks, the group who received the 350 mg/m2 every 12 hours experienced no such rebound during the treatment period and less rebound following cessation of therapy.
- In another study, ten pediatric patients, ages 21 to 72 months, with blood lead levels of 30-57 mcg/dL were treated with succimer 350 mg/m2 every eight hours for five days followed by an additional 19-22 days of therapy at a dose of 350 mg/m2 every 12 hours. The mean blood lead levels decreased and remained stable at under 15 mcg/dL during the extended dosing period.
- In addition to the controlled studies, approximately 250 patients with lead poisoning have been treated with succimer either orally or parenterally in open U.S. and foreign studies with similar results reported. Succimer has been used for the treatment of lead poisoning in one patient with sickle cell anemia and in five patients with glucose-6-phosphodehydrogenase (G6PD) deficiency without adverse reactions.
- Lead Encephalopathy: Three adults with lead encephalopathy have been reported in the literature to have improved with succimer therapy. However, data are not available regarding the use of succimer for the treatment of this rare and sometimes fatal complication of lead poisoning in pediatric patients.
- Other Heavy Metal Poisoning: No controlled clinical studies have been conducted with succimer in poisoning with other heavy metals. A limited number of patients have received succimer for mercury or arsenic poisoning. These patients showed increased urinary excretion of the heavy metal and varying degrees of symptomatic improvement.
## Pharmacokinetics
- In a study performed in healthy adult volunteers, after a single dose of 14C-succimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days.
- In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis and Impairment of Fertility: succimer has not been tested for carcinogenic potential in long-term animal studies. succimer up to a dose of 510 mg/kg/day in males and 100 mg/kg/day in females did not show any adverse effect on fertility and reproductive performance. It was not mutagenic in the Ames bacterial assay and in the mammalian cell forward gene mutation assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Succimer in the drug label.
# How Supplied
- 100 mg capsules in bottle of 100 (NDC 55292-201-11).
- Store between 15°C and 25°C and avoid excessive heat.
## Storage
There is limited information regarding Succimer Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to maintain adequate fluid intake. If rash occurs, patients should consult their physician. Patients should be instructed to promptly report any indication of infection, which may be a sign of neutropenia .
- In young pediatric patients unable to swallow capsules, the contents of the capsule can be administered in a small amount of food
# Precautions with Alcohol
- Alcohol-Succimer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ®[2]
# Look-Alike Drug Names
There is limited information regarding Succimer Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Succimer | |
f19c2351342edc168789400f3e635821ef729911 | wikidoc | Sue Bale | Sue Bale
Professor Sue Bale FRCN, PhD, BA, RGN, NDN, RHV, PG Dip, Dip N is a UK nurse with a special interest in wound healing. She received her Ph D from the University of Glamorgan in 2003.
# Work in wound healing
She was part of the original team that established a unique wound healing service in The Wound Healing Research Unit, Cardiff, based in the University of Wales College of Medicine. She is author of a wide range of books and articles on wound care.
Sue is a founder member of the Wound Care Society (1985); the European Wound Management Association; (1991); the Journal of Wound Care (1992); the European Pressure Ulcer Advisory Panel (1996).
# Work
She works as Associate Director of Nursing (R&D) in Gwent Healthcare NHS Trust and lives in Monmouthshire.
# Fellowship
She is a fellow of the Royal College of Nursing.
# Recent publications:
Bale, Sue (2004). Wound Care Nursing, 2nd Edition - A Patient-Centered Approach. Mosby Ltd. ISBN 0-7234-3344-5. Unknown parameter |coauthors= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Bale, Sue (2004). "The benefits of implementing a new skin care protocol in nursing homes". Journal of Tissue Viability. 14(2): 44–50. Unknown parameter |coauthors= ignored (help)
Bale, Sue (2004). "A topical metronidazole gel used to treat malodorous wounds". British Journal of Nursing. 13(11). Unknown parameter |coauthors= ignored (help)
Jones, V. (2004). Acute and chronic wound healing. In "Wound Care Essentials Practice" (Baronowski S, and E. A. Ayello, Eds. Lippincott Williams and Wilkins. ISBN 1-58255-274-6. Unknown parameter |coauthors= ignored (help) | Sue Bale
Professor Sue Bale FRCN, PhD, BA, RGN, NDN, RHV, PG Dip, Dip N is a UK nurse with a special interest in wound healing. She received her Ph D from the University of Glamorgan in 2003.[1]
# Work in wound healing
She was part of the original team that established a unique wound healing service in The Wound Healing Research Unit, Cardiff, based in the University of Wales College of Medicine. She is author of a wide range of books and articles on wound care.
Sue is a founder member of the Wound Care Society (1985); the European Wound Management Association; (1991); the Journal of Wound Care (1992); the European Pressure Ulcer Advisory Panel (1996). [2]
# Work
She works as Associate Director of Nursing (R&D) in Gwent Healthcare NHS Trust and lives in Monmouthshire.
# Fellowship
She is a fellow of the Royal College of Nursing.[3]
# Recent publications:
Bale, Sue (2004). Wound Care Nursing, 2nd Edition - A Patient-Centered Approach. Mosby Ltd. ISBN 0-7234-3344-5. Unknown parameter |coauthors= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Bale, Sue (2004). "The benefits of implementing a new skin care protocol in nursing homes". Journal of Tissue Viability. 14(2): 44–50. Unknown parameter |coauthors= ignored (help)
Bale, Sue (2004). "A topical metronidazole gel used to treat malodorous wounds". British Journal of Nursing. 13(11). Unknown parameter |coauthors= ignored (help)
Jones, V. (2004). Acute and chronic wound healing. In "Wound Care Essentials Practice" (Baronowski S, and E. A. Ayello, Eds. Lippincott Williams and Wilkins. ISBN 1-58255-274-6. Unknown parameter |coauthors= ignored (help) | https://www.wikidoc.org/index.php/Sue_Bale | |
45eea09b43a2d571b0ec07c4a1a09fe64c45e84a | wikidoc | Sulfiram | Sulfiram
# Overview
Sulfiram (INN) or monosulfiram, trade name Tetmosol, is an ectoparasiticide used in the treatment and prevention of scabies. It is usually sold as a solution or medicated soap, sometimes in combination with benzyl benzoate.
Sulfiram is now rarely used, but, as of 2010, is still available in Brazil, India, and South Africa (as monotherapy) and France (with benzyl benzoate).
# Adverse effects
Dizziness, headache, fatigue and erythematous rash may occur. A single case of toxic epidermal necrolysis was reported in 1968.
Sulfiram is structurally related to disulfiram (Antabuse), and readily converts to disulfiram when exposed to light. Like disulfiram, it can produce an unpleasant reaction when consumed with alcohol. | Sulfiram
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sree Teja Yelamanchili, MBBS [2]
# Overview
Sulfiram (INN) or monosulfiram, trade name Tetmosol, is an ectoparasiticide used in the treatment and prevention of scabies.[1] It is usually sold as a solution or medicated soap, sometimes in combination with benzyl benzoate.
Sulfiram is now rarely used, but, as of 2010[update], is still available in Brazil, India, and South Africa (as monotherapy) and France (with benzyl benzoate).[1]
# Adverse effects
Dizziness, headache, fatigue and erythematous rash may occur.[2] A single case of toxic epidermal necrolysis was reported in 1968.[3]
Sulfiram is structurally related to disulfiram (Antabuse), and readily converts to disulfiram when exposed to light. Like disulfiram, it can produce an unpleasant reaction when consumed with alcohol.[1][4] | https://www.wikidoc.org/index.php/Sulfiram | |
50339ffdc50db0d28eb618f8a05855f9e48bc08c | wikidoc | Sulfotep | Sulfotep
# Overview
Sulfotep (O,O,O',O'-Tetraethyldithiopyrophosphate) is a pesticide commonly used in greenhouses as a fumigative agent. The substance is also known as TEDP, Dithione, Dithiophos and many others. Sulfotep belongs to the class of chemicals named organophosphates. It has a cholinergic effect, involving depression of the cholinesterase activity of the peripheral and central nervous system. The transduction of signals is disturbed at the synapses that make use of acetylcholine.
# History
## Discovery
Sulfotep was first commercially launched by BAYER in 1946. It is kown as an organophosphate, which were also used for war efforts by British and German armies before use in agriculture developed. 2 Sulfotep is synthesized by a reaction of TEPP (tetraethyl pyrophosphate) with sulfur. Tepp itself was first synthesized by Philipe de Clermont in 1854.,
## Incidents
The Dutch company BASF produced and stored sulfotep until 2004. The storage room was repurposed as an office. Some employees complained about lung problems after having worked in those offices.
A gardener who tried to commit suicide took an unknown number of Sulfotep-cointaining compounds. It caused a severe intoxification (unconsciousness, vomiting, cyanosis, gasping, pulmonary edema, clonic-tonic convulsions). A treatment with atropine was successful. The cholinesterase-activity in the serum was 70-80% lower at day one and 35% lower at day 10.
## Use as insecticde
Sulfotep is used in greenhouses as a fumigant formulation to control aphids, spider mites, whiteflies and thrips. It is formulated as impregnated material in smoke generators containing 14 to 15% active ingredient. Smoke generators are placed in the greenhouses and then ignited using inserted sparklers to generate a thick white smoke for fumigation.
# Structure and synthesis
Sulfotep is made by a reaction from tepp and sulfur. An alternative route can be a reaction of diethyl chlorothiophosphate and water in a mixture of Na3CO3. Tepp is made by a reaction of diethylchlorophosphate with water to substitute the chloro-group with a hydroxyl-group. The product can react with another molecule of diethylchlorophosphate to form an ester, the tepp molecule. In this reaction pyridine is often used to clear the reaction from the HCl.
# Available forms
At room temperature sulfotep is a colourless liquid oil. Its boiling point is only available at low pressure. Only at low pressure and high temperature sulfotep is available as a gas. Because of the flash point of -18 °C there is a vapor present at room temperature. The gas is heavier than air. Sulfotep has a garlic-like odor.
# Mechanism of action
Sulfotep, just as all organophosphate pesticides, irreversibly inactivates acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Acetylcholinesterase normally hydrolyses acetylcholine after it was released in the synaps. When the acetylcholine is not degraded, it accumulates in the synaptic cleft. Thus it keeps on stimulating the nerve.
# Metabolism
## Uptake
Sulfotep is taken up well both orally, dermally as well as through inhalation. A few different organizations determined a maximum concentration sulfotep in the air. The maximum allowed concentration is 0.2 mg/m3.
## Phase I
Sulfotep is desulfurated by either cytochrome P450 or the FAD-containing monooxygenases. In this reaction, the sulfur is replaced by oxygen, as seen in figure 2. The metabolites formed are monosulfotep and tetraethyl pyrophosphate (TEPP). To accomplish these reactions, a phospho-oxithirane ring is formed, which is highly reactive. This ring is thought to bind to acetylcholinesterase and cause toxicity.
## Phase II
The two Phase I metabolites are further transformed through a hydrolysis-reaction mediated by a type A-esterase. The products formed are O,O-Diethyldithiophosphate and O,O-Diethylphosphate. The complete metabolism can be found in figure 2.
## Excretion
An experiment in rats who were once given 0,4 mg radioactive phosphor-labelled sulfotep orally, has shown that sulfotep is excreted by both the kidneys (urine) and the liver (bile). The substance is completely metabolised. Two metabolites are found in the urine and faeces. The radioactivity showed that 85-91% was excreted in urine and 5-6% in the faeces.
- 88-96% metabolite 1: O,O-Diethyldithiophosphate
- 4-12% metabolite 2: O,O-Diethylphosphate
# Toxicity
## Acute toxic effects on animals
In the table below you can find the results of different experiments done on different animals. Dogs and cats best mimic the effects found in humans.
Surviving animals completely recovered in 1–4 days.
## Chronic and subchronic toxicity
A long term exposure to a low concentration showed no toxicity.
This was tested in rats. They were exposed to different concentrations of sulfotep. Exposed to the highest concentration of 2.83 mg/m3 for 6 hours a day, 5 days a week for 12 weeks, there was no change in appearance, behavior or body weight. The plasma cholinesterase activity decreased and the weight of the lungs of female rats increased. The red blood cell acetylcholinesterase activity was not effected. At lower concentrations there were no changes at all.
The rats that were orally exposed to 0, 5, 10, 20 or 50 ppm sulfotep for 3 months. Only their plasma cholinesterase activity and RBC acetylcholinesterase activity were decreased. No further symptoms were observed.
Dogs who were orally exposed to 0, 0.5, 3, 5, 15 or 75 ppm (equivalent to 0-3.07 mg/kg/day) for 13 weeks, ate less and lost weight. The plasma cholinesterase activity was already effected by a sulfotep concentration of 3 ppm (or higher). Red blood cell-acetylcholinesterase was decreased at 75 ppm. Diarrhea and vomiting occasionally occurred at 15 ppm, but was common at 75 ppm. The brain cholinesterase activity was uneffected.
## Poisoning symptoms and treatment
Sulfotep causes an organophosphate poisoning. This means that it had an effect on the activity of cholinesterase. There are differences for the indications of a sulfotep poisoning between inhalation, ingestion, intake by the skin and intake by the eyes. However, examples of poisoned greenhouse workers teach us an overall route of symptoms for a sulfotepp poisoning. Within the first hour after a poisonous intake of sulfotep people often suffer from nausea or headaches. After some hours diarrhea and vomiting may occur. People who inhaled sulfotep are often disorientated and have difficulties to breath. A poisonous dose may lead to a coma or death after 24 hours. The point at 24 hours after the poisoning is very important. If the dose is not lethal, the symptoms will slowly disappear after the point of 24 hours.
No embryotoxic or teratogenic effects occurred in tests. Neither were there any signs for carcinogenic effects. It was only mutagenic in one strain of S. typhimurium. In four other bacterial strains as well as in rats and mice it was not mutagenic at all.
There are two cases of acute toxicity known in man. The cholinesterase activity in these people was reduced. It took them 20 respectively 28 days to recover.
The most important poisoning symptoms are shown in the following table. | Sulfotep
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfotep (O,O,O',O'-Tetraethyldithiopyrophosphate) is a pesticide commonly used in greenhouses as a fumigative agent. The substance is also known as TEDP, Dithione, Dithiophos and many others. Sulfotep belongs to the class of chemicals named organophosphates. It has a cholinergic effect, involving depression of the cholinesterase activity of the peripheral and central nervous system.[4] The transduction of signals is disturbed at the synapses that make use of acetylcholine.
# History
## Discovery
Sulfotep was first commercially launched by BAYER in 1946. It is kown as an organophosphate, which were also used for war efforts by British and German armies before use in agriculture developed. 2 Sulfotep is synthesized by a reaction of TEPP (tetraethyl pyrophosphate) with sulfur. Tepp itself was first synthesized by Philipe de Clermont in 1854.,[5][6]
## Incidents
The Dutch company BASF produced and stored sulfotep until 2004. The storage room was repurposed as an office. Some employees complained about lung problems after having worked in those offices.[7]
A gardener who tried to commit suicide took an unknown number of Sulfotep-cointaining compounds. It caused a severe intoxification (unconsciousness, vomiting, cyanosis, gasping, pulmonary edema, clonic-tonic convulsions). A treatment with atropine was successful. The cholinesterase-activity in the serum was 70-80% lower at day one and 35% lower at day 10.[8]
## Use as insecticde
Sulfotep is used in greenhouses as a fumigant formulation to control aphids, spider mites, whiteflies and thrips. It is formulated as impregnated material in smoke generators containing 14 to 15% active ingredient. Smoke generators are placed in the greenhouses and then ignited using inserted sparklers to generate a thick white smoke for fumigation.
# Structure and synthesis
Sulfotep is made by a reaction from tepp and sulfur. An alternative route can be a reaction of diethyl chlorothiophosphate and water in a mixture of Na3CO3. Tepp is made by a reaction of diethylchlorophosphate with water to substitute the chloro-group with a hydroxyl-group. The product can react with another molecule of diethylchlorophosphate to form an ester, the tepp molecule. In this reaction pyridine is often used to clear the reaction from the HCl.[9]
# Available forms
At room temperature sulfotep is a colourless liquid oil. Its boiling point is only available at low pressure. Only at low pressure and high temperature sulfotep is available as a gas. Because of the flash point of -18 °C there is a vapor present at room temperature. The gas is heavier than air. Sulfotep has a garlic-like odor.[10]
# Mechanism of action
Sulfotep, just as all organophosphate pesticides, irreversibly inactivates acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Acetylcholinesterase normally hydrolyses acetylcholine after it was released in the synaps. When the acetylcholine is not degraded, it accumulates in the synaptic cleft. Thus it keeps on stimulating the nerve.[11]
# Metabolism
## Uptake
Sulfotep is taken up well both orally, dermally as well as through inhalation. A few different organizations determined a maximum concentration sulfotep in the air. The maximum allowed concentration is 0.2 mg/m3.
## Phase I
Sulfotep is desulfurated by either cytochrome P450 or the FAD-containing monooxygenases. In this reaction, the sulfur is replaced by oxygen, as seen in figure 2. The metabolites formed are monosulfotep and tetraethyl pyrophosphate (TEPP). To accomplish these reactions, a phospho-oxithirane ring is formed, which is highly reactive. This ring is thought to bind to acetylcholinesterase and cause toxicity.[12]
## Phase II
The two Phase I metabolites are further transformed through a hydrolysis-reaction mediated by a type A-esterase. The products formed are O,O-Diethyldithiophosphate and O,O-Diethylphosphate. The complete metabolism can be found in figure 2.[12]
## Excretion
An experiment in rats who were once given 0,4 mg radioactive phosphor-labelled sulfotep orally, has shown that sulfotep is excreted by both the kidneys (urine) and the liver (bile). The substance is completely metabolised. Two metabolites are found in the urine and faeces. The radioactivity showed that 85-91% was excreted in urine and 5-6% in the faeces.[11]
- 88-96% metabolite 1: O,O-Diethyldithiophosphate
- 4-12% metabolite 2: O,O-Diethylphosphate [2]
# Toxicity
## Acute toxic effects on animals
In the table below you can find the results of different experiments done on different animals. Dogs and cats best mimic the effects found in humans.
Surviving animals completely recovered in 1–4 days.
## Chronic and subchronic toxicity
A long term exposure to a low concentration showed no toxicity.
This was tested in rats. They were exposed to different concentrations of sulfotep. Exposed to the highest concentration of 2.83 mg/m3 for 6 hours a day, 5 days a week for 12 weeks, there was no change in appearance, behavior or body weight. The plasma cholinesterase activity decreased and the weight of the lungs of female rats increased. The red blood cell acetylcholinesterase activity was not effected. At lower concentrations there were no changes at all.
The rats that were orally exposed to 0, 5, 10, 20 or 50 ppm sulfotep for 3 months. Only their plasma cholinesterase activity and RBC acetylcholinesterase activity were decreased. No further symptoms were observed.
Dogs who were orally exposed to 0, 0.5, 3, 5, 15 or 75 ppm (equivalent to 0-3.07 mg/kg/day) for 13 weeks, ate less and lost weight. The plasma cholinesterase activity was already effected by a sulfotep concentration of 3 ppm (or higher). Red blood cell-acetylcholinesterase was decreased at 75 ppm. Diarrhea and vomiting occasionally occurred at 15 ppm, but was common at 75 ppm. The brain cholinesterase activity was uneffected.[10]
## Poisoning symptoms and treatment
Sulfotep causes an organophosphate poisoning. This means that it had an effect on the activity of cholinesterase. There are differences for the indications of a sulfotep poisoning between inhalation, ingestion, intake by the skin and intake by the eyes. However, examples of poisoned greenhouse workers teach us an overall route of symptoms for a sulfotepp poisoning. Within the first hour after a poisonous intake of sulfotep people often suffer from nausea or headaches. After some hours diarrhea and vomiting may occur. People who inhaled sulfotep are often disorientated and have difficulties to breath. A poisonous dose may lead to a coma or death after 24 hours. The point at 24 hours after the poisoning is very important. If the dose is not lethal, the symptoms will slowly disappear after the point of 24 hours.[14][15]
No embryotoxic or teratogenic effects occurred in tests. Neither were there any signs for carcinogenic effects. It was only mutagenic in one strain of S. typhimurium. In four other bacterial strains as well as in rats and mice it was not mutagenic at all.
There are two cases of acute toxicity known in man. The cholinesterase activity in these people was reduced. It took them 20 respectively 28 days to recover.[10]
The most important poisoning symptoms are shown in the following table.[16] | https://www.wikidoc.org/index.php/Sulfotep | |
a7b5e12d6958749197c7e1ff218d3d0b09479a31 | wikidoc | Sultiame | Sultiame
# Overview
Sultiame (rINN, also known as sulthiame) is a sulfonamide and inhibitor of the enzyme carbonic anhydrase. It is used as an anticonvulsant.
# History
Sultiame was first synthesised in the laboratories of Bayer AG in the mid 1950s and eventually launched as Ospolot in Europe and other markets the early 1960s. It never became a registered drug in the USA. The brand was transferred to Desitin GmbH in 1993 and is sold in several European countries, in Israel, Japan, and Australia.
Sultiame became established as a second-line drug for treatment of partial epilepsy in the 1960s and 1970s and was often used in combination with the established anticonvulsant phenytoin. Temporal lobe seizures appeared particularly responsive to sultiame. Doubts subsequently arose as to whether sultiame has intrinsic anticonvulsant properties. After discovering sultiame's ability to raise the blood levels of phenytoin, it was assumed that sultiame would only act in combination with phenytoin. This finding, together with the equivocal results of a study in the US, resulted in a quick decline of sultiame's use. It was only in 1988, that the German child neurologist Hermann Doose discovered its specific effects in benign focal epilepsies of childhood. Today, sulthiame is the drug of choice for benign focal epilepsies of childhood (such as benign rolandic epilepsy) in the German-speaking countries and Israel. There is renewed interest in sultiame's other potential uses, e.g., in West syndrome and other refractory epilepsies
# Indications
Historically, sultiame has been used to treat partial seizures. In Australia, it is currently registered for behavioural disorders associated with epilepsy; hyperkinetic behaviour; temporal lobe epilepsy; myoclonic seizures; grand mal attacks; and Jacksonian seizures. In contrast to other sulfonamide drugs, sultiame is devoid of antibacterial activity.
# Adverse effects
The more common adverse effects are ataxia, paraesthesia of face and limbs, hyperpnoea, dyspnoea, and anorexia. Less common adverse effects include giddiness, rash, Stevens–Johnson syndrome, nausea, weight loss, leukopenia, headache, psychic changes, depression, drooling, increased pain, frequency of fits, insomnia, status epilepticus. Disturbances in calcium and vitamin D metabolism have been occasionally reported after long-term use.
# Interactions
Sultiame taken together with primidone may lead to severe side-effects, including psychotic reactions. The addition of sulthiame to phenytoin therapy has shown to be followed by a rise in the serum levels of phenytoin. Sultiame may also lead to a rise of phenobarbitone blood levels. Alcohol must not be consumed during treatment.
# Overdose
Vomiting, hypotension, headache, vertigo, ataxia, metabolic acidosis with hyperpnoea and catatonic state may occur. There is no specific antidote. It is not known whether dialysis may help in case of overdose.
# Synthesis
p-Aminobenzenesulfonamide can be alkylated by ω-chlorobutylsulfonyl chloride in base via presumed intermediate, which spontaneously cyclizes to give sulthiame. | Sultiame
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sultiame (rINN, also known as sulthiame) is a sulfonamide and inhibitor of the enzyme carbonic anhydrase. It is used as an anticonvulsant.
# History
Sultiame was first synthesised in the laboratories of Bayer AG in the mid 1950s and eventually launched as Ospolot in Europe and other markets the early 1960s. It never became a registered drug in the USA. The brand was transferred to Desitin GmbH in 1993 and is sold in several European countries, in Israel, Japan, and Australia.
Sultiame became established as a second-line drug for treatment of partial epilepsy in the 1960s and 1970s and was often used in combination with the established anticonvulsant phenytoin. Temporal lobe seizures appeared particularly responsive to sultiame. Doubts subsequently arose as to whether sultiame has intrinsic anticonvulsant properties. After discovering sultiame's ability to raise the blood levels of phenytoin,[1] it was assumed that sultiame would only act in combination with phenytoin. This finding, together with the equivocal results of a study in the US,[2] resulted in a quick decline of sultiame's use. It was only in 1988, that the German child neurologist Hermann Doose discovered its specific effects in benign focal epilepsies of childhood.[3] Today, sulthiame is the drug of choice for benign focal epilepsies of childhood (such as benign rolandic epilepsy) in the German-speaking countries and Israel.[4] There is renewed interest in sultiame's other potential uses, e.g., in West syndrome[5] and other refractory epilepsies[6]
# Indications
Historically, sultiame has been used to treat partial seizures. In Australia, it is currently registered for behavioural disorders associated with epilepsy; hyperkinetic behaviour; temporal lobe epilepsy; myoclonic seizures; grand mal attacks; and Jacksonian seizures.[7] In contrast to other sulfonamide drugs, sultiame is devoid of antibacterial activity.
# Adverse effects
The more common adverse effects are ataxia, paraesthesia of face and limbs, hyperpnoea, dyspnoea, and anorexia. Less common adverse effects include giddiness, rash, Stevens–Johnson syndrome, nausea, weight loss, leukopenia, headache, psychic changes, depression, drooling, increased pain, frequency of fits, insomnia, status epilepticus. Disturbances in calcium and vitamin D metabolism have been occasionally reported after long-term use.
# Interactions
Sultiame taken together with primidone may lead to severe side-effects, including psychotic reactions. The addition of sulthiame to phenytoin therapy has shown to be followed by a rise in the serum levels of phenytoin. Sultiame may also lead to a rise of phenobarbitone blood levels. Alcohol must not be consumed during treatment.
# Overdose
Vomiting, hypotension, headache, vertigo, ataxia, metabolic acidosis with hyperpnoea and catatonic state may occur. There is no specific antidote. It is not known whether dialysis may help in case of overdose.
# Synthesis
p-Aminobenzenesulfonamide can be alkylated by ω-chlorobutylsulfonyl chloride in base via presumed intermediate, which spontaneously cyclizes to give sulthiame. | https://www.wikidoc.org/index.php/Sulthiame | |
e88ce30e858dc1e79a8c6e6182ca45ae12e51c98 | wikidoc | Suprofen | Suprofen
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Suprofen is an NSAID that is FDA approved for the treatment of intraoperative miosis. Common adverse reactions include burning, stinging of the eyes, eye discomfort, itching, and redness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- PROFENAL Ophthalmic Solution is indicated for inhibition of intraoperative miosis.
- On the day of surgery, instill two drops into the conjunctival sac at three, two and one hour prior to surgery. Two drops may be instilled into the conjunctival sac every four hours, while awake, the day preceding surgery.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Suprofen in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Suprofen in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Suprofen in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Suprofen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Suprofen in pediatric patients.
# Contraindications
- PROFENAL is contraindicated in epithelial herpes simplex keratitis (dendritic keratitis) and in individuals hypersensitive to any component of the medication.
# Warnings
- The potential exists for cross sensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.
- With nonsteroidal anti-inflammatory drugs, the potential exists for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding tendency of ocular tissues in conjunction with ocular surgery.
### Precautions
- General
- Use of oral suprofen has been associated with a syndrome of acute flank pain and generally reversible renal insufficiency, which may present as acute uric acid nephropathy. This syndrome occurs in approximately 1 in 3500 patients and has been reported with as few as one to two doses of a 200 mg capsule. If PROFENAL 1% Ophthalmic Solution is applied as two drops (1 mg suprofen) to one eye five times on the day prior to surgery and three times on the day of surgery, the total applied dose over the two days would be about 25 times less than a single 200 mg oral dose. Do not touch dropper tip to any surface, as this may contaminate the solution.
- Ocular
- Patients with histories of herpes simplex keratitis should be monitored closely. PROFENAL is contraindicated in patients with active herpes simplex keratitis.
- The possibility of increased ocular bleeding during surgery associated with nonsteroidal anti-inflammatory drugs should be considered.
# Adverse Reactions
## Clinical Trials Experience
- Ocular
- The most frequent adverse reactions reported are burning and stinging of short duration. Instances of discomfort, itching and redness have been reported. Other reactions occurring in less than 0.5% of patients include allergy, iritis, pain, chemosis, photophobia, irritation, and punctate epithelial staining.
- Systemic
- Systemic reactions related to therapy were not reported in the clinical studies. It is known that some systemic absorption does occur with ocularly applied drugs, and that nonsteroidal anti-inflammatory drugs have been shown to increase bleeding time by interference with thrombocyte aggregation. It is recommended that PROFENAL be used with caution in patients with bleeding tendencies and those taking anticoagulants.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Suprofen in the drug label.
# Drug Interactions
- Clinical studies with acetylcholine chloride revealed no interference, and there is no known pharmacological basis for such an interaction. However, with other topical nonsteroidal anti-inflammatory products, there have been reports that acetylcholine chloride and carbachol have been ineffective when used in patients treated with these agents.
- Interaction of PROFENAL with other topical ophthalmic medications has not been fully investigated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Reproductive studies have been performed in rabbits at doses up to 200 mg/kg/day and in rats at doses up to 80 mg/kg/day. In rats, doses of 40 mg/kg/day and above, and in rabbits, doses of 80 mg/kg/day and above, resulted in an increased incidence of fetal resorption associated with maternal toxicity. There was an increase in stillbirths and a decrease in postnatal survival in pregnant rats treated with suprofen at 2.5 mg/kg/day and above. An increased incidence of delayed parturition occurred in rats. As there are no adequate and well-controlled studies in pregnant women, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the known effect of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Suprofen in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Suprofen during labor and delivery.
### Nursing Mothers
- Suprofen is excreted in human milk after a single oral dose. Based on measurements of plasma and milk levels in women taking oral suprofen, the milk concentration is about 1% of the plasma level. Because systemic absorption may occur from topical ocular administration, a decision should be considered to discontinue nursing while receiving PROFENAL®, since the safety of suprofen in human neonates has not been established.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Suprofen with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Suprofen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Suprofen with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Suprofen in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Suprofen in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Suprofen in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Suprofen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Suprofen in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Suprofen in the drug label.
# Overdosage
## Acute Overdose
- Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Suprofen in the drug label.
# Pharmacology
## Mechanism of Action
- Suprofen is one of a series of phenylalkanoic acids that have shown analgesic, antipyretic, and anti-inflammatory activity in animal inflammatory diseases. Its mechanism of action is believed to be through inhibition of the cyclooxygenase enzyme that is essential in the biosynthesis of prostaglandins.
## Structure
- PROFENAL® (suprofen) 1% ophthalmic solution is a topical nonsteroidal anti-inflammatory product for ophthalmic use. Suprofen chemically is α -methyl-4-(2-thienylcarbonyl)benzeneacetic acid, with an empirical formula of C14H12O3S, and a molecular weight of 260.3. The chemical structure of suprofen is:
- PROFENAL Sterile Ophthalmic Solution contains suprofen 1.0% (10 mg/mL), thimerosal 0.005% (0.05 mg/mL), caffeine 2% (20 mg/mL), edetate disodium, dibasic sodium phosphate, monobasic sodium phosphate, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH to 7.4) and purified water.
## Pharmacodynamics
- Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed on animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilatation, increased vascular permeability, leukocytosis, and increased intraocular pressure.
- Prostaglandins appear to play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In clinical studies, PROFENAL has been shown to inhibit the miosis induced during the course of cataract surgery. PROFENAL could possibly interfere with the miotic effect of intraoperatively administered acetylcholine chloride.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Suprofen in the drug label.
## Nonclinical Toxicology
- In an 18-month study in mice, an increased incidence of benign hepatomas occurred in females at a dose of 40 mg/kg/day. Male mice, treated at doses of 2, 5, 10 and 40 mg/kg/day, also had an increased incidence of hepatomas when compared to control animals. No evidence of carcinogenicity was found in long term studies in doses as high as 40 mg/kg/day in the rat and mouse. Based on a battery of mutagenicity tests (Ames, micronucleus, and dominant lethal), suprofen does not appear to have mutagenic potential. Reproductive studies in rats at a dose of up to 40 mg/kg/day revealed no impairment of fertility and only slight reductions of fertility at doses of 80 mg/kg/day. However, testicular atrophy/hypoplasia was observed in a six-month dog study (at 80 mg/kg/day) and a 12-month rat study (at 40 mg/kg/day).
# Clinical Studies
There is limited information regarding Clinical Studies of Suprofen in the drug label.
# How Supplied
- Sterile ophthalmic solution, 2.5 mL in plastic DROP-TAINER® dispensers.
- 2.5 mL NDC 0065-0348-25
- Store at room temperature.
## Storage
There is limited information regarding Suprofen Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Suprofen in the drug label.
# Precautions with Alcohol
- Alcohol-Suprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PROFENAL®
# Look-Alike Drug Names
There is limited information regarding Suprofen Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Suprofen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Suprofen is an NSAID that is FDA approved for the treatment of intraoperative miosis. Common adverse reactions include burning, stinging of the eyes, eye discomfort, itching, and redness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- PROFENAL Ophthalmic Solution is indicated for inhibition of intraoperative miosis.
- On the day of surgery, instill two drops into the conjunctival sac at three, two and one hour prior to surgery. Two drops may be instilled into the conjunctival sac every four hours, while awake, the day preceding surgery.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Suprofen in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Suprofen in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Suprofen in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Suprofen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Suprofen in pediatric patients.
# Contraindications
- PROFENAL is contraindicated in epithelial herpes simplex keratitis (dendritic keratitis) and in individuals hypersensitive to any component of the medication.
# Warnings
- The potential exists for cross sensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.
- With nonsteroidal anti-inflammatory drugs, the potential exists for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding tendency of ocular tissues in conjunction with ocular surgery.
### Precautions
- General
- Use of oral suprofen has been associated with a syndrome of acute flank pain and generally reversible renal insufficiency, which may present as acute uric acid nephropathy. This syndrome occurs in approximately 1 in 3500 patients and has been reported with as few as one to two doses of a 200 mg capsule. If PROFENAL 1% Ophthalmic Solution is applied as two drops (1 mg suprofen) to one eye five times on the day prior to surgery and three times on the day of surgery, the total applied dose over the two days would be about 25 times less than a single 200 mg oral dose. Do not touch dropper tip to any surface, as this may contaminate the solution.
- Ocular
- Patients with histories of herpes simplex keratitis should be monitored closely. PROFENAL is contraindicated in patients with active herpes simplex keratitis.
- The possibility of increased ocular bleeding during surgery associated with nonsteroidal anti-inflammatory drugs should be considered.
# Adverse Reactions
## Clinical Trials Experience
- Ocular
- The most frequent adverse reactions reported are burning and stinging of short duration. Instances of discomfort, itching and redness have been reported. Other reactions occurring in less than 0.5% of patients include allergy, iritis, pain, chemosis, photophobia, irritation, and punctate epithelial staining.
- Systemic
- Systemic reactions related to therapy were not reported in the clinical studies. It is known that some systemic absorption does occur with ocularly applied drugs, and that nonsteroidal anti-inflammatory drugs have been shown to increase bleeding time by interference with thrombocyte aggregation. It is recommended that PROFENAL be used with caution in patients with bleeding tendencies and those taking anticoagulants.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Suprofen in the drug label.
# Drug Interactions
- Clinical studies with acetylcholine chloride revealed no interference, and there is no known pharmacological basis for such an interaction. However, with other topical nonsteroidal anti-inflammatory products, there have been reports that acetylcholine chloride and carbachol have been ineffective when used in patients treated with these agents.
- Interaction of PROFENAL with other topical ophthalmic medications has not been fully investigated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Reproductive studies have been performed in rabbits at doses up to 200 mg/kg/day and in rats at doses up to 80 mg/kg/day. In rats, doses of 40 mg/kg/day and above, and in rabbits, doses of 80 mg/kg/day and above, resulted in an increased incidence of fetal resorption associated with maternal toxicity. There was an increase in stillbirths and a decrease in postnatal survival in pregnant rats treated with suprofen at 2.5 mg/kg/day and above. An increased incidence of delayed parturition occurred in rats. As there are no adequate and well-controlled studies in pregnant women, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the known effect of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Suprofen in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Suprofen during labor and delivery.
### Nursing Mothers
- Suprofen is excreted in human milk after a single oral dose. Based on measurements of plasma and milk levels in women taking oral suprofen, the milk concentration is about 1% of the plasma level. Because systemic absorption may occur from topical ocular administration, a decision should be considered to discontinue nursing while receiving PROFENAL®, since the safety of suprofen in human neonates has not been established.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Suprofen with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Suprofen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Suprofen with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Suprofen in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Suprofen in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Suprofen in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Suprofen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Suprofen in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Suprofen in the drug label.
# Overdosage
## Acute Overdose
- Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Suprofen in the drug label.
# Pharmacology
## Mechanism of Action
- Suprofen is one of a series of phenylalkanoic acids that have shown analgesic, antipyretic, and anti-inflammatory activity in animal inflammatory diseases. Its mechanism of action is believed to be through inhibition of the cyclooxygenase enzyme that is essential in the biosynthesis of prostaglandins.
## Structure
- PROFENAL® (suprofen) 1% ophthalmic solution is a topical nonsteroidal anti-inflammatory product for ophthalmic use. Suprofen chemically is α -methyl-4-(2-thienylcarbonyl)benzeneacetic acid, with an empirical formula of C14H12O3S, and a molecular weight of 260.3. The chemical structure of suprofen is:
- PROFENAL Sterile Ophthalmic Solution contains suprofen 1.0% (10 mg/mL), thimerosal 0.005% (0.05 mg/mL), caffeine 2% (20 mg/mL), edetate disodium, dibasic sodium phosphate, monobasic sodium phosphate, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH to 7.4) and purified water.
## Pharmacodynamics
- Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed on animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilatation, increased vascular permeability, leukocytosis, and increased intraocular pressure.
- Prostaglandins appear to play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In clinical studies, PROFENAL has been shown to inhibit the miosis induced during the course of cataract surgery. PROFENAL could possibly interfere with the miotic effect of intraoperatively administered acetylcholine chloride.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Suprofen in the drug label.
## Nonclinical Toxicology
- In an 18-month study in mice, an increased incidence of benign hepatomas occurred in females at a dose of 40 mg/kg/day. Male mice, treated at doses of 2, 5, 10 and 40 mg/kg/day, also had an increased incidence of hepatomas when compared to control animals. No evidence of carcinogenicity was found in long term studies in doses as high as 40 mg/kg/day in the rat and mouse. Based on a battery of mutagenicity tests (Ames, micronucleus, and dominant lethal), suprofen does not appear to have mutagenic potential. Reproductive studies in rats at a dose of up to 40 mg/kg/day revealed no impairment of fertility and only slight reductions of fertility at doses of 80 mg/kg/day. However, testicular atrophy/hypoplasia was observed in a six-month dog study (at 80 mg/kg/day) and a 12-month rat study (at 40 mg/kg/day).
# Clinical Studies
There is limited information regarding Clinical Studies of Suprofen in the drug label.
# How Supplied
- Sterile ophthalmic solution, 2.5 mL in plastic DROP-TAINER® dispensers.
- 2.5 mL NDC 0065-0348-25
- Store at room temperature.
## Storage
There is limited information regarding Suprofen Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Suprofen in the drug label.
# Precautions with Alcohol
- Alcohol-Suprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PROFENAL®[1]
# Look-Alike Drug Names
There is limited information regarding Suprofen Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Suprofen | |
1aaeb498a6c94710806f37fe8ab9171f7c965179 | wikidoc | Survivin | Survivin
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene. NCBI Reference Sequence: NG_029069.1
Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions to inhibit caspase activation, thereby leading to negative regulation of apoptosis or programmed cell death. This has been shown by disruption of survivin induction pathways leading to increase in apoptosis and decrease in tumour growth. The survivin protein is expressed highly in most human tumours and fetal tissue, but is completely absent in terminally differentiated cells. These data suggest survivin might provide a new target for cancer therapy that would discriminate between transformed and normal cells. Survivin expression is also highly regulated by the cell cycle and is only expressed in the G2-M phase. It is known that Survivin localizes to the mitotic spindle by interaction with tubulin during mitosis and may play a contributing role in regulating mitosis. The molecular mechanisms of survivin regulation are still not well understood, but regulation of survivin seems to be linked to the p53 protein. It also is a direct target gene of the Wnt pathway and is upregulated by beta-catenin.
# IAP family of anti-apoptotic proteins
Survivin is a member of the IAP family of antiapoptotic proteins. It is shown to be conserved in function across evolution as homologues of the protein are found both in vertebrates and invertebrates. The first members of the IAPs identified were from the baculovirus IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host. Later, five more human IAPs that included XIAP, c-IAPl, C-IAP2, NAIP, and survivin were discovered. Survivin, like the others, was discovered by its structural homology to IAP family of proteins in human B-cell lymphoma. The human IAPs, XIAP, c-IAPl, C-IAP2 have been shown to bind to caspase-3 and -7, which are the effector caspases in the signaling pathway of apoptosis. It is not known with absolute certainty though, how the IAPs inhibit apoptosis mechanistically at the molecular level.
A common feature that is present in all IAPs in the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid motif) in one to three copies. It was shown by Tamm et al. that knocking out BIR2 from XIAP was enough to cause a loss of function in terms of XIAPs ability to inhibit caspases. This gives the implication that it is within these BIR motifs that contains the anti-apoptotic function of these IAPs. Survivin's one BIR domain shows a similar sequence compared to that of XIAP's BIR domains.
# Isoforms
The single survivin gene can give rise to four different alternatively spliced transcripts:
- Survivin, which has a three-intron–four-exon structure in both the mouse and human.
- Survivin-2B, which has an insertion of an alternative exon 2.
- Survivin-Delta-Ex-3, which has exon 3 removed. The removal of exon 3 results in a frame shift that generates a unique carboxyl terminus with a new function. This new function may involve a nuclear localization signal. Moreover, a mitochondrial localization signal is also generated.
- Survivin-3B, which has an insertion of an alternative exon 3.
# Structure
A structural feature common to all IAP family proteins is that they all contain at least one baculoviral IAP repeat (BIR) domain characterized by a conserved zinc-coordinating Cys/His motif at the N-terminal half of the protein.
Survivin is distinguished from other IAP family members in that it has only one BIR domain. The mice and human BIR domain of survivin are very similar structurally except for two differences that may affect function variability. The human survivin also contains an elongated C-terminal helix comprising 42 amino acids. Survivin is 16.5 kDa large and is the smallest member of the IAP family.
X-ray crystallography has shown two molecules of human surviving coming together to form a bowtie-shape dimer through a hydrophobic interface. This interface includes N-terminal residues 6-10 just before the BIR domain region and the 10 residue region connecting the BIR domain to the C-terminal helix. The structural integrity of the determined crystal structure of survivin is quite reliable, as physiological conditions were used to obtain the images.
# Function
## Apoptosis
Apoptosis, the process of programmed cell death, involves complex signaling pathways and cascades of molecular events. This process is needed for proper development during embryonic and fetal growth where there is destruction and reconstruction of cellular structures. In adult organisms, apoptosis is needed to maintain differentiated tissue by striking the balance between proliferation and cell death. It is known that intracellular proteases called caspases degrade the cellular contents of the cell by proteolysis upon activation of the death pathway.
Mammalian cells have two main pathways that lead to apoptosis.
1. Extrinsic Pathway: Initiated by extrinsic ligands binding to death receptors on the surface of the cell. An example of this is the binding of tumour necrosis factor-alpha (TNF-alpha) to TNF-alpha receptor. An example of a TNF receptor is Fas (CD95), which recruits activator caspases like caspase-8 upon binding TNF at the cell surface. The activation of the initiator caspases then initiates a downstream cascade of events that results in the induction of effector caspases that function in apoptosis.
2. Intrinsic Pathway: This pathway is initiated by intracellular or environmental stimuli. It is focused on detecting the improper functioning of the mitochondria in the cell and, as a result, activates signaling pathways to commit suicide. The membrane permeability of the mitochondria increases and particular proteins are released into the cytoplasm that facilitates the activation of initiator caspases. The particular protein released from the mitochondria is cytochrome c. Cytochrome c then binds to Apaf-1 in the cytosol and results in the activation of initiator caspase-9. The activation of the initiator caspases then initiates a downstream cascade of events that results in the induction of effector caspases that function in apoptosis.
One family of proteins called IAPs plays a role in regulating cell death by inhibiting the process. IAPs like survivin, inhibit apoptosis by physically binding to and inhibiting proper caspase function. The function of IAPs is evolutionarily conserved as Drosophila homologues of IAPs have been shown to be essential for cell survival.
IAPs have been implicated in studies to have a regulatory effect on cell division. Yeast cells with knock-outs of certain IAP genes did not show problems associated with cell death, but showed defects in mitosis characterized by improper chromosome segregation or failed cytokinesis.
Deletion of particular IAPs does not seem to have a profound effect on the cell-death pathway as there is a redundancy of function by the many IAPs that exist in a cell. They have been implicated, however, to play a role in maintaining an anti-apoptotic environment intracellularly. Changing the expression of particular IAPs has shown an increase in spontaneous cell death induction or increased sensitivity to death stimuli.
## Mechanism of action
### Inhibition of Bax and Fas-induced apoptosis
Tamm et al. have shown that survivin inhibits both Bax and Fas-induced apoptotic pathways. The experiment involved transfecting HEK 293 cells with a Bax-encoding plasmid, which resulted in an increase in apoptosis (~7 fold) as measured by DAPI staining. They then contransfected the 293 cells with Bax-encoding plasmid and survivin-encoding plasmids. They observed that cells transfected along with the survivin showed a significant decrease in apoptosis (~3 fold). A similar result also showed for cells transfected with the Fas-overexpressing plasmid. Immunoblots were performed and confirmed that survivin does not inhibit by mechanism of preventing Bax or Fas protein from being made into fully functional proteins. Therefore, survivin should be acting somewhere downstream of the Bax or Fas signaling pathway to inhibit apoptosis through these pathways.
### Interaction with caspase-3 and -7
In this part of the experiment, Tamm et al. transfected 293 cells with survivin and lysed them to obtain cell lysate. The lysates were incubated with different caspase forms and survivin was immunopercipitated with anti-survivin antibody. The idea behind this is that, if survivin binds physically with the caspase it is incubated with, it will be co-precipitated along with the survivin while everything else in the lysate is washed away. The immunoprecipitates were then run on SDS-PAGE and then immunoblotted for detection of the desired caspase. If the caspase of interest was detected, it meant that it was bound to survivin in the immunoprecipitation step implicating that survivin and the particular caspase had bound beforehand. Active caspase-3 and -7 coimmunoprecipitated with survivin. The inactive proforms of caspase-3 and -7 did not bind survivin. Survivin also does not bind to active caspase-8. Caspase-3 and -7 are effector proteases whereas caspase-8 is an initiator caspase that sits more upstream in the apoptotic pathway. These results demonstrate survivin's capability to bind with particular caspases in vitro, but may not necessarily translate over to actual physiological conditions. Later, a 2001 study confirmed that human survivin tightly binds caspase-3 and -7 when expressed in E. coli.
Further evidence to support the idea that survivin blocks apoptosis by directly inhibiting caspases was given by Tamm et al. 293 cells were transfected with either overexposed caspase-3 or -7 encoding plasmid and with survivin. They showed that survivin inhibited processing of these two caspases into their active forms. While survivin has been shown as mentioned above to bind to only the active forms of these caspases, it is likely here that survivin inhibits the active forms of the caspases resulting from cleaving and activating more of its own proforms. Thus, survivin acts possibly by preventing such a cascade of cleavage and activation amplification from happening resulting in decreased apoptosis.
In similar manner, looking at the mitochondrial pathway of apoptosis, cytochrome c was transiently expressed in 293 cells to look at the inhibitory effects survivin had on this pathway. Although the details are not here, survivin was shown to also inhibit cytochrome c and caspase-8-induced activation of caspases.
### Regulation of cytokinesis
While the mechanism by which survivin may regulate cell mitosis and cytokinesis is not known, the observations made on its localization during mitosis suggests strongly that it is involved in some way in the cytokinetic process.
Proliferating Daoy cells were placed on a glass coverslip, fixed and stained with fluorescent antibodies for survivin and alpha-tubulin. Immunoflourescence using confocal microscopy was used to look at the localization of survivin and tubulin during the cell-cycle to look for any patterns of survivin expression. Survivin was absent in interphase, but present in the G2-M phase.
During the different stages of mitosis, one could see that survivin follows a certain localization pattern. At prophase and metaphase, survivin is mainly nuclear in location. During prophase, as the chromatin condenses so that it is visible under the microscope, survivin starts to move to the centromeres. At prometaphase when the nuclear membrane dissociates and spindle microtubules cross over the nuclear region, survivin stays put at the centromeres. At metaphase, when the chromosomes align at the middle plate and are pulled with high tension to either pole by the kinetochore attachments, survivin then associates with the kinetochores. At anaphase as separation of the chromatids happens, the kinetochore microtubules shorten as the chromosomes move towards to the spindle poles and survivin also moves along to the midplate. Survivin thus accumulates at the midplate at telophase. Finally, survivin localizes to the midbody at the cleavage furrow.
### Interaction and localization to the mitochondria
It has been shown that survivin can heterodimerize individually with the two splice variants Survivin-2B and survivin-deltaEx3. Evidence of the heterodimerization of survivin splice variants with survivin was shown with co-immunoprecipitation experiments after cotransfection with the respective survivin variants with survivin. To determine the localization of exogenously expressed survivin-2B and survivin-deltaEx3, fusion constructs of the proteins were made with GFP and HcRed respectively and Daoy cells were transfected with the plasmid constructs. Survivin was also tagged with a fluorescent protein. The fusion of the survivin variants with the fluorescent molecules allows for simple detection of cellular location by fluorescence microscopy. Survivin-2B by itself, localized to both nuclear and cytoplasmic compartments whereas survivin-deltaEx3 localized only in the nucleus. The localization of the three variants (survivin, Survivin-2B, and survivin-deltaEx3) differ, however, when cotransfected together rather than individually.
To see which subcellular compartments contained the survivin splice variants complexes, fluorescent antibody markers for different organelles in the cell were employed. The assumption is that, under fluorescence microscopy, if the particular survivin complex is located in that particular cell compartment, one would observe an overlap from the fluorescence given off by the tagged survivin complex and the tagged compartment as well. Different color fluorescence is used to distinguish compartment from survivin.
- Endoplasmic reticulum and lyosomes: no colocalization
- Mitochondria and golgi: both survivin/survivin-2B and survivin/survivin-deltaEx3 colocalize
To verify these observations, they fractionated the subcellular compartments and performed western blot analysis to definitively say that survivin complexes did indeed localize at these compartments.
## Role in cancer
### Expression in different carcinomas
Survivin is known to be expressed during fetal development and across most tumour cell types, but is rarely present in normal, non-malignant adult cells. Tamm et al. showed that survivin was expressed in all 60 different human tumour lines used in the National Cancer Institute's cancer drug-screening program, with the highest levels of expression in breast and lung cancer lines and the lowest levels in renal cancers. Knowing the relative expression levels of survivin in different tumour types may prove helpful as survivin-related therapy may be administered depending on the expression level and reliance of the tumour type on survivin for resistance to apoptosis.
### As an oncogene
Survivin can be regarded as an oncogene as its aberrant overexpression in most cancer cells contributes to their resistance to apoptotic stimuli and chemotherapeutic therapies, thus contributing to their ongoing survival.
### Genomic instability
Most human cancers have been found to have gains and losses of chromosomes that may be due to chromosomal instability (CIN). One of the things that cause CIN is the inactivation of genes that control the proper segregation of the sister chromatids during mitosis. In gaining a better understanding of survivin's function in mitotic regulation, scientists have looked into the area of genomic instability. It is known that survivin associates with microtubules of the mitotic spindle at the start of mitosis.
It has been shown in the literature that knocking out survivin in cancer cells will disrupt microtubule formation and result in polyploidy as well as massive apoptosis. It has also been shown that survivin-depleted cells exit mitosis without achieving proper chromosome alignment and then reforms single tetraploid nuclei. Further evidence also suggests that survivin is needed for sustaining mitotic arrest upon encounter with mitosis problems. The evidence mentioned above implicates that survivin plays an important regulatory role both in the progression of mitosis and sustaining mitotic arrest. This seems strange, as survivin is known to be highly upregulated in most cancer cells (that usually contain chromosome instability characteristics), and its function is that which promotes proper regulation of mitosis.
# Regulation by p53
## p53 inhibits survivin expression at the transcriptional level
Wild-type p53 has been shown to repress survivin expression at the mRNA level. Using an adenovirus vector for wild-type p53, human ovarian cancer cell line 2774qw1 (which expresses mutant p53) was transfected. mRNA levels of survivin were analyzed by real-time quantitative PCR (RT-PCR) and showed time-dependent down regulation of survivin mRNA levels when the cells were infected with wild-type p53. A 3.6 fold decrease of survivin mRNA level was observed 16 hours after infection initiation and decreased 6.7 fold 24 hours after infection. Western blot results do show that there is indeed the p53 from the adenoviral vector was being expressed in the cells using antibody specific for p53. The expression of p53 levels indicative of its role in survivin repression shows that p53 started to be expressed 6 hours into infection and had its highest level at 16–24 hours. To further confirm that endogenous wild-type p53 is really causing the repression of survivin gene expression, the authors induced A549 (human lung cancer cell line with wild-type p53) and T47D (human breast cancer cell line with mutant p53) cells with DNA-damaging agent adriamycin to trigger the physiological p53 apoptotic response in these cancer cells and compare the survivin levels measured to the same cells without DNA damage induction. The A549 line, which intrinsically has functioning wild-type p53, showed significant reduction in survivin levels compared to non-induced cells. This same effect was not seen in T47D cells that carry mutant inactive p53.
P53's normal function is to regulate genes that control apoptosis. As survivin is a known inhibitor of apoptosis, it can be implied that p53 repression of survivin is one mechanism by which cells can undergo apoptosis upon induction by apoptotic stimuli or signals. When survivin is over-expressed in the cell lines mentioned in the previous paragraph, apoptotic response from DNA-damaging agent adriamycin decreased in a dose-dependent manner. This suggests that down-regulation of survivin by p53 is important for p53-mediated apoptotic pathway to successfully result in apoptosis. It is known that a defining characteristic of most tumors is the over-expression of survivin and the complete loss of wild-type p53. The evidence put forth by Mirza et al. shows that there exists a link between survivin and p53 that can possibly explain a critical event that contributes to cancer progression.
## p53 suppression of survivin expression
In order to see whether p53 re-expression in cancer cells (that have lost p53 expression) has the suppressive effect on the promoter of the survivin gene, a luciferase reporter construct was made. The isolated survivin promoter was placed upstream of the luciferase reporter gene. In a luciferase reporter assay, if the promoter is active, the luciferase gene is transcribed and translated into a product that gives off light that can measured quantitatively and, thus, represents the activity of the promoter. This construct was transfected into cancer cells that had either wild-type or mutant p53. High luciferase activity was measured in the cells with mutant p53 and significantly lower luciferase levels were measured for cells with wild-type p53.
Transfection of different cell types with wild-type p53 was associated with a strong repression of the survivin promoter. Transfection with mutant p53 was not shown to strongly repress the survivin promoter. More luciferase constructs were prepared with varying degrees of deletion from the 5' end of the survivin promoter region. At one point, there was deletion that caused the survivin levels to be indifferent to the presence of the p53 over-expression plasmid, indicating that there is a specific region proximal to the transcription start site that is needed for p53 suppression of survivin. Although it has been found that two p53 binding sites are located on the survivin gene promoter, analysis using deletions and mutations has shown that these sites are not essential to transcriptional inactivation.
Instead, it is observed that modification of the chromatin inside of the promoter region may be responsible for the transcriptional repression of the survivin gene. This is explained below in the epigenetic regulation section.
## Cell cycle regulation
Survivin is shown to be clearly regulated by the cell cycle, as its expression is found to be dominant only in the G2/M phase. This regulation exists at the transcriptional level, as there is evidence of the presence of cell-cycle-dependent element/cell-cycle gene homology region (CDE/CHR)boxes located in the survivin promoter region. Further evidence to support this mechanism of regulation includes the evidence that surivin is poly-ubiquinated and degraded by proteasomes during interphase of the cell cycle. Moreover, survivin has been shown to localize to components of the mitotic spindle during metaphase and anaphase of mitosis. Physical association between polymerized tubulin and survivin have been shown in vitro as well. It is also shown that post-transcriptional modification of survivin involving the phosphorylation of Thr34 leads to increased protein stability in the G2/M phase of the cell cycle.
It is known from Mirza et al. that repression of survivin by p53 is not a result of any cell cycle progressive regulation. The same experiment by Mirza et al. with regard to determining p53 suppression of survivin at the transcriptional level was repeated, but this time for cells arrested in different stages of the cell cycle. It was shown that, although p53 arrests the numbers of cells to different extents in different phases, the measured level of survivin mRNA and protein levels were the same across all the samples transfected with the wild-type p53. This shows that p53 acts in a cell-cycle independent manner to inhibit survivin expression.
## Epigenetic and genetic regulation
As observed through the literature, survivin is found to be over-expressed across many tumour types. Scientists are not sure of the mechanism that causes this abnormal over-expression of survivin; however, p53 is downregulated in almost all cancers, so it is tempting to suggest that survivin over-expression is due to p53 inactivity. Wagner et al. investigated the possible molecular mechanism involved with the over expression of survivin in acute myeloid leukemia (AML). In their experiments, they did both an epigenetic and a genetic analysis of the survivin gene promoter region in AML patients and compared the observations to what was seen in peripheral blood mononuclear cells (PBMCs) that have been shown to express no survivin. Assuming that the molecular mechanism of survivin re-expression in cancerous cells is at the transcriptional level, the authors decided to look at particular parts of the promoter region of survivin in order to see what happens in cancer cells that does not happen in normal cells that causes such a high level of survivin to be expressed. With regards to an epigenetic mechanism of survivin gene regulation, the authors measured the methylation status of the survivin promoter, since it is accepted that methylation of genes plays an important role in carcinogenesis by silencing of certain genes or vice versa. The authors used methylation specific polymerase chain reaction with bisulfite sequencing methods to measure the promoter methylation status in AML and PBMCs and found unmethylated survivin promoters in both groups. This result shows that DNA methylation status is not an important regulator of survivin re-expression during leukemogenesis. However, De Carvalho et al. performed a DNA methylation screening and identified that DNA methylation of IRAK3 plays a key role in survivin up-regulation in different types of Cancer, suggesting that epigenetic mechanisms plays an indirect role on abnormal over-expression of survivin. With regard to genetic analysis of the survivin promoter region, the isolated DNA of AML and PBMCs were treated with bisulfite, and the survivin promoter region sequence was amplified out with PCR and sequenced to look for any particular genetic changes in the DNA sequence between the two groups. Three single-nucleotide polymorphisms (SNPs) were identified and were all present both in AML patients and in healthy donors. This result suggests that the occurrence of these SNPs in the promoter region of the survivin gene also appears to be of no importance to survivin expression. However, it has not been ruled out yet that there may be other possible epigenetic mechanisms that may be responsible for a high level of survivin expression observed in cancer cells and not in normal cells. For example, the acetylation profile of the survivin promoter region can also be looked at. Different cancer and tissue types may have slight or significant differences in the way survivin expression is regulated in the cell, and, thus, the methylation status or genetic differences in the survivin promoter may be observed to be different in different tissues. Thus, further experiments assessing the epigenetic and genetic profile of different tumour types must be investigated.
# As a drug target
## Expression in cancer as a tool for cancer-directed therapy
Survivin is known to be highly expressed in most tumour cell types and absent in normal cells, making it a good target for cancer therapy. The exploitation of survivin's over-active promoter in most cancer cell types allows for the delivery of therapeutics only in cancer cells and removed from normal cells.
Small interfering RNA (siRNA) are synthetic antisense oligonucleotides to the mRNA of the gene of interest that works to silence the expression of a particular gene by its complementary binding. siRNAs, such as LY2181308, bound to the respective mRNA results in disruption of translation of that particular gene and thus the absence of that protein in the cell. Thus, the use of siRNAs has great potential to be a human therapeutic, as it can target and silence the expression of potentially any protein you want. A problem arises when siRNA expression in a cell cannot be controlled, allowing its constitutive expression to cause toxic side-effects. With regard to practical treatment of cancer, it is required to either deliver the siRNAs specifically into cancer cells or control the siRNA expression. Previous methods of siRNA therapy employ the use of siRNA sequences cloned into vectors under the control of constitutively active promoters. This causes a problem, as this model is non-specific to cancer cells and damages normal cells too. Knowing that survivin is over-expressed specifically in cancer cells and absent in normal cells, one can imply that the survivin promoter is active only in cancer cells. Thus, the exploitation of this difference between cancer cells and normal cells will allow appropriate therapy directed only at the cells in a patient that are harmful. In an experiment to demonstrate this idea, Trang et al. have created a cancer-specific vector expressing siRNA for green fluorescent protein (GFP) under the human survivin promoter. MCF7 breast cancer cells were cotransfected with this vector and a GFP-expressing vector as well. Their major finding was that MCF7 cells transfected with the siRNA vector for GFP under the survivin promoter had a significant reduction in GFP expression then the cells transfected with the siRNA vector under a cancer non-specific promoter. Moreover, normal non-cancerous cells transfected in the same way mentioned above showed no significant reduction in GFP expression. This is implying that, in normal cells, survivin promoter is not active, and, thus, the siRNA will not be expressed under an inactive survivin promoter.
## Antisense oligonucleotides targeting survivin mRNA
As it is known that survivin is over-expressed in most cancers, which may be contributing to the cancer cells' resistance to apoptotic stimuli from the environment. The use of antisense survivin therapy hopes to render cancer cells susceptible to apoptosis by eliminating survivin expression in the cancer cells.
Olie et al. developed different 20-mer phosphorothioate antisense oligonucleotides that target different regions in the mRNA of the survivin gene. The antisense function of the oligonucleotides allows binding to surviving mRNA and, depending on the region on which it binds, might inhibit surviving mRNA from being translated into a functional protein. Real-time PCR was used to assess the levels of mRNA present in a lung adenocarcinoma cell line A549 that overexpresses survivin. The best antisense oligonucleotide was identified that effectively down-regulated survivin mRNA levels and resulted in apoptosis of the cells. Survivin’s role in cancer development in the context of a signaling pathway is its ability to inhibit activation of downstream caspase-3 and -7 from apoptosis inducing stimuli. The overexpression of survivin in tumors may serve to increase the tumors resistance to apoptosis and, thus, contribute to cell immortality even in the presence of death stimuli. In this experiment, the oligonucleotide 4003 that targets nucleotides 232-251 of survivin mRNA was found to be the most effective at down-regulating the levels of survivin mRNA in the A549 tumour line. The 4003 oligonucleotides were introduced into the tumour cells by transfection. Further experiments were then conducted on 4003. One of the additional experiments involved determining the dose-dependent effect of 4003 on the down-regulation of survivin mRNA levels. It was found that a concentration of 400 nM resulted in a maximum down-regulation of 70% of the initial survivin mRNA present. Another experiment on 4003 involved assessing any biological or cytotoxic effect 4003 down-regulation of survivin mRNA has on A549 cells using the MTT assay. The numbers of A549 cells transfected with 4003 significantly decreased with increasing concentration of 4003 compared to cells transfected either with a mismatch form of the 4003 or lipofectin control. Many physical observations that confirmed the induction of apoptosis by 4003 were made. For example, lysates of the 4003-treated cells showed increased levels of caspase-3-like protease activity; nuclei were observed to be condensed and chromatin was fragmented.
## Cancer immunotherapy
Survivin has been a target of attention in recent years for cancer immunotherapy, as it is an antigen that is expressed mostly in cancer cells and absent in normal cells. This is because survivin is deemed to be a crucial player in tumour survival. There has been much evidence accumulated over the years that shows survivin as a strong T-cell-activating antigen, and clinical trials have already been initiated to prove its usefulness in the clinic.
### Activation of the adaptive immune system
A. Cellular T Cell Response
The first evidence of survivin-specific CTL recognition and killing was shown in an assay wherein cytotoxic T cells (CTLs) induced lysis of B cells transfected to present survivin peptides on its surface. The naive CD8+ T cells were primed with dendritic cells and could therefore recognize the specific peptides of survivin presented on the surface Major Histocompatibility Complex I (MHC I) molecules of the B cells.
B. Humoral Antibody Response
Taking blood samples from cancer patients, scientists have found antibodies that are specific for survivin. These antibodies were absent in the blood samples of healthy normal patients. Therefore, this shows that survivin is able to elicit a full humoral immune response. This may prove useful, as one could measure the level of survivin-specific antibodies in the patient's blood as a monitor of tumour progression. In acquiring the humoral response to tumour antigens such as survivin, CD4+ T cells are activated to induce B cells to produce antibodies directed against the particular antigens.
The isolation of the antibodies specific for survivin peptides is useful, as one can look at the structure and sequence of the epitope binding groove of the antibody and, therefore, deduce possible epitopes that may fit in that particular antibody groove. Therefore, one can determine the particular peptide portion of the survivin protein that is bound most efficiently and most commonly by humoral antibodies generated against survivin. This will lead to the production of more specific survivin vaccines that contain a specific portion of the survivin protein that is known to elicit a good immune response, generate immune memory, and allow for protection from tumour development.
### Over-expression in tumours and metastatic tissues
Xiang et al. found a new approach in inhibiting tumour growth and metastasis by simultaneously attacking both the tumour and its vasculature by a cytotoxic T cell (CTL) response against the survivin protein, which will later result in the activation of apoptosis in tumour cells.
The idea and general principle behind his technique is described below. Mice were immunized with the oral vaccination and then subjected to tumour challenges by injecting them in the chest with a certain number of tumour cells and a Matrigel pre-formed extracellular matrix to hold the tumour cells together. The mice were sacrificed and the endothelium tissue was stained with a fluorescent dye that would aid in the quantification of tumour neovascularisation using a Matrigel assay. There was found to be a significant difference between the control and test groups, whereby mice given the vaccine had less angiogenesis from the tumour challenge than the control mice that were not given any of the vaccine prior to tumour challenge. In vitro assays and other tests were also performed to validate the idea of the occurrence of an actual immune response to support what they observed in the mice. For example, the spleen on the challenged mice were isolated and measured for the presence of any cytokines, and specifically activated immune cell groups that would indicative that a specific immune response did occur upon vaccination. The isolated CTLs specific for the survivin protein after vaccination of the mice were used in cytoxicity assays where mice tumour cells expressing survivin were shown to be killed upon incubation with the specific CTLs.
By using an oral DNA vaccine carried in an attenuated non-virulent form of Salmonella typhimurium, which co-encoded secretory chemokine CCL21 and survivin protein in C57BL/6J mice, Xiang et al. have been able to elicit an immune response carried out by dendritic cells (DCs) and CTLs to eliminate and suppress the pulmonary metastases of non-small cell lung carcinoma. The activation of the immune response is most likely taking place in the secondary lymphoid organ called the Peyer’s Patch in the small intestine where DCs take up the survivin protein by phagocytosis and present them on their surface receptors to naive CD8+ T cells (uninactivated CTL) to achieve a specific immune response targeting survivin exclusively. Activated CTLs specific for a particular antigen kill their target cells by first recognizing parts of the survivin protein expressed on MHC I (immunohistocompatability) proteins presented on the surface of tumour cells and vasculature and then releasing granules that induce the tumour cells to undergo apoptosis. The DNA vaccine contained the CCL21 secretory chemokine as a way to enhance the likelihood of eliciting the immune response by better mediating the physical interaction of the antigen-presenting DCs and the naive CD8+ T cells, resulting in a greater likelihood of immune activation.
## Resveratrol-mediated sensitization
It has been shown by Fulda et al. that the naturally occurring compound resveratrol (a polyphenol found in grapes and red wine) can be used as a sensitizer for anticancer drug-induced apoptosis by the action of causing cell cycle arrest. This cell cycle arrest causes a dramatic decline in survivin levels in the cells, as it is known from the literature that survivin expression is highly linked with the cell cycle phase state. Thus, the decrease in survivin, which is a contributing factor to chemotherapy resistance and apoptosis induction therapies, would render the cancer cells more prone to such cancer treatments. Fulda et al. have demonstrated the benefits of resveratrol through a series of experiments. First, the authors of the paper tested the intrinsic cytotoxic effects of resveratrol. They found that it induced moderate apoptosis levels only in SHEP neuroblastoma cells. After, they tested resveratrol in combination with several different known anticancer agents. They found a consistent increase in the level of apoptosis induced by the drugs when resveratrol was also present. Moreover, they varied the order with which either the drugs or resveratrol was introduced to the cancer cells to determine whether the sequence of treatment had any important effect. It was found that the highest levels of apoptosis induction were observed when resveratrol was added prior to anticancer drug treatment. Next, the authors tested for any differential sensitivity to apoptosis linked to the phase of the cell cycle the cells were in. Analysis by flow cytometry revealed an accumulation of cells in S phase upon treatment with resveratrol. The cells were also halted in different phases of the cell cycle using special compounds and then treated with the anticancer drugs. They found that cells halted in S phase were significantly more sensitive to the cytotoxic effects of the drugs.
To determine the involvement of survivin in resveratrol-mediated sensitization, the authors decided to test whether downregulation of the specific survivin protein expression would confer a similar effect on the phenotype of resveratrol-treated cells. In terms of seeing at which level resveratrol worked, they did a northern blot and found that resveratrol treatment resulted in a decrease in survivin mRNA levels, thus implying resveratrol’s inhibitory action at the transcriptional level. To further see whether survivin played a key role in sensitization of the cancer cells to cytotoxic drugs, survivin antisense oligonucleotides were used to knock down any survivin mRNA, and, thus, its possibility to be translated is also eliminated. siRNAs for survivin are complements in sequence to the mRNA sequence encoding survivin. When these siRNAs for survivin are introduced into cells, they will bind to the respective complementary mRNA and, thus, prevent its translation since the mRNA is now impeded from proper physical interaction with the translational machinery. In this way, the siRNAs for survivin effectively downregulates survivin expression level in the cell. Cells treated with antisense oligonucleotides for survivin showed similar sensitization to cytotoxic drugs as cells treated with resveratrol, which offers support for the mechanism of action of resveratrol.
## Prostate cancer
It has been observed that the development of hormone resistance in prostate cancer may be due to the upregulation of antiapoptotic genes, one of which is survivin.
Zhang et al. hypothesize that, if survivin is a significant contributor to the development of hormonal therapy resistance in prostate cancer cells, targeting survivin and blocking it would enhance prostate cancer cell susceptibility to anti-androgen therapy. The basis of anti-androgen therapy involves using drugs that eliminate the presence of androgens in the cell and cellular environment, since the presence of androgens are known to enhance tumour immortality in prostate cancer cells. Zhang et al. first assessed the level of survivin expression of LNCaP (an androgen-dependent prostate cancer cell line that expresses intact androgen receptors) using quantitative Western analysis and found high expression of survivin in these cells. Cells exposed to dihydrotestosterone (DHT), an exogenous androgen, showed increased levels of survivin expression only and not other IAP family members. This result implicates that androgens in the physiological context may upregulate survivin, which contributes to the resistance of apoptosis observed in the tumour cells. Next, with the addition of Flutamide(an antiandrogen) to the cells, survivin levels were observed to significantly decrease. The LNCaP cells were transduced separately with the different constructs of the survivin gene (mutant or wild-type) and subjected to Flutamide treatment and assessed for the apoptosis level. Flutamide-treated survivin mutant-transduced cells were shown to significantly increase apoptosis by double that of Flutamide treatment alone. On the other end, overexpression of the wild-type survivin was found to significantly reduce the apoptosis levels from Flutamide treatment compared to Flutamide treatment alone. Therefore, these results support the hypothesis that asserts that survivin does play a role in contributing the anti-apoptotic nature of the LNCaP cancer cell line and that inhibiting survivin in prostate cancer cells does appear to enhance the therapeutic effect of Flutamide.
# Interactions
Survivin has been shown to interact with:
- Aurora B kinase,
- CDCA8,
- Caspase 3,
- Caspase 7,
- Diablo homolog and
- INCENP. | Survivin
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene.[1][2] NCBI Reference Sequence: NG_029069.1
Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions to inhibit caspase activation, thereby leading to negative regulation of apoptosis or programmed cell death. This has been shown by disruption of survivin induction pathways leading to increase in apoptosis and decrease in tumour growth. The survivin protein is expressed highly in most human tumours and fetal tissue, but is completely absent in terminally differentiated cells.[3] These data suggest survivin might provide a new target for cancer therapy that would discriminate between transformed and normal cells. Survivin expression is also highly regulated by the cell cycle and is only expressed in the G2-M phase. It is known that Survivin localizes to the mitotic spindle by interaction with tubulin during mitosis and may play a contributing role in regulating mitosis. The molecular mechanisms of survivin regulation are still not well understood, but regulation of survivin seems to be linked to the p53 protein. It also is a direct target gene of the Wnt pathway and is upregulated by beta-catenin.[4]
# IAP family of anti-apoptotic proteins
Survivin is a member of the IAP family of antiapoptotic proteins. It is shown to be conserved in function across evolution as homologues of the protein are found both in vertebrates and invertebrates.[5] The first members of the IAPs identified were from the baculovirus IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host.[5] Later, five more human IAPs that included XIAP, c-IAPl, C-IAP2, NAIP, and survivin were discovered. Survivin, like the others, was discovered by its structural homology to IAP family of proteins in human B-cell lymphoma. The human IAPs, XIAP, c-IAPl, C-IAP2 have been shown to bind to caspase-3 and -7, which are the effector caspases in the signaling pathway of apoptosis.[5] It is not known with absolute certainty though, how the IAPs inhibit apoptosis mechanistically at the molecular level.
A common feature that is present in all IAPs in the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid motif) in one to three copies. It was shown by Tamm et al. that knocking out BIR2 from XIAP was enough to cause a loss of function in terms of XIAPs ability to inhibit caspases. This gives the implication that it is within these BIR motifs that contains the anti-apoptotic function of these IAPs. Survivin's one BIR domain shows a similar sequence compared to that of XIAP's BIR domains.[5]
# Isoforms
The single survivin gene can give rise to four different alternatively spliced transcripts:[6]
- Survivin, which has a three-intron–four-exon structure in both the mouse and human.
- Survivin-2B, which has an insertion of an alternative exon 2.
- Survivin-Delta-Ex-3, which has exon 3 removed. The removal of exon 3 results in a frame shift that generates a unique carboxyl terminus with a new function. This new function may involve a nuclear localization signal. Moreover, a mitochondrial localization signal is also generated.
- Survivin-3B, which has an insertion of an alternative exon 3.
# Structure
A structural feature common to all IAP family proteins is that they all contain at least one baculoviral IAP repeat (BIR) domain characterized by a conserved zinc-coordinating Cys/His motif at the N-terminal half of the protein.[7][8]
Survivin is distinguished from other IAP family members in that it has only one BIR domain.[7][8] The mice and human BIR domain of survivin are very similar structurally except for two differences that may affect function variability. The human survivin also contains an elongated C-terminal helix comprising 42 amino acids.[7][8] Survivin is 16.5 kDa large and is the smallest member of the IAP family.[7][8]
X-ray crystallography has shown two molecules of human surviving coming together to form a bowtie-shape dimer through a hydrophobic interface.[7][8] This interface includes N-terminal residues 6-10 just before the BIR domain region and the 10 residue region connecting the BIR domain to the C-terminal helix.[7][8] The structural integrity of the determined crystal structure of survivin is quite reliable, as physiological conditions were used to obtain the images.
# Function
## Apoptosis
Apoptosis, the process of programmed cell death, involves complex signaling pathways and cascades of molecular events. This process is needed for proper development during embryonic and fetal growth where there is destruction and reconstruction of cellular structures. In adult organisms, apoptosis is needed to maintain differentiated tissue by striking the balance between proliferation and cell death. It is known that intracellular proteases called caspases degrade the cellular contents of the cell by proteolysis upon activation of the death pathway.
Mammalian cells have two main pathways that lead to apoptosis.
1. Extrinsic Pathway: Initiated by extrinsic ligands binding to death receptors on the surface of the cell. An example of this is the binding of tumour necrosis factor-alpha (TNF-alpha) to TNF-alpha receptor. An example of a TNF receptor is Fas (CD95), which recruits activator caspases like caspase-8 upon binding TNF at the cell surface. The activation of the initiator caspases then initiates a downstream cascade of events that results in the induction of effector caspases that function in apoptosis.[5][9]
2. Intrinsic Pathway: This pathway is initiated by intracellular or environmental stimuli. It is focused on detecting the improper functioning of the mitochondria in the cell and, as a result, activates signaling pathways to commit suicide. The membrane permeability of the mitochondria increases and particular proteins are released into the cytoplasm that facilitates the activation of initiator caspases. The particular protein released from the mitochondria is cytochrome c. Cytochrome c then binds to Apaf-1 in the cytosol and results in the activation of initiator caspase-9. The activation of the initiator caspases then initiates a downstream cascade of events that results in the induction of effector caspases that function in apoptosis.[5][9]
One family of proteins called IAPs plays a role in regulating cell death by inhibiting the process. IAPs like survivin, inhibit apoptosis by physically binding to and inhibiting proper caspase function.[5] The function of IAPs is evolutionarily conserved as Drosophila homologues of IAPs have been shown to be essential for cell survival.[5]
IAPs have been implicated in studies to have a regulatory effect on cell division. Yeast cells with knock-outs of certain IAP genes did not show problems associated with cell death, but showed defects in mitosis characterized by improper chromosome segregation or failed cytokinesis.[5]
Deletion of particular IAPs does not seem to have a profound effect on the cell-death pathway as there is a redundancy of function by the many IAPs that exist in a cell.[5] They have been implicated, however, to play a role in maintaining an anti-apoptotic environment intracellularly. Changing the expression of particular IAPs has shown an increase in spontaneous cell death induction or increased sensitivity to death stimuli.[5]
## Mechanism of action
### Inhibition of Bax and Fas-induced apoptosis
Tamm et al. have shown that survivin inhibits both Bax and Fas-induced apoptotic pathways.[5] The experiment involved transfecting HEK 293 cells with a Bax-encoding plasmid, which resulted in an increase in apoptosis (~7 fold) as measured by DAPI staining.[5] They then contransfected the 293 cells with Bax-encoding plasmid and survivin-encoding plasmids. They observed that cells transfected along with the survivin showed a significant decrease in apoptosis (~3 fold). A similar result also showed for cells transfected with the Fas-overexpressing plasmid. Immunoblots were performed and confirmed that survivin does not inhibit by mechanism of preventing Bax or Fas protein from being made into fully functional proteins.[5] Therefore, survivin should be acting somewhere downstream of the Bax or Fas signaling pathway to inhibit apoptosis through these pathways.[5]
### Interaction with caspase-3 and -7
In this part of the experiment, Tamm et al. transfected 293 cells with survivin and lysed them to obtain cell lysate. The lysates were incubated with different caspase forms and survivin was immunopercipitated with anti-survivin antibody. The idea behind this is that, if survivin binds physically with the caspase it is incubated with, it will be co-precipitated along with the survivin while everything else in the lysate is washed away. The immunoprecipitates were then run on SDS-PAGE and then immunoblotted for detection of the desired caspase. If the caspase of interest was detected, it meant that it was bound to survivin in the immunoprecipitation step implicating that survivin and the particular caspase had bound beforehand. Active caspase-3 and -7 coimmunoprecipitated with survivin. The inactive proforms of caspase-3 and -7 did not bind survivin.[5] Survivin also does not bind to active caspase-8.[5] Caspase-3 and -7 are effector proteases whereas caspase-8 is an initiator caspase that sits more upstream in the apoptotic pathway.[5] These results demonstrate survivin's capability to bind with particular caspases in vitro, but may not necessarily translate over to actual physiological conditions. Later, a 2001 study confirmed that human survivin tightly binds caspase-3 and -7 when expressed in E. coli.[10]
Further evidence to support the idea that survivin blocks apoptosis by directly inhibiting caspases was given by Tamm et al. 293 cells were transfected with either overexposed caspase-3 or -7 encoding plasmid and with survivin. They showed that survivin inhibited processing of these two caspases into their active forms. While survivin has been shown as mentioned above to bind to only the active forms of these caspases, it is likely here that survivin inhibits the active forms of the caspases resulting from cleaving and activating more of its own proforms. Thus, survivin acts possibly by preventing such a cascade of cleavage and activation amplification from happening resulting in decreased apoptosis.[5]
In similar manner, looking at the mitochondrial pathway of apoptosis, cytochrome c was transiently expressed in 293 cells to look at the inhibitory effects survivin had on this pathway. Although the details are not here, survivin was shown to also inhibit cytochrome c and caspase-8-induced activation of caspases.[5]
### Regulation of cytokinesis
While the mechanism by which survivin may regulate cell mitosis and cytokinesis is not known, the observations made on its localization during mitosis suggests strongly that it is involved in some way in the cytokinetic process.
Proliferating Daoy cells were placed on a glass coverslip, fixed and stained with fluorescent antibodies for survivin and alpha-tubulin. Immunoflourescence using confocal microscopy was used to look at the localization of survivin and tubulin during the cell-cycle to look for any patterns of survivin expression. Survivin was absent in interphase, but present in the G2-M phase.[6]
During the different stages of mitosis, one could see that survivin follows a certain localization pattern. At prophase and metaphase, survivin is mainly nuclear in location.[6] During prophase, as the chromatin condenses so that it is visible under the microscope, survivin starts to move to the centromeres.[6] At prometaphase when the nuclear membrane dissociates and spindle microtubules cross over the nuclear region, survivin stays put at the centromeres.[6] At metaphase, when the chromosomes align at the middle plate and are pulled with high tension to either pole by the kinetochore attachments, survivin then associates with the kinetochores.[6] At anaphase as separation of the chromatids happens, the kinetochore microtubules shorten as the chromosomes move towards to the spindle poles and survivin also moves along to the midplate.[6] Survivin thus accumulates at the midplate at telophase.[6] Finally, survivin localizes to the midbody at the cleavage furrow.[6]
### Interaction and localization to the mitochondria
It has been shown that survivin can heterodimerize individually with the two splice variants Survivin-2B and survivin-deltaEx3.[6] Evidence of the heterodimerization of survivin splice variants with survivin was shown with co-immunoprecipitation experiments after cotransfection with the respective survivin variants with survivin. To determine the localization of exogenously expressed survivin-2B and survivin-deltaEx3, fusion constructs of the proteins were made with GFP and HcRed respectively and Daoy cells were transfected with the plasmid constructs. Survivin was also tagged with a fluorescent protein. The fusion of the survivin variants with the fluorescent molecules allows for simple detection of cellular location by fluorescence microscopy. Survivin-2B by itself, localized to both nuclear and cytoplasmic compartments whereas survivin-deltaEx3 localized only in the nucleus.[6] The localization of the three variants (survivin, Survivin-2B, and survivin-deltaEx3) differ, however, when cotransfected together rather than individually.[6]
To see which subcellular compartments contained the survivin splice variants complexes, fluorescent antibody markers for different organelles in the cell were employed. The assumption is that, under fluorescence microscopy, if the particular survivin complex is located in that particular cell compartment, one would observe an overlap from the fluorescence given off by the tagged survivin complex and the tagged compartment as well. Different color fluorescence is used to distinguish compartment from survivin.
- Endoplasmic reticulum and lyosomes: no colocalization
- Mitochondria and golgi: both survivin/survivin-2B and survivin/survivin-deltaEx3 colocalize
To verify these observations, they fractionated the subcellular compartments and performed western blot analysis to definitively say that survivin complexes did indeed localize at these compartments.
## Role in cancer
### Expression in different carcinomas
Survivin is known to be expressed during fetal development and across most tumour cell types, but is rarely present in normal, non-malignant adult cells.[11] Tamm et al. showed that survivin was expressed in all 60 different human tumour lines used in the National Cancer Institute's cancer drug-screening program, with the highest levels of expression in breast and lung cancer lines and the lowest levels in renal cancers.[5] Knowing the relative expression levels of survivin in different tumour types may prove helpful as survivin-related therapy may be administered depending on the expression level and reliance of the tumour type on survivin for resistance to apoptosis.
### As an oncogene
Survivin can be regarded as an oncogene as its aberrant overexpression in most cancer cells contributes to their resistance to apoptotic stimuli and chemotherapeutic therapies, thus contributing to their ongoing survival.
### Genomic instability
Most human cancers have been found to have gains and losses of chromosomes that may be due to chromosomal instability (CIN). One of the things that cause CIN is the inactivation of genes that control the proper segregation of the sister chromatids during mitosis. In gaining a better understanding of survivin's function in mitotic regulation, scientists have looked into the area of genomic instability. It is known that survivin associates with microtubules of the mitotic spindle at the start of mitosis.[12]
It has been shown in the literature that knocking out survivin in cancer cells will disrupt microtubule formation and result in polyploidy as well as massive apoptosis.[12] It has also been shown that survivin-depleted cells exit mitosis without achieving proper chromosome alignment and then reforms single tetraploid nuclei.[12] Further evidence also suggests that survivin is needed for sustaining mitotic arrest upon encounter with mitosis problems.[12] The evidence mentioned above implicates that survivin plays an important regulatory role both in the progression of mitosis and sustaining mitotic arrest. This seems strange, as survivin is known to be highly upregulated in most cancer cells (that usually contain chromosome instability characteristics), and its function is that which promotes proper regulation of mitosis.
# Regulation by p53
## p53 inhibits survivin expression at the transcriptional level
Wild-type p53 has been shown to repress survivin expression at the mRNA level.[13] Using an adenovirus vector for wild-type p53, human ovarian cancer cell line 2774qw1 (which expresses mutant p53) was transfected. mRNA levels of survivin were analyzed by real-time quantitative PCR (RT-PCR) and showed time-dependent down regulation of survivin mRNA levels when the cells were infected with wild-type p53.[13] A 3.6 fold decrease of survivin mRNA level was observed 16 hours after infection initiation and decreased 6.7 fold 24 hours after infection.[13] Western blot results do show that there is indeed the p53 from the adenoviral vector was being expressed in the cells using antibody specific for p53. The expression of p53 levels indicative of its role in survivin repression shows that p53 started to be expressed 6 hours into infection and had its highest level at 16–24 hours.[13] To further confirm that endogenous wild-type p53 is really causing the repression of survivin gene expression, the authors induced A549 (human lung cancer cell line with wild-type p53) and T47D (human breast cancer cell line with mutant p53) cells with DNA-damaging agent adriamycin to trigger the physiological p53 apoptotic response in these cancer cells and compare the survivin levels measured to the same cells without DNA damage induction. The A549 line, which intrinsically has functioning wild-type p53, showed significant reduction in survivin levels compared to non-induced cells.[13] This same effect was not seen in T47D cells that carry mutant inactive p53.[13]
P53's normal function is to regulate genes that control apoptosis. As survivin is a known inhibitor of apoptosis, it can be implied that p53 repression of survivin is one mechanism by which cells can undergo apoptosis upon induction by apoptotic stimuli or signals. When survivin is over-expressed in the cell lines mentioned in the previous paragraph, apoptotic response from DNA-damaging agent adriamycin decreased in a dose-dependent manner.[13] This suggests that down-regulation of survivin by p53 is important for p53-mediated apoptotic pathway to successfully result in apoptosis. It is known that a defining characteristic of most tumors is the over-expression of survivin and the complete loss of wild-type p53.[13] The evidence put forth by Mirza et al. shows that there exists a link between survivin and p53 that can possibly explain a critical event that contributes to cancer progression.
## p53 suppression of survivin expression
In order to see whether p53 re-expression in cancer cells (that have lost p53 expression) has the suppressive effect on the promoter of the survivin gene, a luciferase reporter construct was made. The isolated survivin promoter was placed upstream of the luciferase reporter gene. In a luciferase reporter assay, if the promoter is active, the luciferase gene is transcribed and translated into a product that gives off light that can measured quantitatively and, thus, represents the activity of the promoter. This construct was transfected into cancer cells that had either wild-type or mutant p53. High luciferase activity was measured in the cells with mutant p53 and significantly lower luciferase levels were measured for cells with wild-type p53.[13]
Transfection of different cell types with wild-type p53 was associated with a strong repression of the survivin promoter.[13] Transfection with mutant p53 was not shown to strongly repress the survivin promoter.[13] More luciferase constructs were prepared with varying degrees of deletion from the 5' end of the survivin promoter region. At one point, there was deletion that caused the survivin levels to be indifferent to the presence of the p53 over-expression plasmid, indicating that there is a specific region proximal to the transcription start site that is needed for p53 suppression of survivin.[13] Although it has been found that two p53 binding sites are located on the survivin gene promoter, analysis using deletions and mutations has shown that these sites are not essential to transcriptional inactivation.[13]
Instead, it is observed that modification of the chromatin inside of the promoter region may be responsible for the transcriptional repression of the survivin gene. This is explained below in the epigenetic regulation section.[13]
## Cell cycle regulation
Survivin is shown to be clearly regulated by the cell cycle, as its expression is found to be dominant only in the G2/M phase.[9] This regulation exists at the transcriptional level, as there is evidence of the presence of cell-cycle-dependent element/cell-cycle gene homology region (CDE/CHR)boxes located in the survivin promoter region.[9] Further evidence to support this mechanism of regulation includes the evidence that surivin is poly-ubiquinated and degraded by proteasomes during interphase of the cell cycle.[9] Moreover, survivin has been shown to localize to components of the mitotic spindle during metaphase and anaphase of mitosis.[9] Physical association between polymerized tubulin and survivin have been shown in vitro as well.[9] It is also shown that post-transcriptional modification of survivin involving the phosphorylation of Thr34 leads to increased protein stability in the G2/M phase of the cell cycle.[9]
It is known from Mirza et al. that repression of survivin by p53 is not a result of any cell cycle progressive regulation. The same experiment by Mirza et al. with regard to determining p53 suppression of survivin at the transcriptional level was repeated, but this time for cells arrested in different stages of the cell cycle. It was shown that, although p53 arrests the numbers of cells to different extents in different phases, the measured level of survivin mRNA and protein levels were the same across all the samples transfected with the wild-type p53. This shows that p53 acts in a cell-cycle independent manner to inhibit survivin expression.[13]
## Epigenetic and genetic regulation
As observed through the literature, survivin is found to be over-expressed across many tumour types. Scientists are not sure of the mechanism that causes this abnormal over-expression of survivin; however, p53 is downregulated in almost all cancers, so it is tempting to suggest that survivin over-expression is due to p53 inactivity. Wagner et al. investigated the possible molecular mechanism involved with the over expression of survivin in acute myeloid leukemia (AML). In their experiments, they did both an epigenetic and a genetic analysis of the survivin gene promoter region in AML patients and compared the observations to what was seen in peripheral blood mononuclear cells (PBMCs) that have been shown to express no survivin. Assuming that the molecular mechanism of survivin re-expression in cancerous cells is at the transcriptional level, the authors decided to look at particular parts of the promoter region of survivin in order to see what happens in cancer cells that does not happen in normal cells that causes such a high level of survivin to be expressed. With regards to an epigenetic mechanism of survivin gene regulation, the authors measured the methylation status of the survivin promoter, since it is accepted that methylation of genes plays an important role in carcinogenesis by silencing of certain genes or vice versa. The authors used methylation specific polymerase chain reaction with bisulfite sequencing methods to measure the promoter methylation status in AML and PBMCs and found unmethylated survivin promoters in both groups.[14] This result shows that DNA methylation status is not an important regulator of survivin re-expression during leukemogenesis.[14] However, De Carvalho et al. performed a DNA methylation screening and identified that DNA methylation of IRAK3 plays a key role in survivin up-regulation in different types of Cancer,[15] suggesting that epigenetic mechanisms plays an indirect role on abnormal over-expression of survivin. With regard to genetic analysis of the survivin promoter region, the isolated DNA of AML and PBMCs were treated with bisulfite, and the survivin promoter region sequence was amplified out with PCR and sequenced to look for any particular genetic changes in the DNA sequence between the two groups. Three single-nucleotide polymorphisms (SNPs) were identified and were all present both in AML patients and in healthy donors. This result suggests that the occurrence of these SNPs in the promoter region of the survivin gene also appears to be of no importance to survivin expression.[14] However, it has not been ruled out yet that there may be other possible epigenetic mechanisms that may be responsible for a high level of survivin expression observed in cancer cells and not in normal cells. For example, the acetylation profile of the survivin promoter region can also be looked at. Different cancer and tissue types may have slight or significant differences in the way survivin expression is regulated in the cell, and, thus, the methylation status or genetic differences in the survivin promoter may be observed to be different in different tissues. Thus, further experiments assessing the epigenetic and genetic profile of different tumour types must be investigated.
# As a drug target
## Expression in cancer as a tool for cancer-directed therapy
Survivin is known to be highly expressed in most tumour cell types and absent in normal cells, making it a good target for cancer therapy.[16][17][18][19][20] The exploitation of survivin's over-active promoter in most cancer cell types allows for the delivery of therapeutics only in cancer cells and removed from normal cells.[21]
Small interfering RNA (siRNA) are synthetic antisense oligonucleotides to the mRNA of the gene of interest that works to silence the expression of a particular gene by its complementary binding. siRNAs, such as LY2181308, bound to the respective mRNA results in disruption of translation of that particular gene and thus the absence of that protein in the cell. Thus, the use of siRNAs has great potential to be a human therapeutic, as it can target and silence the expression of potentially any protein you want. A problem arises when siRNA expression in a cell cannot be controlled, allowing its constitutive expression to cause toxic side-effects. With regard to practical treatment of cancer, it is required to either deliver the siRNAs specifically into cancer cells or control the siRNA expression. Previous methods of siRNA therapy employ the use of siRNA sequences cloned into vectors under the control of constitutively active promoters.[21] This causes a problem, as this model is non-specific to cancer cells and damages normal cells too.[21] Knowing that survivin is over-expressed specifically in cancer cells and absent in normal cells, one can imply that the survivin promoter is active only in cancer cells. Thus, the exploitation of this difference between cancer cells and normal cells will allow appropriate therapy directed only at the cells in a patient that are harmful. In an experiment to demonstrate this idea, Trang et al. have created a cancer-specific vector expressing siRNA for green fluorescent protein (GFP) under the human survivin promoter. MCF7 breast cancer cells were cotransfected with this vector and a GFP-expressing vector as well. Their major finding was that MCF7 cells transfected with the siRNA vector for GFP under the survivin promoter had a significant reduction in GFP expression then the cells transfected with the siRNA vector under a cancer non-specific promoter.[21] Moreover, normal non-cancerous cells transfected in the same way mentioned above showed no significant reduction in GFP expression.[21] This is implying that, in normal cells, survivin promoter is not active, and, thus, the siRNA will not be expressed under an inactive survivin promoter.[21]
## Antisense oligonucleotides targeting survivin mRNA
As it is known that survivin is over-expressed in most cancers, which may be contributing to the cancer cells' resistance to apoptotic stimuli from the environment. The use of antisense survivin therapy hopes to render cancer cells susceptible to apoptosis by eliminating survivin expression in the cancer cells.[4]
Olie et al. developed different 20-mer phosphorothioate antisense oligonucleotides that target different regions in the mRNA of the survivin gene. The antisense function of the oligonucleotides allows binding to surviving mRNA and, depending on the region on which it binds, might inhibit surviving mRNA from being translated into a functional protein. Real-time PCR was used to assess the levels of mRNA present in a lung adenocarcinoma cell line A549 that overexpresses survivin. The best antisense oligonucleotide was identified that effectively down-regulated survivin mRNA levels and resulted in apoptosis of the cells. Survivin’s role in cancer development in the context of a signaling pathway is its ability to inhibit activation of downstream caspase-3 and -7 from apoptosis inducing stimuli. The overexpression of survivin in tumors may serve to increase the tumors resistance to apoptosis and, thus, contribute to cell immortality even in the presence of death stimuli.[21] In this experiment, the oligonucleotide 4003 that targets nucleotides 232-251 of survivin mRNA was found to be the most effective at down-regulating the levels of survivin mRNA in the A549 tumour line.[21] The 4003 oligonucleotides were introduced into the tumour cells by transfection. Further experiments were then conducted on 4003. One of the additional experiments involved determining the dose-dependent effect of 4003 on the down-regulation of survivin mRNA levels. It was found that a concentration of 400 nM resulted in a maximum down-regulation of 70% of the initial survivin mRNA present.[21] Another experiment on 4003 involved assessing any biological or cytotoxic effect 4003 down-regulation of survivin mRNA has on A549 cells using the MTT assay. The numbers of A549 cells transfected with 4003 significantly decreased with increasing concentration of 4003 compared to cells transfected either with a mismatch form of the 4003 or lipofectin control.[21] Many physical observations that confirmed the induction of apoptosis by 4003 were made. For example, lysates of the 4003-treated cells showed increased levels of caspase-3-like protease activity; nuclei were observed to be condensed and chromatin was fragmented.
## Cancer immunotherapy
Survivin has been a target of attention in recent years for cancer immunotherapy, as it is an antigen that is expressed mostly in cancer cells and absent in normal cells. This is because survivin is deemed to be a crucial player in tumour survival. There has been much evidence accumulated over the years that shows survivin as a strong T-cell-activating antigen, and clinical trials have already been initiated to prove its usefulness in the clinic.[22]
### Activation of the adaptive immune system
A. Cellular T Cell Response
The first evidence of survivin-specific CTL recognition and killing was shown in an assay wherein cytotoxic T cells (CTLs) induced lysis of B cells transfected to present survivin peptides on its surface.[22] The naive CD8+ T cells were primed with dendritic cells and could therefore recognize the specific peptides of survivin presented on the surface Major Histocompatibility Complex I (MHC I) molecules of the B cells.
B. Humoral Antibody Response
Taking blood samples from cancer patients, scientists have found antibodies that are specific for survivin.[22] These antibodies were absent in the blood samples of healthy normal patients.[22] Therefore, this shows that survivin is able to elicit a full humoral immune response. This may prove useful, as one could measure the level of survivin-specific antibodies in the patient's blood as a monitor of tumour progression.[22] In acquiring the humoral response to tumour antigens such as survivin, CD4+ T cells are activated to induce B cells to produce antibodies directed against the particular antigens.
The isolation of the antibodies specific for survivin peptides is useful, as one can look at the structure and sequence of the epitope binding groove of the antibody and, therefore, deduce possible epitopes that may fit in that particular antibody groove.[22] Therefore, one can determine the particular peptide portion of the survivin protein that is bound most efficiently and most commonly by humoral antibodies generated against survivin. This will lead to the production of more specific survivin vaccines that contain a specific portion of the survivin protein that is known to elicit a good immune response, generate immune memory, and allow for protection from tumour development.
### Over-expression in tumours and metastatic tissues
Xiang et al. found a new approach in inhibiting tumour growth and metastasis by simultaneously attacking both the tumour and its vasculature by a cytotoxic T cell (CTL) response against the survivin protein, which will later result in the activation of apoptosis in tumour cells.[23]
The idea and general principle behind his technique is described below. Mice were immunized with the oral vaccination and then subjected to tumour challenges by injecting them in the chest with a certain number of tumour cells and a Matrigel pre-formed extracellular matrix to hold the tumour cells together. The mice were sacrificed and the endothelium tissue was stained with a fluorescent dye that would aid in the quantification of tumour neovascularisation using a Matrigel assay. There was found to be a significant difference between the control and test groups, whereby mice given the vaccine had less angiogenesis from the tumour challenge than the control mice that were not given any of the vaccine prior to tumour challenge.[23] In vitro assays and other tests were also performed to validate the idea of the occurrence of an actual immune response to support what they observed in the mice.[23] For example, the spleen on the challenged mice were isolated and measured for the presence of any cytokines, and specifically activated immune cell groups that would indicative that a specific immune response did occur upon vaccination. The isolated CTLs specific for the survivin protein after vaccination of the mice were used in cytoxicity assays where mice tumour cells expressing survivin were shown to be killed upon incubation with the specific CTLs.[23]
By using an oral DNA vaccine carried in an attenuated non-virulent form of Salmonella typhimurium, which co-encoded secretory chemokine CCL21 and survivin protein in C57BL/6J mice, Xiang et al. have been able to elicit an immune response carried out by dendritic cells (DCs) and CTLs to eliminate and suppress the pulmonary metastases of non-small cell lung carcinoma. The activation of the immune response is most likely taking place in the secondary lymphoid organ called the Peyer’s Patch in the small intestine where DCs take up the survivin protein by phagocytosis and present them on their surface receptors to naive CD8+ T cells (uninactivated CTL) to achieve a specific immune response targeting survivin exclusively.[23] Activated CTLs specific for a particular antigen kill their target cells by first recognizing parts of the survivin protein expressed on MHC I (immunohistocompatability) proteins presented on the surface of tumour cells and vasculature and then releasing granules that induce the tumour cells to undergo apoptosis. The DNA vaccine contained the CCL21 secretory chemokine as a way to enhance the likelihood of eliciting the immune response by better mediating the physical interaction of the antigen-presenting DCs and the naive CD8+ T cells, resulting in a greater likelihood of immune activation.[23]
## Resveratrol-mediated sensitization
It has been shown by Fulda et al. that the naturally occurring compound resveratrol (a polyphenol found in grapes and red wine) can be used as a sensitizer for anticancer drug-induced apoptosis by the action of causing cell cycle arrest.[24] This cell cycle arrest causes a dramatic decline in survivin levels in the cells, as it is known from the literature that survivin expression is highly linked with the cell cycle phase state. Thus, the decrease in survivin, which is a contributing factor to chemotherapy resistance and apoptosis induction therapies, would render the cancer cells more prone to such cancer treatments. Fulda et al. have demonstrated the benefits of resveratrol through a series of experiments. First, the authors of the paper tested the intrinsic cytotoxic effects of resveratrol. They found that it induced moderate apoptosis levels only in SHEP neuroblastoma cells.[24] After, they tested resveratrol in combination with several different known anticancer agents. They found a consistent increase in the level of apoptosis induced by the drugs when resveratrol was also present.[24] Moreover, they varied the order with which either the drugs or resveratrol was introduced to the cancer cells to determine whether the sequence of treatment had any important effect. It was found that the highest levels of apoptosis induction were observed when resveratrol was added prior to anticancer drug treatment.[24] Next, the authors tested for any differential sensitivity to apoptosis linked to the phase of the cell cycle the cells were in. Analysis by flow cytometry revealed an accumulation of cells in S phase upon treatment with resveratrol. The cells were also halted in different phases of the cell cycle using special compounds and then treated with the anticancer drugs. They found that cells halted in S phase were significantly more sensitive to the cytotoxic effects of the drugs.[24]
To determine the involvement of survivin in resveratrol-mediated sensitization, the authors decided to test whether downregulation of the specific survivin protein expression would confer a similar effect on the phenotype of resveratrol-treated cells. In terms of seeing at which level resveratrol worked, they did a northern blot and found that resveratrol treatment resulted in a decrease in survivin mRNA levels,[24] thus implying resveratrol’s inhibitory action at the transcriptional level. To further see whether survivin played a key role in sensitization of the cancer cells to cytotoxic drugs, survivin antisense oligonucleotides were used to knock down any survivin mRNA, and, thus, its possibility to be translated is also eliminated. siRNAs for survivin are complements in sequence to the mRNA sequence encoding survivin. When these siRNAs for survivin are introduced into cells, they will bind to the respective complementary mRNA and, thus, prevent its translation since the mRNA is now impeded from proper physical interaction with the translational machinery. In this way, the siRNAs for survivin effectively downregulates survivin expression level in the cell. Cells treated with antisense oligonucleotides for survivin showed similar sensitization to cytotoxic drugs as cells treated with resveratrol, which offers support for the mechanism of action of resveratrol.[24]
## Prostate cancer
It has been observed that the development of hormone resistance in prostate cancer may be due to the upregulation of antiapoptotic genes, one of which is survivin.[25]
Zhang et al. hypothesize that, if survivin is a significant contributor to the development of hormonal therapy resistance in prostate cancer cells, targeting survivin and blocking it would enhance prostate cancer cell susceptibility to anti-androgen therapy. The basis of anti-androgen therapy involves using drugs that eliminate the presence of androgens in the cell and cellular environment, since the presence of androgens are known to enhance tumour immortality in prostate cancer cells. Zhang et al. first assessed the level of survivin expression of LNCaP (an androgen-dependent prostate cancer cell line that expresses intact androgen receptors) using quantitative Western analysis and found high expression of survivin in these cells.[25] Cells exposed to dihydrotestosterone (DHT), an exogenous androgen, showed increased levels of survivin expression only and not other IAP family members.[25] This result implicates that androgens in the physiological context may upregulate survivin, which contributes to the resistance of apoptosis observed in the tumour cells.[25] Next, with the addition of Flutamide(an antiandrogen) to the cells, survivin levels were observed to significantly decrease.[25] The LNCaP cells were transduced separately with the different constructs of the survivin gene (mutant or wild-type) and subjected to Flutamide treatment and assessed for the apoptosis level. Flutamide-treated survivin mutant-transduced cells were shown to significantly increase apoptosis by double that of Flutamide treatment alone.[25] On the other end, overexpression of the wild-type survivin was found to significantly reduce the apoptosis levels from Flutamide treatment compared to Flutamide treatment alone.[25] Therefore, these results support the hypothesis that asserts that survivin does play a role in contributing the anti-apoptotic nature of the LNCaP cancer cell line and that inhibiting survivin in prostate cancer cells does appear to enhance the therapeutic effect of Flutamide.
# Interactions
Survivin has been shown to interact with:
- Aurora B kinase,[26][27]
- CDCA8,[28][29]
- Caspase 3,[10][30]
- Caspase 7,[10][30]
- Diablo homolog[31] and
- INCENP.[26] | https://www.wikidoc.org/index.php/Survivin | |
0f59da1e7d99e6c9e62fa172d826b626a34b042f | wikidoc | Sushruta | Sushruta
# Overview
Sushruta (also spelt Susruta or Sushrutha) (c. 6th century BC) was the first surgeon in the world who lived in ancient India and is the author of the book Sushruta Samhita, in which he describes over 120 surgical instruments, 300 surgical procedures and classifies human surgery in 8 categories. He lived and taught and practiced his art on the banks of the Ganga in the area that corresponds to the present day city of Varanasi in North India.
In the Sushruta school, the first person to expound Āyurvedic knowledge was Dhanvantari who then taught it to Divodasa who, in turn, taught it to Sushruta, Aupadhenava, Aurabhra, Paushakalāvata, Gopurarakshita, and Bhoja.
Because of his seminal and numerous contributions to the science and art of surgery he is also known by the title "Father of Surgery." Much of what is known about this inventive surgeon is contained in a series of volumes he authored, which are collectively known as the Susrutha Samhita. The "Samhita" has some writings that date as late as the 1st century, and some scholars believe that there were contributions and additions to his teachings from generations of his students and disciples. Susrutha is also the father of Plastic Surgery and Cosmetic Surgery since his technique of forehead flap rhinoplasty (repairing the disfigured nose with a flap of skin from the forehead),that he used to reconstruct noses that were amputated, is practiced almost unchanged in technique to this day. The Susrutha Samhita contains the first known description of several operations, including the uniting of bowel, the removal of the prostate gland, the removal of cataract lenses and the draining of abscesses. Susrutha was also the first surgeon to advocate the practice of operations on inanimate objects such as watermelons, clay plots and reeds; thus predating the modern practice of the surgical workshop by half a millennium.
Sushruta was also a notable teacher. He told his pupils that one could become a good physician only if one knew both theory and practice. He advised his pupils to use carcases and models for practice before surgery.In addition to classifying worms that infect the human body, leeches for bloodletting, medicinal herbs, alkalies and metals, Sushruta gave a vague classification of animals. | Sushruta
# Overview
Sushruta (also spelt Susruta or Sushrutha) (c. 6th century BC) was the first surgeon in the world who lived in ancient India and is the author of the book Sushruta Samhita, in which he describes over 120 surgical instruments, 300 surgical procedures and classifies human surgery in 8 categories. He lived and taught and practiced his art on the banks of the Ganga in the area that corresponds to the present day city of Varanasi in North India.
In the Sushruta school, the first person to expound Āyurvedic knowledge was Dhanvantari who then taught it to Divodasa who, in turn, taught it to Sushruta, Aupadhenava, Aurabhra, Paushakalāvata, Gopurarakshita, and Bhoja.
Because of his seminal and numerous contributions to the science and art of surgery he is also known by the title "Father of Surgery." Much of what is known about this inventive surgeon is contained in a series of volumes he authored, which are collectively known as the Susrutha Samhita. The "Samhita" has some writings that date as late as the 1st century, and some scholars believe that there were contributions and additions to his teachings from generations of his students and disciples. Susrutha is also the father of Plastic Surgery and Cosmetic Surgery since his technique of forehead flap rhinoplasty (repairing the disfigured nose with a flap of skin from the forehead),that he used to reconstruct noses that were amputated, is practiced almost unchanged in technique to this day. The Susrutha Samhita contains the first known description of several operations, including the uniting of bowel, the removal of the prostate gland, the removal of cataract lenses and the draining of abscesses. Susrutha was also the first surgeon to advocate the practice of operations on inanimate objects such as watermelons, clay plots and reeds; thus predating the modern practice of the surgical workshop by half a millennium.
Sushruta was also a notable teacher. He told his pupils that one could become a good physician only if one knew both theory and practice. He advised his pupils to use carcases and models for practice before surgery.In addition to classifying worms that infect the human body, leeches for bloodletting, medicinal herbs, alkalies and metals, Sushruta gave a vague classification of animals. | https://www.wikidoc.org/index.php/Sushruta | |
97710bdc34809cc2a6b37aafff2b2f1ab14681fe | wikidoc | Swelling | Swelling
- Edema
Swelling can mean:
- In medicine:
Swelling (medical) is the enlargement of organs caused by accumulation of excess fluid in tissues, called edema.
- Swelling (medical) is the enlargement of organs caused by accumulation of excess fluid in tissues, called edema.
- In engineering:
Increase of volume of material, due to absorption of a solvent (common for plastic polymers)
Neutron-induced swelling caused by neutron radiation.
- Increase of volume of material, due to absorption of a solvent (common for plastic polymers)
- Neutron-induced swelling caused by neutron radiation. | Swelling
Redirect to:
- Edema
Swelling can mean:
Template:Wikt
- In medicine:
Swelling (medical) is the enlargement of organs caused by accumulation of excess fluid in tissues, called edema.
- Swelling (medical) is the enlargement of organs caused by accumulation of excess fluid in tissues, called edema.
- In engineering:
Increase of volume of material, due to absorption of a solvent (common for plastic polymers)
Neutron-induced swelling caused by neutron radiation.
- Increase of volume of material, due to absorption of a solvent (common for plastic polymers)
- Neutron-induced swelling caused by neutron radiation.
Template:Disambig | https://www.wikidoc.org/index.php/Swell | |
bee837393edcb4edc16a2a43bbca35665c59c5c0 | wikidoc | Sylvatic | Sylvatic
Sylvatic is a scientific term referring to diseases or pathogens affecting only wild (sylvan means forest-dwelling) animals. In the context of animal research, its opposite is domestic, which refers to pets, farm animals or other animals which do not dwell in the wild.
- Examples: sylvatic rabies; sylvatic and domestic bacterial strains; sylvatic yellow fever
The word "sylvatic" is also simply a synonym for "sylvan" (or "silvan") = "of the forest". | Sylvatic
Sylvatic is a scientific term referring to diseases or pathogens affecting only wild (sylvan means forest-dwelling) animals. In the context of animal research, its opposite is domestic, which refers to pets, farm animals or other animals which do not dwell in the wild.
- Examples: sylvatic rabies; sylvatic and domestic bacterial strains; sylvatic yellow fever
The word "sylvatic" is also simply a synonym for "sylvan" (or "silvan") = "of the forest". | https://www.wikidoc.org/index.php/Sylvatic | |
ff677f4ea967a32713044ce8edc0be71de5abe8c | wikidoc | Symmetry | Symmetry
Symmetry generally conveys two primary meanings. The first is an imprecise sense of harmonious or aesthetically-pleasing proportionality and balance; such that it reflects beauty or perfection. The second meaning is a precise and well-defined concept of balance or "patterned self-similarity" that can be demonstrated or proved according to the rules of a formal system: by geometry, through physics or otherwise.
Although the meanings are distinguishable, in some contexts, both meanings of "symmetry" are related and discussed in parallel.
The "precise" notions of symmetry have various measures and operational definitions. For example, symmetry may be observed:
- with respect to the passage of time;
- as a spatial relationship;
- through geometric transformations such as scaling, reflection, and rotation;
- through other kinds of functional transformations; and
- as an aspect of abstract objects, theoretic models, language, music and even knowledge itself.
This article describes these notions of symmetry from three perspectives. The first is that of mathematics, in which symmetries are defined and categorized precisely. The second perspective describes symmetry as it relates to science and technology. In this context, symmetries underlie some of the most profound results of modern physics, including aspects of space and time. Finally, a third perspective discusses symmetry in the humanities, covering its rich and varied use in history, architecture, art, and religion.
The opposite of symmetry is asymmetry.
# Symmetry in the field of mathematics
In formal terms, we say that an object is symmetric with respect to a given mathematical operation, if, when applied to the object, this operation does not change the object or its appearance.
Two objects are symmetric to each other with respect to a given group of operations if one is obtained from the other by some of the operations (and vice versa).
Symmetries may also be found in living organisms including humans and other animals (see symmetry in biology below).
In 2D geometry the main kinds of symmetry of interest are with respect to the basic Euclidean plane isometries: translations, rotations, reflections, and glide reflections.
## Mathematical model for symmetry
The set of all symmetry operations considered, on all objects in a set X, can be modelled as a group action g : G × X → X, where the image of g in G and x in X is written as g·x. If, for some g, g·x = y then x and y are said to be symmetrical to each other. For each object x, operations g for which g·x = x form a group, the symmetry group of the object, a subgroup of G. If the symmetry group of x is the trivial group then x is said to be asymmetric, otherwise symmetric.
A general example is that G is a group of bijections g: V → V acting on the set of functions x: V → W by (gx)(v)=x(g−1(v)) (or a restricted set of such functions that is closed under the group action). Thus a group of bijections of space induces a group action on "objects" in it. The symmetry group of x consists of all g for which x(v)=x(g(v)) for all v. G is the symmetry group of the space itself, and of any object that is uniform throughout space. Some subgroups of G may not be the symmetry group of any object. For example, if the group contains for every v and w in V a g such that g(v)=w, then only the symmetry groups of constant functions x contain that group. However, the symmetry group of constant functions is G itself.
In a modified version for vector fields, we have (gx)(v)=h(g,x(g−1(v))) where h rotates any vectors and pseudovectors in x, and inverts any vectors (but not pseudovectors) according to rotation and inversion in g, see symmetry in physics. The symmetry group of x consists of all g for which x(v)=h(g,x(g(v))) for all v. In this case the symmetry group of a constant function may be a proper subgroup of G: a constant vector has only rotational symmetry with respect to rotation about an axis if that axis is in the direction of the vector, and only inversion symmetry if it is zero.
For a common notion of symmetry in Euclidean space, G is the Euclidean group E(n), the group of isometries, and V is the Euclidean space. The rotation group of an object is the symmetry group if G is restricted to E+(n), the group of direct isometries. (For generalizations, see the next subsection.) Objects can be modeled as functions x, of which a value may represent a selection of properties such as color, density, chemical composition, etc. Depending on the selection we consider just symmetries of sets of points (x is just a boolean function of position v), or, at the other extreme, e.g. symmetry of right and left hand with all their structure.
For a given symmetry group, the properties of part of the object, fully define the whole object. Considering points equivalent which, due to the symmetry, have the same properties, the equivalence classes are the orbits of the group action on the space itself. We need the value of x at one point in every orbit to define the full object. A set of such representatives forms a fundamental domain. The smallest fundamental domain does not have a symmetry; in this sense, one can say that symmetry relies upon asymmetry.
An object with a desired symmetry can be produced by choosing for every orbit a single function value. Starting from a given object x we can e.g.:
- take the values in a fundamental domain (i.e., add copies of the object)
- take for each orbit some kind of average or sum of the values of x at the points of the orbit (ditto, where the copies may overlap)
If it is desired to have no more symmetry than that in the symmetry group, then the object to be copied should be asymmetric.
As pointed out above, some groups of isometries are not the symmetry group of any object, except in the modified model for vector fields. For example, this applies in 1D for the group of all translations. The fundamental domain is only one point, so we can not make it asymmetric, so any "pattern" invariant under translation is also invariant under reflection (these are the uniform "patterns").
In the vector field version continuous translational symmetry does not imply reflectional symmetry: the function value is constant, but if it contains nonzero vectors, there is no reflectional symmetry. If there is also reflectional symmetry, the constant function value contains no nonzero vectors, but it may contain nonzero pseudovectors. A corresponding 3D example is an infinite cylinder with a current perpendicular to the axis; the magnetic field (a pseudovector) is, in the direction of the cylinder, constant, but nonzero. For vectors (in particular the current density) we have symmetry in every plane perpendicular to the cylinder, as well as cylindrical symmetry. This cylindrical symmetry without mirror planes through the axis is also only possible in the vector field version of the symmetry concept. A similar example is a cylinder rotating about its axis, where magnetic field and current density are replaced by angular momentum and velocity, respectively.
A symmetry group is said to act transitively on a repeated feature of an object if, for every pair of occurrences of the feature there is a symmetry operation mapping the first to the second. For example, in 1D, the symmetry group of {...,1,2,5,6,9,10,13,14,...} acts transitively on all these points, while {...,1,2,3,5,6,7,9,10,11,13,14,15,...} does not act transitively on all points. Equivalently, the first set is only one conjugacy class with respect to isometries, while the second has two classes.
## Non-isometric symmetry
As mentioned above, G (the symmetry group of the space itself) may differ from the Euclidean group, the group of isometries.
Examples:
- G is the group of similarity transformations, i.e. affine transformations with a matrix A that is a scalar times an orthogonal matrix. Thus dilations are added, self-similarity is considered a symmetry
- G is the group of affine transformations with a matrix A with determinant 1 or -1, i.e. the transformation which preserve area; this adds e.g. oblique reflection symmetry.
- G is the group of all bijective affine transformations
- In inversive geometry, G includes circle reflections, etc.
- More generally, an involution defines a symmetry with respect to that involution.
## Directional symmetry
## Reflection symmetry
Reflection symmetry, mirror symmetry, mirror-image symmetry, or bilateral symmetry is symmetry with respect to reflection.
In 1D, there is a point of symmetry. In 2D there is an axis of symmetry, in 3D a plane of symmetry. An object or figure which is indistinguishable from its transformed image is called mirror symmetric (see mirror image).
The axis of symmetry of a two-dimensional figure is a line such that, if a perpendicular is constructed, any two points lying on the perpendicular at equal distances from the axis of symmetry are identical. Another way to think about it is that if the shape were to be folded in half over the axis, the two halves would be identical: the two halves are each other's mirror image. Thus a square has four axes of symmetry, because there are four different ways to fold it and have the edges all match. A circle has infinitely many axes of symmetry, for the same reason.
If the letter T is reflected along a vertical axis, it appears the same. Note that this is sometimes called horizontal symmetry, and sometimes vertical symmetry! One can better use an unambiguous formulation, e.g. "T has a vertical symmetry axis."
The triangles with this symmetry are isosceles, the quadrilaterals with this symmetry are the kites and the isosceles trapezoids.
For each line or plane of reflection, the symmetry group is isomorphic with Cs (see point groups in three dimensions), one of the three types of order two (involutions), hence algebraically C2. The fundamental domain is a half-plane or half-space.
Bilateria (bilateral animals, including humans) are more or less symmetric with respect to the sagittal plane.
In certain contexts there is rotational symmetry anyway. Then mirror-image symmetry is equivalent with inversion symmetry; in such contexts in modern physics the term P-symmetry is used for both (P stands for parity).
For more general types of reflection there are corresponding more general types of reflection symmetry. Examples:
- with respect to a non-isometric affine involution (an oblique reflection in a line, plane, etc).
- with respect to circle inversion
## Rotational symmetry
Rotational symmetry is symmetry with respect to some or all rotations in m-dimensional Euclidean space. Rotations are direct isometries, i.e., isometries preserving orientation. Therefore a symmetry group of rotational symmetry is a subgroup of E+(m) (see Euclidean group).
Symmetry with respect to all rotations about all points implies translational symmetry with respect to all translations, and the symmetry group is the whole E+(m). This does not apply for objects because it makes space homogeneous, but it may apply for physical laws.
For symmetry with respect to rotations about a point we can take that point as origin. These rotations form the special orthogonal group SO(m), the group of m×m orthogonal matrices with determinant 1. For m=3 this is the rotation group.
In another meaning of the word, the rotation group of an object is the symmetry group within E+(n), the group of direct isometries; in other words, the intersection of the full symmetry group and the group of direct isometries. For chiral objects it is the same as the full symmetry group.
Laws of physics are SO(3)-invariant if they do not distinguish different directions in space. Because of Noether's theorem, rotational symmetry of a physical system is equivalent to the angular momentum conservation law. See also rotational invariance.
## Translational symmetry
See main article translational symmetry.
Translational symmetry leaves an object invariant under a discrete or continuous group of translations T_a(p)=p+a
## Glide reflection symmetry
A glide reflection symmetry (in 3D: a glide plane symmetry) means that a reflection in a line or plane combined with a translation along the line / in the plane, results in the same object. It implies translational symmetry with twice the translation vector.
The symmetry group is isomorphic with Z.
## Rotoreflection symmetry
In 3D, rotoreflection or improper rotation in the strict sense is rotation about an axis, combined with reflection in a plane perpendicular to that axis. As symmetry groups with regard to a roto-reflection we can distinguish:
- the angle has no common divisor with 360°, the symmetry group is not discrete
- 2n-fold rotoreflection (angle of 180°/n) with symmetry group S2n of order 2n (not to be confused with symmetric groups, for which the same notation is used; abstract group C2n); a special case is n=1, inversion, because it does not depend on the axis and the plane, it is characterized by just the point of inversion.
- Cnh (angle of 360°/n); for odd n this is generated by a single symmetry, and the abstract group is C2n, for even n this is not a basic symmetry but a combination. See also point groups in three dimensions.
## Helical symmetry
Helical symmetry is the kind of symmetry seen in such everyday objects as springs, Slinky toys, drill bits, and augers. It can be thought of as rotational symmetry along with translation along the axis of rotation, the screw axis). The concept of helical symmetry can be visualized as the tracing in three-dimensional space that results from rotating an object at an even angular speed while simultaneously moving at another even speed along its axis of rotation (translation). At any one point in time, these two motions combine to give a coiling angle that helps define the properties of the tracing. When the tracing object rotates quickly and translates slowly, the coiling angle will be close to 0°. Conversely, if the rotation is slow and the translation speedy, the coiling angle will approach 90°.
Three main classes of helical symmetry can be distinguished based on the interplay of the angle of coiling and translation symmetries along the axis:
- Infinite helical symmetry. If there are no distinguishing features along the length of a helix or helix-like object, the object will have infinite symmetry much like that of a circle, but with the additional requirement of translation along the long axis of the object to return it to its original appearance. A helix-like object is one that has at every point the regular angle of coiling of a helix, but which can also have a cross section of indefinitely high complexity, provided only that precisely the same cross section exists (usually after a rotation) at every point along the length of the object. Simple examples include evenly coiled springs, slinkies, drill bits, and augers. Stated more precisely, an object has infinite helical symmetries if for any small rotation of the object around its central axis there exists a point nearby (the translation distance) on that axis at which the object will appear exactly as it did before. It is this infinite helical symmetry that gives rise to the curious illusion of movement along the length of an auger or screw bit that is being rotated. It also provides the mechanically useful ability of such devices to move materials along their length, provided that they are combined with a force such as gravity or friction that allows the materials to resist simply rotating along with the drill or auger.
- n-fold helical symmetry. If the requirement that every cross section of the helical object be identical is relaxed, additional lesser helical symmetries become possible. For example, the cross section of the helical object may change, but still repeats itself in a regular fashion along the axis of the helical object. Consequently, objects of this type will exhibit a symmetry after a rotation by some fixed angle \theta and a translation by some fixed distance, but will not in general be invariant for any rotation angle. If the angle (rotation) at which the symmetry occurs divides evenly into a full circle (360°), the result is the helical equivalent of a regular polygon. This case is called n-fold helical symmetry, where n = 360°/\theta, see e.g. double helix. This concept can be further generalized to include cases where m\theta is a multiple of 360°—that is, the cycle does eventually repeat, but only after more than one full rotation of the helical object.
- Non-repeating helical symmetry. This is the case in which the angle of rotation \theta required to observe the symmetry is an irrational number such as \sqrt 2 radians that never repeats exactly no matter how many times the helix is rotated. Such symmetries are created by using a non-repeating point group in two dimensions. DNA is an example of this type of non-repeating helical symmetry.
## Scale symmetry and fractals
Scale symmetry refers to the idea that if an object is expanded or reduced in size, the new object has the same properties as the original. Scale symmetry is notable for the fact that it does not exist for most physical systems, a point that was first discerned by Galileo. Simple examples of the lack of scale symmetry in the physical world include the difference in the strength and size of the legs of elephants versus mice, and the observation that if a candle made of soft wax was enlarged to the size of a tall tree, it would immediately collapse under its own weight.
A more subtle form of scale symmetry is demonstrated by fractals. As conceived by Mandelbrot, fractals are a mathematical concept in which the structure of a complex form looks exactly the same no matter what degree of magnification is used to examine it. A coast is an example of a naturally occurring fractal, since it retains roughly comparable and similar-appearing complexity at every level from the view of a satellite to a microscopic examination of how the water laps up against individual grains of sand. The branching of trees, which enables children to use small twigs as stand-ins for full trees in dioramas, is another example.
This similarity to naturally occurring phenomena provides fractals with an everyday familiarity not typically seen with mathematically generated functions. As a consequence, they can produce strikingly beautiful results such as the Mandelbrot set. Intriguingly, fractals have also found a place in CG, or computer-generated movie effects, where their ability to create very complex curves with fractal symmetries results in more realistic virtual worlds.
## Symmetry combinations
# Symmetry in science
## Symmetry in physics
Symmetry in physics has been generalized to mean invariance—that is, lack of any visible change—under any kind of transformation. This concept has become one of the most powerful tools of theoretical physics, as it has become evident that practically all laws of nature originate in symmetries. In fact, this role inspired the Nobel laureate PW Anderson to write in his widely-read 1972 article More is Different that "it is only slightly overstating the case to say that physics is the study of symmetry." See Noether's theorem (which, as a gross oversimplification, states that for every continuous mathematical symmetry, there is a corresponding conserved quantity; a conserved current, in Noether's original language); and also, Wigner's classification, which says that the symmetries of the laws of physics determine the properties of the particles found in nature.
## Symmetry in physical objects
### Classical objects
Although an everyday object may appear exactly the same after a symmetry operation such as a rotation or an exchange of two identical parts has been performed on it, it is readily apparent that such a symmetry is true only as an approximation for any ordinary physical object.
For example, if one rotates a precisely machined aluminum equilateral triangle 120 degrees around its center, a casual observer brought in before and after the rotation will be unable to decide whether or not such a rotation took place. However, the reality is that each corner of a triangle will always appear unique when examined with sufficient precision. An observer armed with sufficiently detailed measuring equipment such as optical or electron microscopes will not be fooled; he will immediately recognize that the object has been rotated by looking for details such as crystals or minor deformities.
Such simple thought experiments show that assertions of symmetry in everyday physical objects are always a matter of approximate similarity rather than of precise mathematical sameness. The most important consequence of this approximate nature of symmetries in everyday physical objects is that such symmetries have minimal or no impacts on the physics of such objects. Consequently, only the deeper symmetries of space and time play a major role in classical physics—that is, the physics of large, everyday objects.
### Quantum objects
Remarkably, there exists a realm of physics for which mathematical assertions of simple symmetries in real objects cease to be approximations. That is the domain of quantum physics, which for the most part is the physics of very small, very simple objects such as electrons, protons, light, and atoms.
Unlike everyday objects, objects such as electrons have very limited numbers of configurations, called states, in which they can exist. This means that when symmetry operations such as exchanging the positions of components are applied to them, the resulting new configurations often cannot be distinguished from the originals no matter how diligent an observer is. Consequently, for sufficiently small and simple objects the generic mathematical symmetry assertion F(x) = x ceases to be approximate, and instead becomes an experimentally precise and accurate description of the situation in the real world.
### Consequences of quantum symmetry
While it makes sense that symmetries could become exact when applied to very simple objects, the immediate intuition is that such a detail should not affect the physics of such objects in any significant way. This is in part because it is very difficult to view the concept of exact similarity as physically meaningful. Our mental picture of such situations is invariably the same one we use for large objects: We picture objects or configurations that are very, very similar, but for which if we could "look closer" we would still be able to tell the difference.
However, the assumption that exact symmetries in very small objects should not make any difference in their physics was discovered in the early 1900s to be spectacularly incorrect. The situation was succinctly summarized by Richard Feynman in the direct transcripts of his Feynman Lectures on Physics, Volume III, Section 3.4, Identical particles. (Unfortunately, the quote was edited out of the printed version of the same lecture.)
The word "interferes" in this context is a quick way of saying that such objects fall under the rules of quantum mechanics, in which they behave more like waves that interfere than like everyday large objects.
In short, when an object becomes so simple that a symmetry assertion of the form F(x) = x becomes an exact statement of experimentally verifiable sameness, x ceases to follow the rules of classical physics and must instead be modeled using the more complex—and often far less intuitive—rules of quantum physics.
This transition also provides an important insight into why the mathematics of symmetry are so deeply intertwined with those of quantum mechanics. When physical systems make the transition from symmetries that are approximate to ones that are exact, the mathematical expressions of those symmetries cease to be approximations and are transformed into precise definitions of the underlying nature of the objects. From that point on, the correlation of such objects to their mathematical descriptions becomes so close that it is difficult to separate the two.
## Symmetry as a unifying principle of geometry
The German geometer Felix Klein enunciated a very influential Erlangen programme in 1872, suggesting symmetry as unifying and organising principle in geometry (at a time when that was read 'geometries'). This is a broad rather than deep principle. Initially it led to interest in the groups attached to geometries, and the slogan transformation geometry (an aspect of the New Math, but hardly controversial in modern mathematical practice). By now it has been applied in numerous forms, as kind of standard attack on problems.
## Symmetry in mathematics
An example of a mathematical expression exhibiting symmetry is a²c + 3ab + b²c. If a and b are exchanged, the expression remains unchanged due to the commutativity of addition and multiplication.
Like in geometry, for the terms there are two possibilities:
- It is itself symmetric
- It has one or more other terms symmetric with it, in accordance with the symmetry kind
See also symmetric function, duality (mathematics)
## Symmetry in logic
A dyadic relation R is symmetric if and only if, whenever it's true that Rab, it's true that Rba. Thus, “is the same age as” is symmetrical, for if Paul is the same age as Mary, then Mary is the same age as Paul.
Symmetric binary logical connectives are "and" (∧, \land, or &), "or" (∨), "biconditional" (iff) (↔), NAND ("not-and"), XOR ("not-biconditional"), and NOR ("not-or").
## Generalizations of symmetry
If we have a given set of objects with some structure, then it is possible for a symmetry to merely convert only one object into another, instead of acting upon all possible objects simultaneously. This requires a generalization from the concept of symmetry group to that of a groupoid. Indeed, A. Connes in his book `Non-commutative_geometry' writes that Heisenberg discovered quantum mechanics by considering the groupoid of transitions of the hydrogen spectrum.
The notion of groupoid also leads to notions of multiple groupoids, namely sets with many compatible groupoid structures, a structure which trivialises to abelian groups if one restricts to groups. This leads to prospects of `higher order symmetry' which have been a little explored, as follows.
The automorphisms of a set, or a set with some structure, form a group, which models a homotopy 1-type. The automorphisms of a group G naturally form a crossed module $G \to Aut(G)$, and crossed modules give an algebraic model of homotopy 2-types. At the next stage, automorphisms of a crossed module fit into a structure known as a crossed square, and this structure is know to give an algebraic model of homotopy 3-types. It is not known how this procedure of generalising symmetry may be continued, although crossed n-cubes have been defined and used in algebraic topology, and these structures are only slowly being brought into theoretical physics. The web site n-category cafe has much discussion of n-groups. More information is on `Higher dimensional group theory'.
Physicists have come up with other directions of generalization, such as supersymmetry and quantum groups.
## Symmetry in biology
See symmetry (biology) and facial symmetry.
## Symmetry in chemistry
Symmetry is important to chemistry because it explains observations in spectroscopy, quantum chemistry and crystallography. It draws heavily on group theory.
# Symmetry in history, religion, and culture
In any human endeavor for which an impressive visual result is part of the desired objective, symmetries play a profound role. The innate appeal of symmetry can be found in our reactions to happening across highly symmetrical natural objects, such as precisely formed crystals or beautifully spiraled seashells. Our first reaction in finding such an object often is to wonder whether we have found an object created by a fellow human, followed quickly by surprise that the symmetries that caught out attention are derived from nature itself. In both reactions we give away our inclination to view symmetries both as beautiful and, in some fashion, informative of the world around us.
## Symmetry in religious symbols
The tendency of people to see purpose in symmetry suggests at least one reason why symmetries are often an integral part of the symbols of world religions. Just a few of many examples include the sixfold rotational symmetry of Judaism's Star of David, the twofold point symmetry of Taoism's Taijitu or Yin-Yang, the bilateral symmetry of Christianity's cross and Sikhism's Khanda, or the fourfold point symmetry of Jain's ancient (and peacefully intended) version of the swastika. With its strong prohibitions against the use of representational images, Islam, and in particular the Sunni branch of Islam, has developed some of the most intricate and visually impressive use of symmetries for decorative uses of any major religion.
The ancient Taijitu image of Taoism is a particularly fascinating use of symmetry around a central point, combined with black-and-white inversion of color at opposite distances from that central point. The image, which is often misunderstood in the Western world as representing good (white) versus evil (black), is actually intended as a graphical representative of the complementary need for two abstract concepts of "maleness" (white) and "femaleness" (black). The symmetry of the symbol in this case is used not just to create a symbol that catches the attention of the eye, but to make a significant statement about the philosophical beliefs of the people and groups that use it. Also an important symmetrical religious symbol is the Shintoist "Torii" "The gate of the birds", usually the gate of the Shintoist temples called "Jinjas".
## Symmetry in Social Interactions
People observe the symmetrical nature, often including asymmetrical balance, of social interactions in a variety of contexts. These include assessments of reciprocity, empathy, apology, dialog, respect, justice, and revenge. Symmetrical interactions send the message "we are all the same" while asymmetrical interactions send the message "I am special; better than you". Peer relationships are based on symmetry, power relationships are based on asymmetry.
## Symmetry in architecture
Another human endeavor in which the visual result plays a vital part in the overall result is architecture. Both in ancient times, the ability of a large structure to impress or even intimidate its viewers has often been a major part of its purpose, and the use of symmetry is an inescapable aspect of how to accomplish such goals.
Just a few examples of ancient examples of architectures that made powerful use of symmetry to impress those around them included the Egyptian Pyramids, the Greek Parthenon, and the first and second Temple of Jerusalem, China's Forbidden City, Cambodia's Angkor Wat complex, and the many temples and pyramids of ancient Pre-Columbian civilizations. More recent historical examples of architectures emphasizing symmetries include Gothic architecture cathedrals, and American President Thomas Jefferson's Monticello home. India's unparalleled Taj Mahal is in a category by itself, as it may arguably be one of the most impressive and beautiful uses of symmetry in architecture that the world has ever seen.
An interesting example of a broken symmetry in architecture is the Leaning Tower of Pisa, whose notoriety stems in no small part not for the intended symmetry of its design, but for the violation of that symmetry from the lean that developed while it was still under construction. Modern examples of architectures that make impressive or complex use of various symmetries include Australia's astonishing Sydney Opera House and Houston, Texas's simpler Astrodome.
Symmetry finds its ways into architecture at every scale, from the overall external views, through the layout of the individual floor plans, and down to the design of individual building elements such as intricately caved doors, stained glass windows, tile mosaics, friezes, stairwells, stair rails, and balustradess. For sheer complexity and sophistication in the exploitation of symmetry as an architectural element, Islamic buildings such as the Taj Mahal often eclipse those of other cultures and ages, due in part to the general prohibition of Islam against using images or people or animals.
Links related to symmetry in architecture include:
- Williams: Symmetry in Architecture
- Aslaksen: Mathematics in Art and Architecture
## Symmetry in pottery and metal vessels
Since the earliest uses of pottery wheels to help shape clay vessels, pottery has had a strong relationship to symmetry. As a minimum, pottery created using a wheel necessarily begins with full rotational symmetry in its cross-section, while allowing substantial freedom of shape in the vertical direction. Upon this inherently symmetrical starting point cultures from ancient times have tended to add further patterns that tend to exploit or in many cases reduce the original full rotational symmetry to a point where some specific visual objective is achieved. For example, Persian pottery dating from the fourth millennium B.C. and earlier used symmetric zigzags, squares, cross-hatchings, and repetitions of figures to produce more complex and visually striking overall designs.
Cast metal vessels lacked the inherent rotational symmetry of wheel-made pottery, but otherwise provided a similar opportunity to decorate their surfaces with patterns pleasing to those who used them. The ancient Chinese, for example, used symmetrical patterns in their bronze castings as early as the 17th century B.C. Bronze vessels exhibited both a bilateral main motif and a repetitive translated border design.
Links:
- Chinavoc: The Art of Chinese Bronzes
- Grant: Iranian Pottery in the Oriental Institute
- The Metropolitan Museum of Art - Islamic Art
## Symmetry in quilts
As quilts are made from square blocks (usually 9, 16, or 25 pieces to a block) with each smaller piece usually consisting of fabric triangles, the craft lends itself readily to the application of symmetry.
Links:
- Quate: Exploring Geometry Through Quilts
## Symmetry in carpets and rugs
A long tradition of the use of symmetry in carpet and rug patterns spans a variety of cultures. American Navajo Indians used bold diagonals and rectangular motifs. Many Oriental rugs have intricate reflected centers and borders that translate a pattern. Not surprisingly, rectangular rugs typically use quadrilateral symmetry—that is, motifs that are reflected across both the horizontal and vertical axes.
Links:
- Mallet: Tribal Oriental Rugs
- Dilucchio: Navajo Rugs
## Symmetry in music
Symmetry is of course not restricted to the visual arts. Its role in the history of music touches many aspects of the creation and perception of music.
### Musical form
Symmetry has been used as a formal constraint by many composers, such as the arch form (ABCBA) used by Steve Reich, Béla Bartók, and James Tenney (or swell). In classical music, Bach used the symmetry concepts of permutation and invariance; see (external link "Fugue No. 21," pdf or Shockwave).
### Pitch structures
Symmetry is also an important consideration in the formation of scales and chords, traditional or tonal music being made up of non-symmetrical groups of pitches, such as the diatonic scale or the major chord. Symmetrical scales or chords, such as the whole tone scale, augmented chord, or diminished seventh chord (diminished-diminished seventh), are said to lack direction or a sense of forward motion, are ambiguous as to the key or tonal center, and have a less specific diatonic functionality. However, composers such as Alban Berg, Béla Bartók, and George Perle have used axes of symmetry and/or interval cycles in an analogous way to keys or non-tonal tonal centers.
Perle (1992) explains "C-E, D-F#, Eb-G, are different instances of the same interval...the other kind of identity. ..has to do with axes of symmetry. C-E belongs to a family of symmetrically related dyads as follows:"
Thus in addition to being part of the interval-4 family, C-E is also a part of the sum-4 family (with C equal to 0).
Interval cycles are symmetrical and thus non-diatonic. However, a seven pitch segment of C5 (the cycle of fifths, which are enharmonic with the cycle of fourths) will produce the diatonic major scale. Cyclic tonal progressions in the works of Romantic composers such as Gustav Mahler and Richard Wagner form a link with the cyclic pitch successions in the atonal music of Modernists such as Bartók, Alexander Scriabin, Edgard Varèse, and the Vienna school. At the same time, these progressions signal the end of tonality.
The first extended composition consistently based on symmetrical pitch relations was probably Alban Berg's Quartet, Op. 3 (1910). (Perle, 1990)
### Equivalency
Tone rows or pitch class sets which are invariant under retrograde are horizontally symmetrical, under inversion vertically. See also Asymmetric rhythm.
## Symmetry in other arts and crafts
The concept of symmetry is applied to the design of objects of all shapes and sizes. Other examples include beadwork, furniture, sand paintings, knotwork, masks, musical instruments, and many other endeavors.
## Symmetry in aesthetics
The relationship of symmetry to aesthetics is complex. Certain simple symmetries, and in particular bilateral symmetry, seem to be deeply ingrained in the inherent perception by humans of the likely health or fitness of other living creatures, as can be seen by the simple experiment of distorting one side of the image of an attractive face and asking viewers to rate the attractiveness of the resulting image. Consequently, such symmetries that mimic biology tend to have an innate appeal that in turn drives a powerful tendency to create artifacts with similar symmetry. One only needs to imagine the difficulty in trying to market a highly asymmetrical car or truck to general automotive buyers to understand the power of biologically inspired symmetries such as bilateral symmetry.
Another more subtle appeal of symmetry is that of simplicity, which in turn has an implication of safety, security, and familiarity. A highly symmetrical room, for example, is unavoidably also a room in which anything out of place or potentially threatening can be identified easily and quickly. For example, people who have grown up in houses full of exact right angles and precisely identical artifacts can find their first experience in staying in a room with no exact right angles and no exactly identical artifacts to be highly disquieting. Symmetry thus can be a source of comfort not only as an indicator of biological health, but also of a safe and well-understood living environment.
Opposed to this is the tendency for excessive symmetry to be perceived as boring or uninteresting. Humans in particular have a powerful desire to exploit new opportunities or explore new possibilities, and an excessive degree of symmetry can convey a lack of such opportunities.
Yet another possibility is that when symmetries become too complex or too challenging, the human mind has a tendency to "tune them out" and perceive them in yet another fashion: as noise that conveys no useful information.
Finally, perceptions and appreciation of symmetries are also dependent on cultural background. The far greater use of complex geometric symmetries in many Islamic cultures, for example, makes it more likely that people from such cultures will appreciate such art forms (or, conversely, to rebel against them).
As in many human endeavors, the result of the confluence of many such factors is that effective use of symmetry in art and architecture is complex, intuitive, and highly dependent on the skills of the individuals who must weave and combine such factors within their own creative work. Along with texture, color, proportion, and other factors, symmetry is a powerful ingredient in any such synthesis; one only need to examine the Taj Mahal to powerful role that symmetry plays in determining the aesthetic appeal of an object.
A few examples of the more explicit use of symmetries in art can be found in the remarkable art of M. C. Escher, the creative design of the mathematical concept of a wallpaper group, and the many applications (both mathematical and real world) of tiling.
## Symmetry in games and puzzles
- See also symmetric games.
- See sudoku.
Board games
- The Symmetrical Chess Collection
## Symmetry in literature
See palindrome.
## Moral symmetry
- Tit for tat
- Reciprocity
- Golden Rule
- Empathy & Sympathy
- Reflective equilibrium | Symmetry
Symmetry generally conveys two primary meanings. The first is an imprecise sense of harmonious or aesthetically-pleasing proportionality and balance; such that it reflects beauty or perfection. The second meaning is a precise and well-defined concept of balance or "patterned self-similarity" that can be demonstrated or proved according to the rules of a formal system: by geometry, through physics or otherwise.
Although the meanings are distinguishable, in some contexts, both meanings of "symmetry" are related and discussed in parallel.[1][2]
The "precise" notions of symmetry have various measures and operational definitions. For example, symmetry may be observed:
- with respect to the passage of time;
- as a spatial relationship;
- through geometric transformations such as scaling, reflection, and rotation;
- through other kinds of functional transformations[3]; and
- as an aspect of abstract objects, theoretic models, language, music and even knowledge itself.[4][5]
This article describes these notions of symmetry from three perspectives. The first is that of mathematics, in which symmetries are defined and categorized precisely. The second perspective describes symmetry as it relates to science and technology. In this context, symmetries underlie some of the most profound results of modern physics, including aspects of space and time. Finally, a third perspective discusses symmetry in the humanities, covering its rich and varied use in history, architecture, art, and religion.
The opposite of symmetry is asymmetry.
# Symmetry in the field of mathematics
In formal terms, we say that an object is symmetric with respect to a given mathematical operation, if, when applied to the object, this operation does not change the object or its appearance.
Two objects are symmetric to each other with respect to a given group of operations if one is obtained from the other by some of the operations (and vice versa).
Symmetries may also be found in living organisms including humans and other animals (see symmetry in biology below).
In 2D geometry the main kinds of symmetry of interest are with respect to the basic Euclidean plane isometries: translations, rotations, reflections, and glide reflections.
## Mathematical model for symmetry
The set of all symmetry operations considered, on all objects in a set X, can be modelled as a group action g : G × X → X, where the image of g in G and x in X is written as g·x. If, for some g, g·x = y then x and y are said to be symmetrical to each other. For each object x, operations g for which g·x = x form a group, the symmetry group of the object, a subgroup of G. If the symmetry group of x is the trivial group then x is said to be asymmetric, otherwise symmetric.
A general example is that G is a group of bijections g: V → V acting on the set of functions x: V → W by (gx)(v)=x(g−1(v)) (or a restricted set of such functions that is closed under the group action). Thus a group of bijections of space induces a group action on "objects" in it. The symmetry group of x consists of all g for which x(v)=x(g(v)) for all v. G is the symmetry group of the space itself, and of any object that is uniform throughout space. Some subgroups of G may not be the symmetry group of any object. For example, if the group contains for every v and w in V a g such that g(v)=w, then only the symmetry groups of constant functions x contain that group. However, the symmetry group of constant functions is G itself.
In a modified version for vector fields, we have (gx)(v)=h(g,x(g−1(v))) where h rotates any vectors and pseudovectors in x, and inverts any vectors (but not pseudovectors) according to rotation and inversion in g, see symmetry in physics. The symmetry group of x consists of all g for which x(v)=h(g,x(g(v))) for all v. In this case the symmetry group of a constant function may be a proper subgroup of G: a constant vector has only rotational symmetry with respect to rotation about an axis if that axis is in the direction of the vector, and only inversion symmetry if it is zero.
For a common notion of symmetry in Euclidean space, G is the Euclidean group E(n), the group of isometries, and V is the Euclidean space. The rotation group of an object is the symmetry group if G is restricted to E+(n), the group of direct isometries. (For generalizations, see the next subsection.) Objects can be modeled as functions x, of which a value may represent a selection of properties such as color, density, chemical composition, etc. Depending on the selection we consider just symmetries of sets of points (x is just a boolean function of position v), or, at the other extreme, e.g. symmetry of right and left hand with all their structure.
For a given symmetry group, the properties of part of the object, fully define the whole object. Considering points equivalent which, due to the symmetry, have the same properties, the equivalence classes are the orbits of the group action on the space itself. We need the value of x at one point in every orbit to define the full object. A set of such representatives forms a fundamental domain. The smallest fundamental domain does not have a symmetry; in this sense, one can say that symmetry relies upon asymmetry.
An object with a desired symmetry can be produced by choosing for every orbit a single function value. Starting from a given object x we can e.g.:
- take the values in a fundamental domain (i.e., add copies of the object)
- take for each orbit some kind of average or sum of the values of x at the points of the orbit (ditto, where the copies may overlap)
If it is desired to have no more symmetry than that in the symmetry group, then the object to be copied should be asymmetric.
As pointed out above, some groups of isometries are not the symmetry group of any object, except in the modified model for vector fields. For example, this applies in 1D for the group of all translations. The fundamental domain is only one point, so we can not make it asymmetric, so any "pattern" invariant under translation is also invariant under reflection (these are the uniform "patterns").
In the vector field version continuous translational symmetry does not imply reflectional symmetry: the function value is constant, but if it contains nonzero vectors, there is no reflectional symmetry. If there is also reflectional symmetry, the constant function value contains no nonzero vectors, but it may contain nonzero pseudovectors. A corresponding 3D example is an infinite cylinder with a current perpendicular to the axis; the magnetic field (a pseudovector) is, in the direction of the cylinder, constant, but nonzero. For vectors (in particular the current density) we have symmetry in every plane perpendicular to the cylinder, as well as cylindrical symmetry. This cylindrical symmetry without mirror planes through the axis is also only possible in the vector field version of the symmetry concept. A similar example is a cylinder rotating about its axis, where magnetic field and current density are replaced by angular momentum and velocity, respectively.
A symmetry group is said to act transitively on a repeated feature of an object if, for every pair of occurrences of the feature there is a symmetry operation mapping the first to the second. For example, in 1D, the symmetry group of {...,1,2,5,6,9,10,13,14,...} acts transitively on all these points, while {...,1,2,3,5,6,7,9,10,11,13,14,15,...} does not act transitively on all points. Equivalently, the first set is only one conjugacy class with respect to isometries, while the second has two classes.
## Non-isometric symmetry
As mentioned above, G (the symmetry group of the space itself) may differ from the Euclidean group, the group of isometries.
Examples:
- G is the group of similarity transformations, i.e. affine transformations with a matrix A that is a scalar times an orthogonal matrix. Thus dilations are added, self-similarity is considered a symmetry
- G is the group of affine transformations with a matrix A with determinant 1 or -1, i.e. the transformation which preserve area; this adds e.g. oblique reflection symmetry.
- G is the group of all bijective affine transformations
- In inversive geometry, G includes circle reflections, etc.
- More generally, an involution defines a symmetry with respect to that involution.
## Directional symmetry
## Reflection symmetry
Reflection symmetry, mirror symmetry, mirror-image symmetry, or bilateral symmetry is symmetry with respect to reflection.
In 1D, there is a point of symmetry. In 2D there is an axis of symmetry, in 3D a plane of symmetry. An object or figure which is indistinguishable from its transformed image is called mirror symmetric (see mirror image).
The axis of symmetry of a two-dimensional figure is a line such that, if a perpendicular is constructed, any two points lying on the perpendicular at equal distances from the axis of symmetry are identical. Another way to think about it is that if the shape were to be folded in half over the axis, the two halves would be identical: the two halves are each other's mirror image. Thus a square has four axes of symmetry, because there are four different ways to fold it and have the edges all match. A circle has infinitely many axes of symmetry, for the same reason.
If the letter T is reflected along a vertical axis, it appears the same. Note that this is sometimes called horizontal symmetry, and sometimes vertical symmetry! One can better use an unambiguous formulation, e.g. "T has a vertical symmetry axis."
The triangles with this symmetry are isosceles, the quadrilaterals with this symmetry are the kites and the isosceles trapezoids.
For each line or plane of reflection, the symmetry group is isomorphic with Cs (see point groups in three dimensions), one of the three types of order two (involutions), hence algebraically C2. The fundamental domain is a half-plane or half-space.
Bilateria (bilateral animals, including humans) are more or less symmetric with respect to the sagittal plane.
In certain contexts there is rotational symmetry anyway. Then mirror-image symmetry is equivalent with inversion symmetry; in such contexts in modern physics the term P-symmetry is used for both (P stands for parity).
For more general types of reflection there are corresponding more general types of reflection symmetry. Examples:
- with respect to a non-isometric affine involution (an oblique reflection in a line, plane, etc).
- with respect to circle inversion
## Rotational symmetry
Rotational symmetry is symmetry with respect to some or all rotations in m-dimensional Euclidean space. Rotations are direct isometries, i.e., isometries preserving orientation. Therefore a symmetry group of rotational symmetry is a subgroup of E+(m) (see Euclidean group).
Symmetry with respect to all rotations about all points implies translational symmetry with respect to all translations, and the symmetry group is the whole E+(m). This does not apply for objects because it makes space homogeneous, but it may apply for physical laws.
For symmetry with respect to rotations about a point we can take that point as origin. These rotations form the special orthogonal group SO(m), the group of m×m orthogonal matrices with determinant 1. For m=3 this is the rotation group.
In another meaning of the word, the rotation group of an object is the symmetry group within E+(n), the group of direct isometries; in other words, the intersection of the full symmetry group and the group of direct isometries. For chiral objects it is the same as the full symmetry group.
Laws of physics are SO(3)-invariant if they do not distinguish different directions in space. Because of Noether's theorem, rotational symmetry of a physical system is equivalent to the angular momentum conservation law. See also rotational invariance.
## Translational symmetry
See main article translational symmetry.
Translational symmetry leaves an object invariant under a discrete or continuous group of translations <math>T_a(p)=p+a</math>
## Glide reflection symmetry
A glide reflection symmetry (in 3D: a glide plane symmetry) means that a reflection in a line or plane combined with a translation along the line / in the plane, results in the same object. It implies translational symmetry with twice the translation vector.
The symmetry group is isomorphic with Z.
## Rotoreflection symmetry
In 3D, rotoreflection or improper rotation in the strict sense is rotation about an axis, combined with reflection in a plane perpendicular to that axis. As symmetry groups with regard to a roto-reflection we can distinguish:
- the angle has no common divisor with 360°, the symmetry group is not discrete
- 2n-fold rotoreflection (angle of 180°/n) with symmetry group S2n of order 2n (not to be confused with symmetric groups, for which the same notation is used; abstract group C2n); a special case is n=1, inversion, because it does not depend on the axis and the plane, it is characterized by just the point of inversion.
- Cnh (angle of 360°/n); for odd n this is generated by a single symmetry, and the abstract group is C2n, for even n this is not a basic symmetry but a combination. See also point groups in three dimensions.
## Helical symmetry
Helical symmetry is the kind of symmetry seen in such everyday objects as springs, Slinky toys, drill bits, and augers. It can be thought of as rotational symmetry along with translation along the axis of rotation, the screw axis). The concept of helical symmetry can be visualized as the tracing in three-dimensional space that results from rotating an object at an even angular speed while simultaneously moving at another even speed along its axis of rotation (translation). At any one point in time, these two motions combine to give a coiling angle that helps define the properties of the tracing. When the tracing object rotates quickly and translates slowly, the coiling angle will be close to 0°. Conversely, if the rotation is slow and the translation speedy, the coiling angle will approach 90°.
Three main classes of helical symmetry can be distinguished based on the interplay of the angle of coiling and translation symmetries along the axis:
- Infinite helical symmetry. If there are no distinguishing features along the length of a helix or helix-like object, the object will have infinite symmetry much like that of a circle, but with the additional requirement of translation along the long axis of the object to return it to its original appearance. A helix-like object is one that has at every point the regular angle of coiling of a helix, but which can also have a cross section of indefinitely high complexity, provided only that precisely the same cross section exists (usually after a rotation) at every point along the length of the object. Simple examples include evenly coiled springs, slinkies, drill bits, and augers. Stated more precisely, an object has infinite helical symmetries if for any small rotation of the object around its central axis there exists a point nearby (the translation distance) on that axis at which the object will appear exactly as it did before. It is this infinite helical symmetry that gives rise to the curious illusion of movement along the length of an auger or screw bit that is being rotated. It also provides the mechanically useful ability of such devices to move materials along their length, provided that they are combined with a force such as gravity or friction that allows the materials to resist simply rotating along with the drill or auger.
- n-fold helical symmetry. If the requirement that every cross section of the helical object be identical is relaxed, additional lesser helical symmetries become possible. For example, the cross section of the helical object may change, but still repeats itself in a regular fashion along the axis of the helical object. Consequently, objects of this type will exhibit a symmetry after a rotation by some fixed angle <math>\theta</math> and a translation by some fixed distance, but will not in general be invariant for any rotation angle. If the angle (rotation) at which the symmetry occurs divides evenly into a full circle (360°), the result is the helical equivalent of a regular polygon. This case is called n-fold helical symmetry, where n = 360°/<math>\theta</math>, see e.g. double helix. This concept can be further generalized to include cases where <math>m\theta</math> is a multiple of 360°—that is, the cycle does eventually repeat, but only after more than one full rotation of the helical object.
- Non-repeating helical symmetry. This is the case in which the angle of rotation <math>\theta</math> required to observe the symmetry is an irrational number such as <math>\sqrt 2</math> radians that never repeats exactly no matter how many times the helix is rotated. Such symmetries are created by using a non-repeating point group in two dimensions. DNA is an example of this type of non-repeating helical symmetry.
## Scale symmetry and fractals
Scale symmetry refers to the idea that if an object is expanded or reduced in size, the new object has the same properties as the original. Scale symmetry is notable for the fact that it does not exist for most physical systems, a point that was first discerned by Galileo. Simple examples of the lack of scale symmetry in the physical world include the difference in the strength and size of the legs of elephants versus mice, and the observation that if a candle made of soft wax was enlarged to the size of a tall tree, it would immediately collapse under its own weight.
A more subtle form of scale symmetry is demonstrated by fractals. As conceived by Mandelbrot, fractals are a mathematical concept in which the structure of a complex form looks exactly the same no matter what degree of magnification is used to examine it. A coast is an example of a naturally occurring fractal, since it retains roughly comparable and similar-appearing complexity at every level from the view of a satellite to a microscopic examination of how the water laps up against individual grains of sand. The branching of trees, which enables children to use small twigs as stand-ins for full trees in dioramas, is another example.
This similarity to naturally occurring phenomena provides fractals with an everyday familiarity not typically seen with mathematically generated functions. As a consequence, they can produce strikingly beautiful results such as the Mandelbrot set. Intriguingly, fractals have also found a place in CG, or computer-generated movie effects, where their ability to create very complex curves with fractal symmetries results in more realistic virtual worlds.
## Symmetry combinations
# Symmetry in science
## Symmetry in physics
Symmetry in physics has been generalized to mean invariance—that is, lack of any visible change—under any kind of transformation. This concept has become one of the most powerful tools of theoretical physics, as it has become evident that practically all laws of nature originate in symmetries. In fact, this role inspired the Nobel laureate PW Anderson to write in his widely-read 1972 article More is Different that "it is only slightly overstating the case to say that physics is the study of symmetry." See Noether's theorem (which, as a gross oversimplification, states that for every continuous mathematical symmetry, there is a corresponding conserved quantity; a conserved current, in Noether's original language); and also, Wigner's classification, which says that the symmetries of the laws of physics determine the properties of the particles found in nature.
## Symmetry in physical objects
### Classical objects
Although an everyday object may appear exactly the same after a symmetry operation such as a rotation or an exchange of two identical parts has been performed on it, it is readily apparent that such a symmetry is true only as an approximation for any ordinary physical object.
For example, if one rotates a precisely machined aluminum equilateral triangle 120 degrees around its center, a casual observer brought in before and after the rotation will be unable to decide whether or not such a rotation took place. However, the reality is that each corner of a triangle will always appear unique when examined with sufficient precision. An observer armed with sufficiently detailed measuring equipment such as optical or electron microscopes will not be fooled; he will immediately recognize that the object has been rotated by looking for details such as crystals or minor deformities.
Such simple thought experiments show that assertions of symmetry in everyday physical objects are always a matter of approximate similarity rather than of precise mathematical sameness. The most important consequence of this approximate nature of symmetries in everyday physical objects is that such symmetries have minimal or no impacts on the physics of such objects. Consequently, only the deeper symmetries of space and time play a major role in classical physics—that is, the physics of large, everyday objects.
### Quantum objects
Remarkably, there exists a realm of physics for which mathematical assertions of simple symmetries in real objects cease to be approximations. That is the domain of quantum physics, which for the most part is the physics of very small, very simple objects such as electrons, protons, light, and atoms.
Unlike everyday objects, objects such as electrons have very limited numbers of configurations, called states, in which they can exist. This means that when symmetry operations such as exchanging the positions of components are applied to them, the resulting new configurations often cannot be distinguished from the originals no matter how diligent an observer is. Consequently, for sufficiently small and simple objects the generic mathematical symmetry assertion F(x) = x ceases to be approximate, and instead becomes an experimentally precise and accurate description of the situation in the real world.
### Consequences of quantum symmetry
While it makes sense that symmetries could become exact when applied to very simple objects, the immediate intuition is that such a detail should not affect the physics of such objects in any significant way. This is in part because it is very difficult to view the concept of exact similarity as physically meaningful. Our mental picture of such situations is invariably the same one we use for large objects: We picture objects or configurations that are very, very similar, but for which if we could "look closer" we would still be able to tell the difference.
However, the assumption that exact symmetries in very small objects should not make any difference in their physics was discovered in the early 1900s to be spectacularly incorrect. The situation was succinctly summarized by Richard Feynman in the direct transcripts of his Feynman Lectures on Physics, Volume III, Section 3.4, Identical particles. (Unfortunately, the quote was edited out of the printed version of the same lecture.)
The word "interferes" in this context is a quick way of saying that such objects fall under the rules of quantum mechanics, in which they behave more like waves that interfere than like everyday large objects.
In short, when an object becomes so simple that a symmetry assertion of the form F(x) = x becomes an exact statement of experimentally verifiable sameness, x ceases to follow the rules of classical physics and must instead be modeled using the more complex—and often far less intuitive—rules of quantum physics.
This transition also provides an important insight into why the mathematics of symmetry are so deeply intertwined with those of quantum mechanics. When physical systems make the transition from symmetries that are approximate to ones that are exact, the mathematical expressions of those symmetries cease to be approximations and are transformed into precise definitions of the underlying nature of the objects. From that point on, the correlation of such objects to their mathematical descriptions becomes so close that it is difficult to separate the two.
## Symmetry as a unifying principle of geometry
The German geometer Felix Klein enunciated a very influential Erlangen programme in 1872, suggesting symmetry as unifying and organising principle in geometry (at a time when that was read 'geometries'). This is a broad rather than deep principle. Initially it led to interest in the groups attached to geometries, and the slogan transformation geometry (an aspect of the New Math, but hardly controversial in modern mathematical practice). By now it has been applied in numerous forms, as kind of standard attack on problems.
## Symmetry in mathematics
An example of a mathematical expression exhibiting symmetry is a²c + 3ab + b²c. If a and b are exchanged, the expression remains unchanged due to the commutativity of addition and multiplication.
Like in geometry, for the terms there are two possibilities:
- It is itself symmetric
- It has one or more other terms symmetric with it, in accordance with the symmetry kind
See also symmetric function, duality (mathematics)
## Symmetry in logic
A dyadic relation R is symmetric if and only if, whenever it's true that Rab, it's true that Rba. Thus, “is the same age as” is symmetrical, for if Paul is the same age as Mary, then Mary is the same age as Paul.
Symmetric binary logical connectives are "and" (∧, <math>\land</math>, or &), "or" (∨), "biconditional" (iff) (↔), NAND ("not-and"), XOR ("not-biconditional"), and NOR ("not-or").
## Generalizations of symmetry
If we have a given set of objects with some structure, then it is possible for a symmetry to merely convert only one object into another, instead of acting upon all possible objects simultaneously. This requires a generalization from the concept of symmetry group to that of a groupoid. Indeed, A. Connes in his book `Non-commutative_geometry' writes that Heisenberg discovered quantum mechanics by considering the groupoid of transitions of the hydrogen spectrum.
The notion of groupoid also leads to notions of multiple groupoids, namely sets with many compatible groupoid structures, a structure which trivialises to abelian groups if one restricts to groups. This leads to prospects of `higher order symmetry' which have been a little explored, as follows.
The automorphisms of a set, or a set with some structure, form a group, which models a homotopy 1-type. The automorphisms of a group G naturally form a crossed module $G \to Aut(G)$, and crossed modules give an algebraic model of homotopy 2-types. At the next stage, automorphisms of a crossed module fit into a structure known as a crossed square, and this structure is know to give an algebraic model of homotopy 3-types. It is not known how this procedure of generalising symmetry may be continued, although crossed n-cubes have been defined and used in algebraic topology, and these structures are only slowly being brought into theoretical physics. The web site n-category cafe has much discussion of n-groups. More information is on `Higher dimensional group theory'.
Physicists have come up with other directions of generalization, such as supersymmetry and quantum groups.
## Symmetry in biology
See symmetry (biology) and facial symmetry.
## Symmetry in chemistry
Symmetry is important to chemistry because it explains observations in spectroscopy, quantum chemistry and crystallography. It draws heavily on group theory.
# Symmetry in history, religion, and culture
In any human endeavor for which an impressive visual result is part of the desired objective, symmetries play a profound role. The innate appeal of symmetry can be found in our reactions to happening across highly symmetrical natural objects, such as precisely formed crystals or beautifully spiraled seashells. Our first reaction in finding such an object often is to wonder whether we have found an object created by a fellow human, followed quickly by surprise that the symmetries that caught out attention are derived from nature itself. In both reactions we give away our inclination to view symmetries both as beautiful and, in some fashion, informative of the world around us.
## Symmetry in religious symbols
The tendency of people to see purpose in symmetry suggests at least one reason why symmetries are often an integral part of the symbols of world religions. Just a few of many examples include the sixfold rotational symmetry of Judaism's Star of David, the twofold point symmetry of Taoism's Taijitu or Yin-Yang, the bilateral symmetry of Christianity's cross and Sikhism's Khanda, or the fourfold point symmetry of Jain's ancient (and peacefully intended) version of the swastika. With its strong prohibitions against the use of representational images, Islam, and in particular the Sunni branch of Islam, has developed some of the most intricate and visually impressive use of symmetries for decorative uses of any major religion.
The ancient Taijitu image of Taoism is a particularly fascinating use of symmetry around a central point, combined with black-and-white inversion of color at opposite distances from that central point. The image, which is often misunderstood in the Western world as representing good (white) versus evil (black), is actually intended as a graphical representative of the complementary need for two abstract concepts of "maleness" (white) and "femaleness" (black). The symmetry of the symbol in this case is used not just to create a symbol that catches the attention of the eye, but to make a significant statement about the philosophical beliefs of the people and groups that use it. Also an important symmetrical religious symbol is the Shintoist "Torii" "The gate of the birds", usually the gate of the Shintoist temples called "Jinjas".
## Symmetry in Social Interactions
People observe the symmetrical nature, often including asymmetrical balance, of social interactions in a variety of contexts. These include assessments of reciprocity, empathy, apology, dialog, respect, justice, and revenge. Symmetrical interactions send the message "we are all the same" while asymmetrical interactions send the message "I am special; better than you". Peer relationships are based on symmetry, power relationships are based on asymmetry. [6]
## Symmetry in architecture
Another human endeavor in which the visual result plays a vital part in the overall result is architecture. Both in ancient times, the ability of a large structure to impress or even intimidate its viewers has often been a major part of its purpose, and the use of symmetry is an inescapable aspect of how to accomplish such goals.
Just a few examples of ancient examples of architectures that made powerful use of symmetry to impress those around them included the Egyptian Pyramids, the Greek Parthenon, and the first and second Temple of Jerusalem, China's Forbidden City, Cambodia's Angkor Wat complex, and the many temples and pyramids of ancient Pre-Columbian civilizations. More recent historical examples of architectures emphasizing symmetries include Gothic architecture cathedrals, and American President Thomas Jefferson's Monticello home. India's unparalleled Taj Mahal is in a category by itself, as it may arguably be one of the most impressive and beautiful uses of symmetry in architecture that the world has ever seen.
An interesting example of a broken symmetry in architecture is the Leaning Tower of Pisa, whose notoriety stems in no small part not for the intended symmetry of its design, but for the violation of that symmetry from the lean that developed while it was still under construction. Modern examples of architectures that make impressive or complex use of various symmetries include Australia's astonishing Sydney Opera House and Houston, Texas's simpler Astrodome.
Symmetry finds its ways into architecture at every scale, from the overall external views, through the layout of the individual floor plans, and down to the design of individual building elements such as intricately caved doors, stained glass windows, tile mosaics, friezes, stairwells, stair rails, and balustradess. For sheer complexity and sophistication in the exploitation of symmetry as an architectural element, Islamic buildings such as the Taj Mahal often eclipse those of other cultures and ages, due in part to the general prohibition of Islam against using images or people or animals.
Links related to symmetry in architecture include:
- Williams: Symmetry in Architecture
- Aslaksen: Mathematics in Art and Architecture
## Symmetry in pottery and metal vessels
Since the earliest uses of pottery wheels to help shape clay vessels, pottery has had a strong relationship to symmetry. As a minimum, pottery created using a wheel necessarily begins with full rotational symmetry in its cross-section, while allowing substantial freedom of shape in the vertical direction. Upon this inherently symmetrical starting point cultures from ancient times have tended to add further patterns that tend to exploit or in many cases reduce the original full rotational symmetry to a point where some specific visual objective is achieved. For example, Persian pottery dating from the fourth millennium B.C. and earlier used symmetric zigzags, squares, cross-hatchings, and repetitions of figures to produce more complex and visually striking overall designs.
Cast metal vessels lacked the inherent rotational symmetry of wheel-made pottery, but otherwise provided a similar opportunity to decorate their surfaces with patterns pleasing to those who used them. The ancient Chinese, for example, used symmetrical patterns in their bronze castings as early as the 17th century B.C. Bronze vessels exhibited both a bilateral main motif and a repetitive translated border design.
Links:
- Chinavoc: The Art of Chinese Bronzes
- Grant: Iranian Pottery in the Oriental Institute
- The Metropolitan Museum of Art - Islamic Art
## Symmetry in quilts
As quilts are made from square blocks (usually 9, 16, or 25 pieces to a block) with each smaller piece usually consisting of fabric triangles, the craft lends itself readily to the application of symmetry.
Links:
- Quate: Exploring Geometry Through Quilts
## Symmetry in carpets and rugs
A long tradition of the use of symmetry in carpet and rug patterns spans a variety of cultures. American Navajo Indians used bold diagonals and rectangular motifs. Many Oriental rugs have intricate reflected centers and borders that translate a pattern. Not surprisingly, rectangular rugs typically use quadrilateral symmetry—that is, motifs that are reflected across both the horizontal and vertical axes.
Links:
- Mallet: Tribal Oriental Rugs
- Dilucchio: Navajo Rugs
## Symmetry in music
Symmetry is of course not restricted to the visual arts. Its role in the history of music touches many aspects of the creation and perception of music.
### Musical form
Symmetry has been used as a formal constraint by many composers, such as the arch form (ABCBA) used by Steve Reich, Béla Bartók, and James Tenney (or swell). In classical music, Bach used the symmetry concepts of permutation and invariance; see (external link "Fugue No. 21," pdf or Shockwave).
### Pitch structures
Symmetry is also an important consideration in the formation of scales and chords, traditional or tonal music being made up of non-symmetrical groups of pitches, such as the diatonic scale or the major chord. Symmetrical scales or chords, such as the whole tone scale, augmented chord, or diminished seventh chord (diminished-diminished seventh), are said to lack direction or a sense of forward motion, are ambiguous as to the key or tonal center, and have a less specific diatonic functionality. However, composers such as Alban Berg, Béla Bartók, and George Perle have used axes of symmetry and/or interval cycles in an analogous way to keys or non-tonal tonal centers.
Perle (1992) explains "C-E, D-F#, [and] Eb-G, are different instances of the same interval...the other kind of identity. ..has to do with axes of symmetry. C-E belongs to a family of symmetrically related dyads as follows:"
Thus in addition to being part of the interval-4 family, C-E is also a part of the sum-4 family (with C equal to 0).
Interval cycles are symmetrical and thus non-diatonic. However, a seven pitch segment of C5 (the cycle of fifths, which are enharmonic with the cycle of fourths) will produce the diatonic major scale. Cyclic tonal progressions in the works of Romantic composers such as Gustav Mahler and Richard Wagner form a link with the cyclic pitch successions in the atonal music of Modernists such as Bartók, Alexander Scriabin, Edgard Varèse, and the Vienna school. At the same time, these progressions signal the end of tonality.
The first extended composition consistently based on symmetrical pitch relations was probably Alban Berg's Quartet, Op. 3 (1910). (Perle, 1990)
### Equivalency
Tone rows or pitch class sets which are invariant under retrograde are horizontally symmetrical, under inversion vertically. See also Asymmetric rhythm.
## Symmetry in other arts and crafts
The concept of symmetry is applied to the design of objects of all shapes and sizes. Other examples include beadwork, furniture, sand paintings, knotwork, masks, musical instruments, and many other endeavors.
## Symmetry in aesthetics
The relationship of symmetry to aesthetics is complex. Certain simple symmetries, and in particular bilateral symmetry, seem to be deeply ingrained in the inherent perception by humans of the likely health or fitness of other living creatures, as can be seen by the simple experiment of distorting one side of the image of an attractive face and asking viewers to rate the attractiveness of the resulting image. Consequently, such symmetries that mimic biology tend to have an innate appeal that in turn drives a powerful tendency to create artifacts with similar symmetry. One only needs to imagine the difficulty in trying to market a highly asymmetrical car or truck to general automotive buyers to understand the power of biologically inspired symmetries such as bilateral symmetry.
Another more subtle appeal of symmetry is that of simplicity, which in turn has an implication of safety, security, and familiarity. A highly symmetrical room, for example, is unavoidably also a room in which anything out of place or potentially threatening can be identified easily and quickly. For example, people who have grown up in houses full of exact right angles and precisely identical artifacts can find their first experience in staying in a room with no exact right angles and no exactly identical artifacts to be highly disquieting. Symmetry thus can be a source of comfort not only as an indicator of biological health, but also of a safe and well-understood living environment.
Opposed to this is the tendency for excessive symmetry to be perceived as boring or uninteresting. Humans in particular have a powerful desire to exploit new opportunities or explore new possibilities, and an excessive degree of symmetry can convey a lack of such opportunities.
Yet another possibility is that when symmetries become too complex or too challenging, the human mind has a tendency to "tune them out" and perceive them in yet another fashion: as noise that conveys no useful information.
Finally, perceptions and appreciation of symmetries are also dependent on cultural background. The far greater use of complex geometric symmetries in many Islamic cultures, for example, makes it more likely that people from such cultures will appreciate such art forms (or, conversely, to rebel against them).
As in many human endeavors, the result of the confluence of many such factors is that effective use of symmetry in art and architecture is complex, intuitive, and highly dependent on the skills of the individuals who must weave and combine such factors within their own creative work. Along with texture, color, proportion, and other factors, symmetry is a powerful ingredient in any such synthesis; one only need to examine the Taj Mahal to powerful role that symmetry plays in determining the aesthetic appeal of an object.
A few examples of the more explicit use of symmetries in art can be found in the remarkable art of M. C. Escher, the creative design of the mathematical concept of a wallpaper group, and the many applications (both mathematical and real world) of tiling.
## Symmetry in games and puzzles
- See also symmetric games.
- See sudoku.
Board games
- The Symmetrical Chess Collection
## Symmetry in literature
See palindrome.
## Moral symmetry
- Tit for tat
- Reciprocity
- Golden Rule
- Empathy & Sympathy
- Reflective equilibrium | https://www.wikidoc.org/index.php/Symmetry | |
32657b7aa4d1a104b48aafd777927b4ea88a2939 | wikidoc | Symplast | Symplast
The symplast of a plant is the inner side of the plasma membrane in which water (and low molecular solutes) can freely diffuse.
The plasmodesmata allow the direct flow of small molecules such as sugars, amino acids and ions between cells. Larger molecules can also be transported through with the help of actin structures.
This allows direct cytoplasm to cytoplasm flow of water and other nutrients allow concentration gradients. It is particularly used in the root systems to bring in nutrients from soil. It moves these solutes from epidermis cells through the cortex into the endodermis and eventually the pericycle where it can be moved into the xylem for long distance transport.
It is contrasted with the apoplastic flow which uses cell wall transport. | Symplast
The symplast of a plant is the inner side of the plasma membrane in which water (and low molecular solutes) can freely diffuse.
The plasmodesmata allow the direct flow of small molecules such as sugars, amino acids and ions between cells. Larger molecules can also be transported through with the help of actin structures.
This allows direct cytoplasm to cytoplasm flow of water and other nutrients allow concentration gradients. It is particularly used in the root systems to bring in nutrients from soil. It moves these solutes from epidermis cells through the cortex into the endodermis and eventually the pericycle where it can be moved into the xylem for long distance transport.
It is contrasted with the apoplastic flow which uses cell wall transport. | https://www.wikidoc.org/index.php/Symplast | |
ed20af8ad26d314677402155833c4be56d9392a0 | wikidoc | Syndrome | Syndrome
In medicine and psychology, the term syndrome refers to the association of several clinically recognizable features, signs (discovered by a physician), symptoms (reported by the patient), phenomena or characteristics which often occur together, so that the presence of one feature alerts the physician to the presence of the others. In recent decades the term has been used outside of medicine to refer to a combination of phenomena seen in association.
In technical medical language, a "syndrome" refers only to the set of detectable characteristics. A specific disease, condition, or disorder may or may not be identified as the underlying cause. Confusingly, even once a physical cause has been identified, the word "syndrome" is sometimes kept in the name of the disease. Subjective medical conditions are not supported by evidence of an underlying physical cause.
The term syndrome derives from the Greek and means literally "run together," as the features do. It is most often used when the reason that the features occur together (the pathophysiology of the syndrome) has not yet been discovered. A familiar syndrome name often continues to be used even after an underlying cause has been found, or when there are a number of different primary causes that all give rise to the same combination of symptoms and signs. Many syndromes are named after the physicians credited with first reporting the association; these are "eponymous" syndromes (see also the list of eponymous diseases, many of which are referred to as "syndromes"). Otherwise, disease features or presumed causes, as well as references to geography, history or poetry, can lend their names to syndromes.
A culture-bound syndrome is a set of symptoms where there is no evidence of an underlying biological cause, and which is only recognized as a "disease" in a particular culture.
# Syndromes and associated conditions
The description of a syndrome usually includes a number of essential characteristics, which when concurrent lead to the diagnosis of the condition. Frequently these are classified as a combination of typical major symptoms and signs - essential to the diagnosis - together with minor findings, some or all of which may be absent. A formal description may specify the minimum number of major and minor findings respectively, that are required for the diagnosis.
In contrast to the major and minor findings which are typical of the syndrome, there may be an association with other conditions, meaning that in persons with the specified syndrome these associated conditions occur more frequently than would be expected by chance. While the syndrome and the associated conditions may be statistically related, they do not have a clear cause and effect relationship - i.e. there is likely to be a separate underlying problem or risk factor that explains the association. An example would be Down syndrome which has the associated condition of diabetes mellitus. A knowledge of associated conditions would dictate that they are specifically looked for in the management of the syndrome.
# Case studies
One recent case study is Acquired Immune Deficiency Syndrome (AIDS), so named because most syndromal immune deficiencies are either genetically precoded, or secondary to either metabolic disorders or hematological disease.
AIDS was originally termed "Gay Related Immune Disease" (or GRID), a name which was revised as the disease turned out to also affect heterosexuals. Several years passed after the recognition of AIDS before HIV (human immunodeficiency virus) was first described, finally explaining the hitherto mysterious "syndrome".
SARS (severe acute respiratory syndrome) is an even more recent example of a syndrome that was later explained with the identification of a causative coronavirus. | Syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In medicine and psychology, the term syndrome refers to the association of several clinically recognizable features, signs (discovered by a physician), symptoms (reported by the patient), phenomena or characteristics which often occur together, so that the presence of one feature alerts the physician to the presence of the others. In recent decades the term has been used outside of medicine to refer to a combination of phenomena seen in association.
In technical medical language, a "syndrome" refers only to the set of detectable characteristics. A specific disease, condition, or disorder may or may not be identified as the underlying cause. Confusingly, even once a physical cause has been identified, the word "syndrome" is sometimes kept in the name of the disease. Subjective medical conditions are not supported by evidence of an underlying physical cause.
The term syndrome derives from the Greek and means literally "run together," as the features do. It is most often used when the reason that the features occur together (the pathophysiology of the syndrome) has not yet been discovered. A familiar syndrome name often continues to be used even after an underlying cause has been found, or when there are a number of different primary causes that all give rise to the same combination of symptoms and signs. Many syndromes are named after the physicians credited with first reporting the association; these are "eponymous" syndromes (see also the list of eponymous diseases, many of which are referred to as "syndromes"). Otherwise, disease features or presumed causes, as well as references to geography, history or poetry, can lend their names to syndromes.
A culture-bound syndrome is a set of symptoms where there is no evidence of an underlying biological cause, and which is only recognized as a "disease" in a particular culture.
# Syndromes and associated conditions
The description of a syndrome usually includes a number of essential characteristics, which when concurrent lead to the diagnosis of the condition. Frequently these are classified as a combination of typical major symptoms and signs - essential to the diagnosis - together with minor findings, some or all of which may be absent. A formal description may specify the minimum number of major and minor findings respectively, that are required for the diagnosis.
In contrast to the major and minor findings which are typical of the syndrome, there may be an association with other conditions, meaning that in persons with the specified syndrome these associated conditions occur more frequently than would be expected by chance. While the syndrome and the associated conditions may be statistically related, they do not have a clear cause and effect relationship - i.e. there is likely to be a separate underlying problem or risk factor that explains the association. An example would be Down syndrome which has the associated condition of diabetes mellitus. A knowledge of associated conditions would dictate that they are specifically looked for in the management of the syndrome.
# Case studies
One recent case study is Acquired Immune Deficiency Syndrome (AIDS), so named because most syndromal immune deficiencies are either genetically precoded, or secondary to either metabolic disorders or hematological disease.
AIDS was originally termed "Gay Related Immune Disease" (or GRID), a name which was revised as the disease turned out to also affect heterosexuals. Several years passed after the recognition of AIDS before HIV (human immunodeficiency virus) was first described, finally explaining the hitherto mysterious "syndrome".
SARS (severe acute respiratory syndrome) is an even more recent example of a syndrome that was later explained with the identification of a causative coronavirus. | https://www.wikidoc.org/index.php/Syndrome | |
b4de13a9b48e0fa3f5515ac3ded86d4bf4e00e76 | wikidoc | Synovium | Synovium
# Overview
Synovium is the soft tissue that lines the non-cartilaginous surfaces within joints with cavities (synovial joints). The word synovium comes from a Latin word meaning "with egg," because the synovial fluid in joints that have a cavity between the bearing surfaces is like egg white.
# Structure
Synovium is very variable but often has two layers. The outer layer, or subintima, can be of almost any type: fibrous, fatty or loosely "areolar". The inner layer, or intima, consists of a sheet of cells thinner than a piece of paper. Where the underlying subintima is loose the intima sits on a pliable membrane, giving rise to the term synovial membrane. This membrane, together with the cells of the intima, provides something like an inner tube, sealing the synovial fluid from the surrounding tissue (effectively stopping the joints being squeezed dry when subject to impact, such as running). The intimal cells are of two types, fibroblasts and macrophages, both of which are different in certain respects from similar cells in other tissues. The fibroblasts manufacture a long chain sugar polymer called hyaluronan, which is what makes the synovial fluid "ropy" like egg-white, together with a molecule called lubricin, which lubricates the joint surfaces. The water of synovial fluid is not secreted as such, but is effectively trapped in the joint space by the hyaluronan. The macrophages are responsible for the removal of undesirable substances from the synovial fluid. The surface of synovium may be flat or may be covered with finger-like projections or villi, which probably help to allow the soft tissue to change shape as the joint surfaces move one on another. Just beneath the intima most synovium has a dense net of small blood vessels which provide nutrients not only for synovium, but also for the avascular cartilage. In any one position much of the cartilage is close enough to get nutrition direct from synovium. Some areas of cartilage have to obtain nutrients indirectly and may do so either from diffusion through cartilage or possibly by 'stirring' of synovial fluid, although the film is very thin.
# Mechanics
Although a biological joint can resemble a man-made joint in being a hinge or a ball and socket, the engineering problems that nature must solve are very different because the joint works within an almost completely solid structure, with no wheels or nuts and bolts. In general the bearing surfaces of man made joints interlock, as in a hinge. This is rare for biological joints, although the badger's jaw interlocks. More often the surfaces are held together by cord-like ligaments. Virtually all the space between muscles, ligaments, bones and cartilage is filled with pliable solid tissue. The fluid-filled gap is mostly only a twentieth of a millimetre thick. This means that synovium has certain rather unexpected jobs to do. These may include:
- Providing a plane of separation, or disconnection, between solid tissues so that movement can occur with minimum bending of solid components. If this separation is lost, as in a 'frozen shoulder' the joint cannot move.
- Providing a packing that can change shape in whatever way is needed to allow the bearing surfaces to move on each other.
- Controlling the volume of fluid in the cavity so that it is just enough to allow the solid components to move over each other freely. This volume is normally so small that the joint is under slight suction.
# Pathology
Synovium can become irritated and thickened in conditions such as rheumatoid arthritis. When this happens, the synovium can become a danger to the bearing surface structure in a variety of ways. Excess synovial fluid weeping from inflamed synovium can provide a barrier to diffusion of nutrients to cartilage. The synovial cells may also use up nutrients so that the glucose level in the tissue is almost zero. These factors may lead to starvation and death of cartilage cells. Synovial cells may also produce enzymes which can digest the cartilage surface, although it is not clear that these will damage cartilage with healthy cells. | Synovium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Synovium is the soft tissue that lines the non-cartilaginous surfaces within joints with cavities (synovial joints). The word synovium comes from a Latin word meaning "with egg," because the synovial fluid in joints that have a cavity between the bearing surfaces is like egg white.
# Structure
Synovium is very variable but often has two layers. The outer layer, or subintima, can be of almost any type: fibrous, fatty or loosely "areolar". The inner layer, or intima, consists of a sheet of cells thinner than a piece of paper. Where the underlying subintima is loose the intima sits on a pliable membrane, giving rise to the term synovial membrane. This membrane, together with the cells of the intima, provides something like an inner tube, sealing the synovial fluid from the surrounding tissue (effectively stopping the joints being squeezed dry when subject to impact, such as running). The intimal cells are of two types, fibroblasts and macrophages, both of which are different in certain respects from similar cells in other tissues. The fibroblasts manufacture a long chain sugar polymer called hyaluronan, which is what makes the synovial fluid "ropy" like egg-white, together with a molecule called lubricin, which lubricates the joint surfaces. The water of synovial fluid is not secreted as such, but is effectively trapped in the joint space by the hyaluronan. The macrophages are responsible for the removal of undesirable substances from the synovial fluid. The surface of synovium may be flat or may be covered with finger-like projections or villi, which probably help to allow the soft tissue to change shape as the joint surfaces move one on another. Just beneath the intima most synovium has a dense net of small blood vessels which provide nutrients not only for synovium, but also for the avascular cartilage. In any one position much of the cartilage is close enough to get nutrition direct from synovium. Some areas of cartilage have to obtain nutrients indirectly and may do so either from diffusion through cartilage or possibly by 'stirring' of synovial fluid, although the film is very thin.
# Mechanics
Although a biological joint can resemble a man-made joint in being a hinge or a ball and socket, the engineering problems that nature must solve are very different because the joint works within an almost completely solid structure, with no wheels or nuts and bolts. In general the bearing surfaces of man made joints interlock, as in a hinge. This is rare for biological joints, although the badger's jaw interlocks. More often the surfaces are held together by cord-like ligaments. Virtually all the space between muscles, ligaments, bones and cartilage is filled with pliable solid tissue. The fluid-filled gap is mostly only a twentieth of a millimetre thick. This means that synovium has certain rather unexpected jobs to do. These may include:
- Providing a plane of separation, or disconnection, between solid tissues so that movement can occur with minimum bending of solid components. If this separation is lost, as in a 'frozen shoulder' the joint cannot move.
- Providing a packing that can change shape in whatever way is needed to allow the bearing surfaces to move on each other.
- Controlling the volume of fluid in the cavity so that it is just enough to allow the solid components to move over each other freely. This volume is normally so small that the joint is under slight suction.
# Pathology
Synovium can become irritated and thickened in conditions such as rheumatoid arthritis. When this happens, the synovium can become a danger to the bearing surface structure in a variety of ways. Excess synovial fluid weeping from inflamed synovium can provide a barrier to diffusion of nutrients to cartilage. The synovial cells may also use up nutrients so that the glucose level in the tissue is almost zero. These factors may lead to starvation and death of cartilage cells. Synovial cells may also produce enzymes which can digest the cartilage surface, although it is not clear that these will damage cartilage with healthy cells. | https://www.wikidoc.org/index.php/Synovial_membrane | |
02a714bc49c0935ab8d8fc0404fa6329b1d80652 | wikidoc | T-tubule | T-tubule
# Overview
A T-tubule (or transverse tubule), is a deep invagination of the plasma membrane found in skeletal and cardiac muscle cells. These invaginations allow depolarization of the membrane to quickly penetrate to the interior of the cell.
# Structure
Each muscle fiber consists of T-tubules which run perpendicularly (transversely) to the long axis of the fiber. As they are invaginations of the plasma membrane, each T-tubule is composed of a phospholipid bilayer in which are embedded a large number of L-type calcium channels. The T-tubule extends from the surface of the muscle fiber into its interior, effectively bringing the extracellular environment in proximity to the innermost confines of the cell.
In skeletal and cardiac muscle, the T-tubules are adjacent to the terminal sacs (or terminal cisternae) of the fiber's sarcoplasmic reticulum. In skeletal muscle, the T-tubule is surrounded by a pair of terminal cisternae in an arrangement called a triad that is found at the junction of the A and I bands. Cardiac muscle has a similar structure, the diad, which is composed of a T-tubule and a single terminal cisterna; it occurs at the Z line.
# Excitation-contraction coupling
T-tubules are the major sites for the coupling of excitation and contraction, which is the process whereby the spreading depolarization is converted into force production by muscle fibers. The L-type calcium channels in T-tubules activate in response to electrical stimulation; their opening allows calcium to flow down its electrochemical gradient and into the cell. Activation of the L-type channel also causes a mechanical interaction between it and calcium-release channels located on the adjacent sarcoplasmic reticulum membrane.
In skeletal muscle, the influx of calcium through the L-type calcium channel on the T-tubule contributes little to excitation-contraction coupling, whereas it is crucial to the proper function of cardiac muscle (see Cardiac action potential). Conversely, the mechanical interaction between the T-tubule's L-type calcium channel and the calcium-release channel is critical to proper skeletal muscle contraction, whereas it contributes little to the contraction of cardiac muscle.
# Detubulation
It is possible to physically and functionally uncouple T-tubules from the surface membrane using a technique known as detubulation. This relies on osmotically active chemicals, such as glycerol (for skeletal muscle) or formamide (mainly for cardiac muscle). Addition of these chemicals to the solution surrounding muscle cells causes the cells to shrink; when the chemical is withdrawn the cells rapidly expand before returning to their normal size. The rapid expansion is thought to cause the t-tubules to detach from the surface membrane, which reseals, and to reseal within the cell. This technique can be used to investigate the function of the t-tubules.
There is some evidence that heart failure precipitates the loss of the T-tubule network, again indicating their importance. | T-tubule
# Overview
A T-tubule (or transverse tubule), is a deep invagination of the plasma membrane found in skeletal and cardiac muscle cells. These invaginations allow depolarization of the membrane to quickly penetrate to the interior of the cell.
# Structure
Each muscle fiber consists of T-tubules which run perpendicularly (transversely) to the long axis of the fiber. As they are invaginations of the plasma membrane, each T-tubule is composed of a phospholipid bilayer in which are embedded a large number of L-type calcium channels. The T-tubule extends from the surface of the muscle fiber into its interior, effectively bringing the extracellular environment in proximity to the innermost confines of the cell.
In skeletal and cardiac muscle, the T-tubules are adjacent to the terminal sacs (or terminal cisternae) of the fiber's sarcoplasmic reticulum. In skeletal muscle, the T-tubule is surrounded by a pair of terminal cisternae in an arrangement called a triad that is found at the junction of the A and I bands. Cardiac muscle has a similar structure, the diad, which is composed of a T-tubule and a single terminal cisterna; it occurs at the Z line.
# Excitation-contraction coupling
T-tubules are the major sites for the coupling of excitation and contraction, which is the process whereby the spreading depolarization is converted into force production by muscle fibers. The L-type calcium channels in T-tubules activate in response to electrical stimulation; their opening allows calcium to flow down its electrochemical gradient and into the cell. Activation of the L-type channel also causes a mechanical interaction between it and calcium-release channels located on the adjacent sarcoplasmic reticulum membrane.
In skeletal muscle, the influx of calcium through the L-type calcium channel on the T-tubule contributes little to excitation-contraction coupling, whereas it is crucial to the proper function of cardiac muscle (see Cardiac action potential). Conversely, the mechanical interaction between the T-tubule's L-type calcium channel and the calcium-release channel is critical to proper skeletal muscle contraction, whereas it contributes little to the contraction of cardiac muscle.
# Detubulation
It is possible to physically and functionally uncouple T-tubules from the surface membrane using a technique known as detubulation. This relies on osmotically active chemicals, such as glycerol (for skeletal muscle) or formamide (mainly for cardiac muscle). Addition of these chemicals to the solution surrounding muscle cells causes the cells to shrink; when the chemical is withdrawn the cells rapidly expand before returning to their normal size. The rapid expansion is thought to cause the t-tubules to detach from the surface membrane, which reseals, and to reseal within the cell. This technique can be used to investigate the function of the t-tubules.
There is some evidence that heart failure precipitates the loss of the T-tubule network, again indicating their importance. | https://www.wikidoc.org/index.php/T-tubule | |
b5d44dcd4b4618d7836e7a548b8b57771c2942f6 | wikidoc | T.O.T.E. | T.O.T.E.
T.O.T.E., standing for "Test - Operate - Test - Exit", is an iterative problem solving strategy based on feedback loops.
The self-control mechanisms in human tasking have been explained in terms of both operations and monitoring processes (Miller, Gallanter, and Pibram, 1960). Each recurring operation would be associated to a monitoring process, to test if the intended control was met or not.
Its premise is that a common algorithm for solving non-deterministic problems in a complex system, is to test where the system is currently, then perform some operation that makes a change, then retest again, and to repeat this until the answer is satisfactory, at which point the process is complete and ends (or exits).
TOTEs are often nested within other TOTEs, since as a means to meet a goal, they are applicable to sub-goals too.
It is commonly used in many disciplines where iterative methods are applicable, such as engineering, artificial intelligence, and cybernetics. In psychology, it is explicitly used as a key strategy within neuro-linguistic programming.
# More
Generic TOTE structure:
- Test to obtain some representation of the problem state
- Operate - intervene in some way
- Test again to see if the problem state is the same - if it is loop back to operate if it isn't
- Exit - problem solved
## Simple example
When driving a car and looking for the appropriate turn off.
- Test - is this the turnoff? - No
- Operate - keep driving
- Test - is this the turnoff? - No
- Operate - keep driving
- Test - is this the turnoff? - Yes
- Exit
(this only finds the correct turnoff, and would be embedded in a larger TOTE)
## Examples of nested TOTEs
Cooking a meal:
- The top level TOTE for "testing if meal is cooked" is:
Check meal -- leave a while -- recheck meal - take out of oven.
- As part of the "leave a while" part, there is a nested TOTE:
Check 5 minutes is up -- wait a while -- recheck 5 minutes is up -- exit (ie "leave a while" subgoal is achieved)
# Principles
- Working memory is limited to 7±2 chunks of information.
- Planning, consisting of TOTE units, is essential in cognitive process.
- Control of behavior exposes a set of chunks and TOTE units | T.O.T.E.
Template:Cleanup
T.O.T.E., standing for "Test - Operate - Test - Exit", is an iterative problem solving strategy based on feedback loops.
The self-control mechanisms in human tasking have been explained in terms of both operations and monitoring processes (Miller, Gallanter, and Pibram, 1960). Each recurring operation would be associated to a monitoring process, to test if the intended control was met or not.
Its premise is that a common algorithm for solving non-deterministic problems in a complex system, is to test where the system is currently, then perform some operation that makes a change, then retest again, and to repeat this until the answer is satisfactory, at which point the process is complete and ends (or exits).
TOTEs are often nested within other TOTEs, since as a means to meet a goal, they are applicable to sub-goals too.
It is commonly used in many disciplines where iterative methods are applicable, such as engineering, artificial intelligence, and cybernetics. In psychology, it is explicitly used as a key strategy within neuro-linguistic programming.
# More
Generic TOTE structure:
- Test to obtain some representation of the problem state
- Operate - intervene in some way
- Test again to see if the problem state is the same - if it is loop back to operate if it isn't
- Exit - problem solved
## Simple example
When driving a car and looking for the appropriate turn off.
- Test - is this the turnoff? - No
- Operate - keep driving
- Test - is this the turnoff? - No
- Operate - keep driving
- Test - is this the turnoff? - Yes
- Exit
(this only finds the correct turnoff, and would be embedded in a larger TOTE)
## Examples of nested TOTEs
Cooking a meal:
- The top level TOTE for "testing if meal is cooked" is:
Check meal -- leave a while -- recheck meal - take out of oven.
- As part of the "leave a while" part, there is a nested TOTE:
Check 5 minutes is up -- wait a while -- recheck 5 minutes is up -- exit (ie "leave a while" subgoal is achieved)
# Principles
- Working memory is limited to 7±2 chunks of information.
- Planning, consisting of TOTE units, is essential in cognitive process.
- Control of behavior exposes a set of chunks and TOTE units
# External links
- An article by George A. Miller on T.O.T.E. and Information Processing Theory | https://www.wikidoc.org/index.php/T.O.T.E. | |
6c408b76fa4b45af7b45adb9bc01b5b709109946 | wikidoc | Tafazzin | Tafazzin
Tafazzin is a protein that in humans is encoded by the TAZ gene. Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid-lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases). It catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties. Several different isoforms of the tafazzin protein are produced from the TAZ gene. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells. Mutations in the TAZ gene have been associated with mitochondrial deficiency, Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, left ventricular noncompaction (LVNC), breast cancer, papillary thyroid carcinoma, non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.
# Structure
The TAZ gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs. The TAZ gene produces a 21.3 kDa protein composed of 184 amino acids. The structure of the encoded protein has been found to differ at their N terminus and the central region, which are two functionally notable regions. A 30 residue hydrophobic stretch at the N terminus may function as a membrane anchor, which does not exist in the shortest forms of tafazzins. The second region is a variable exposed loop located between amino acids 124 and 195 in the central region. This hydrophilic region is known to interact with other proteins. TAZ has no known resemblance to other proteins.
Tafazzin is encoded by the TAZ gene. It is very unfortunate that a protein called TAZ (a 50kDA protein) which is a part of the Hippo/YAP/TAZ pathway gets confused with Tafazzin due to this misnaming often.
Tafazzin has at least 4 different isoforms. It has a molecular weight around 35kDa but may also appear in lower molecular weights due to species differences in isoform expression.
# Function
The TAZ gene provides instructions for producing a protein called tafazzin, which is located in structures called mitochondria, which are the energy-producing centers of cells. Tafazzin is involved in altering a fat (lipid) called cardiolipin (CL), which plays critical roles in the mitochondrial inner membrane.
## Transacylase (remodeling)
After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. The remodeling process of cardiolipin involves reaching a final acyl composition. TAZ interacts with an immature cardiolipin by adding a fatty acid called linoleic acid, which catalyzes the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation-reacylation cycle. The deacylation-reacylation cycle, also known as the Lands cycle begins with a deacylation mediated by a phospholipase and ends which forms monolyso-CL (MLCL). The cycle ends with a CoA-dependent reacylation. In contrast, transacylation involves the transfer of a linoleic acid (LA) group from phosphatidylcholine (PC) to MLCL. Such enzymatic activity forms lyso-PC and CL, and enriches the specific acyl chain of cardiolipin. The process has been shown to be specific for linoleoyl-containing PC. Such remodeling processes converts cardiolipin into a mature composition that contains a predominance of tetralinoleoyl moieties. The process enables the proper function of cardiolipin.
## Cardiolipin in mitochondrial structure and function
Cardiolipin is a complex glycerophospholipid which contains 4 acyl groups linked to three glycerol moietie localized in the mitochondrial inner membrane. These acyl groups include oleic acid and linoleic acid. Due to this composition, cardiolipin exhibits a conical structure, which allows for membrane curvature called cristae. Such qualities allow CL to play essential roles in maintaining mitochondrial shape, energy production, and protein transport within cells.
During apoptosis and similar processes, CL is known to act as a platform for proteins and other machinery involved.
## Influence of cardiolipin on the respiratory chain
Cardiolipin has been shown to assist in energy production of the mitochondria. Several proteins in the mitochondrial respiratory chain require CL for optimal function.
CL has been found to be involved in the stabilization of each respiratory chain complex, enabling efficient electron transport. CL assists in forming super-complexes with proteins localized in the inner mitochondrial matrix, which include the ATP/ADP translocase, pyruvate carrier, carnitine carrier, and all of the respiratory chain complexes (I, III,IV, V). CL also enables trapping of protons in the intermembrane space, aiding ATP synthase to carry out its function of channeling protons into the mitochondrial matrix.
# Clinical significance
Mutations in the TAZ gene have been associated with a number of mitochondrial deficiencies and associated disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC). TAZ has also been associated with various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.
## Barth Syndrome
Barth syndrome is an X-linked disease caused by mutations in the TAZ gene. More than 160 mutations in the TAZ gene have been found to this disease. It is a rare condition that occurs almost exclusively in males. TAZ gene mutations that cause barth syndrome result in the production of tafazzin proteins with little or no function. As a result, linoleic acid is not added to cardiolipin, which causes problems with normal mitochondrial shape and functions such as energy production and protein transport. Tissues with high energy demands, such as the heart and other muscles, are most susceptible to cell death due to reduced energy production in mitochondria. Additionally, affected white blood cells have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened immune system and recurrent infections. Dysfunctional mitochondria likely lead to other signs and symptoms of Barth syndrome.
Common clinical manifestations include:
- dilated cardiomyopathy (enlarged and weakened heart)
- muscle weakness
- recurrent infections
- short stature
- endocardial fibroelastosis
- growth retardation
- neutropenia
- organic aciduria (3-methylglutaconic acid)
Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.
A c.348C>T mutation resulted in dilated cardiomyopathy with noncompaction of the ventricular myocardium. A frame shift mutation of c.227delC displayed symptoms of neutropenia, cardiomegaly, and other common symptoms of Bath Syndrome. Another a c.C153G mutation resulted in severe metabolic acidosis, cardiomegaly, and other major symptoms of Barth syndrome.
In conclusion, tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL), the signature lipid of the mitochondrial inner membrane. Therefore, a dysfunctioning tafazzin has been found to lead to an impaired mitochondrial respiratory chain. As a result, Barth syndrome patients exhibit defects in cardiolipin metabolism, including aberrant cardiolipin fatty acyl composition, accumulation of monolysocardiolipin (MLCL) and reduced total cardiolipin levels. This may lead to acute metabolic decompensation and sudden death. Cardiac transplantation is the only possibility at the present time.
## Dilated cardiomyopathy (DCM)
Some mutations in the TAZ gene cause dilated cardiomyopathy without the other features of Barth syndrome. Dilated cardiomyopathy is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently, often resulting in heart failure. The decreased blood flow can lead to swelling in the legs and abdomen, fluid in the lungs, and an increased risk of blood clots.
## Isolated noncompaction of left ventricular myocardium (INVM)
Mutations in the TAZ gene can cause a heart condition called isolated noncompaction of left ventricular myocardium (INVM). This condition occurs when the lower left chamber of the heart (left ventricle) does not develop correctly. In INVM, the heart muscle is weakened and cannot pump blood efficiently. Abnormal heart rhythms (arrhythmias) can also occur. INVM frequently causes heart failure.
## Cancer
Highly elevated TAZ activity has been linked to tumorigenesis and oncogenic activity. It has also been associated with and various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, and glioma. In breast cancer, TAZ has been shown to be required for cancer cells to sustain self-renewal and create tumors. Additionally, TAZ has been found to be highly expressed in gastric cancer cells resistant to cisplatin. This resistance was identified to be due to the acquired ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT). The findings that TAZ is involved in inducing EMT as well as its high levels in these cancer cells may point to its involvement in gastric cancer. High expression of TAZ was also found in rectal cancer and thyroid neoplasms, indicating that TAZ may promote tumorigenesis and inhibit apoptosis. In a study of 140 Swedish rectal cancer patients, high levels of TAZ was linked to rectal cancer development. Additionally, the levels of TAZ were connected to the radiotherapy response of the patients, potentially offering insight into cancer recurrence in patients. A potential link between PI3K and TAZ indicates a possible association between PI3K signaling and TAZ as both were highly elevated in PTEN mutant cancer cells.
# Interactions
TAZ has been shown to have protein-protein interactions with the following and more.
- FUT11
- BTRC
- NAGA
- NID2
- ANKRD46
- VWDE
- ITGA8
# History
The protein was identified by Italian scientists Silvia Bione et al. in 1996. Owing to the complex procedure required for the identification of tafazzin, the protein was named after "Tafazzi", a masochistic comic character in an Italian television show. | Tafazzin
Tafazzin is a protein that in humans is encoded by the TAZ gene.[1] Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid-lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases).[2][3] It catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties.[4] Several different isoforms of the tafazzin protein are produced from the TAZ gene. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells.[5][1] Mutations in the TAZ gene have been associated with mitochondrial deficiency, Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, left ventricular noncompaction (LVNC), breast cancer, papillary thyroid carcinoma, non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.[1][6][7][8]
# Structure
The TAZ gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs.[1] The TAZ gene produces a 21.3 kDa protein composed of 184 amino acids.[9][10] The structure of the encoded protein has been found to differ at their N terminus and the central region, which are two functionally notable regions. A 30 residue hydrophobic stretch at the N terminus may function as a membrane anchor, which does not exist in the shortest forms of tafazzins. The second region is a variable exposed loop located between amino acids 124 and 195 in the central region. This hydrophilic region is known to interact with other proteins. TAZ has no known resemblance to other proteins.[11]
Tafazzin is encoded by the TAZ gene. It is very unfortunate that a protein called TAZ (a 50kDA protein) which is a part of the Hippo/YAP/TAZ pathway gets confused with Tafazzin due to this misnaming often.
Tafazzin has at least 4 different isoforms. It has a molecular weight around 35kDa but may also appear in lower molecular weights due to species differences in isoform expression.
# Function
The TAZ gene provides instructions for producing a protein called tafazzin, which is located in structures called mitochondria, which are the energy-producing centers of cells. Tafazzin is involved in altering a fat (lipid) called cardiolipin (CL), which plays critical roles in the mitochondrial inner membrane.[5]
## Transacylase (remodeling)
After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. The remodeling process of cardiolipin involves reaching a final acyl composition. TAZ interacts with an immature cardiolipin by adding a fatty acid called linoleic acid, which catalyzes the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation-reacylation cycle. The deacylation-reacylation cycle, also known as the Lands cycle begins with a deacylation mediated by a phospholipase and ends which forms monolyso-CL (MLCL). The cycle ends with a CoA-dependent reacylation. In contrast, transacylation involves the transfer of a linoleic acid (LA) group from phosphatidylcholine (PC) to MLCL. Such enzymatic activity forms lyso-PC and CL, and enriches the specific acyl chain of cardiolipin. The process has been shown to be specific for linoleoyl-containing PC. Such remodeling processes converts cardiolipin into a mature composition that contains a predominance of tetralinoleoyl moieties. The process enables the proper function of cardiolipin.[4][5][12]
## Cardiolipin in mitochondrial structure and function
Cardiolipin is a complex glycerophospholipid which contains 4 acyl groups linked to three glycerol moietie localized in the mitochondrial inner membrane. These acyl groups include oleic acid and linoleic acid. Due to this composition, cardiolipin exhibits a conical structure, which allows for membrane curvature called cristae. Such qualities allow CL to play essential roles in maintaining mitochondrial shape, energy production, and protein transport within cells.[5]
During apoptosis and similar processes, CL is known to act as a platform for proteins and other machinery involved.
## Influence of cardiolipin on the respiratory chain
Cardiolipin has been shown to assist in energy production of the mitochondria. Several proteins in the mitochondrial respiratory chain require CL for optimal function.[13]
CL has been found to be involved in the stabilization of each respiratory chain complex, enabling efficient electron transport.[14] CL assists in forming super-complexes with proteins localized in the inner mitochondrial matrix, which include the ATP/ADP translocase, pyruvate carrier, carnitine carrier, and all of the respiratory chain complexes (I, III,IV, V).[15][16] CL also enables trapping of protons in the intermembrane space, aiding ATP synthase to carry out its function of channeling protons into the mitochondrial matrix.[12]
# Clinical significance
Mutations in the TAZ gene have been associated with a number of mitochondrial deficiencies and associated disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC).[1] TAZ has also been associated with various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.[6][7][8]
## Barth Syndrome
Barth syndrome is an X-linked disease caused by mutations in the TAZ gene.[17][18] More than 160 mutations in the TAZ gene have been found to this disease. It is a rare condition that occurs almost exclusively in males. TAZ gene mutations that cause barth syndrome result in the production of tafazzin proteins with little or no function. As a result, linoleic acid is not added to cardiolipin, which causes problems with normal mitochondrial shape and functions such as energy production and protein transport. Tissues with high energy demands, such as the heart and other muscles, are most susceptible to cell death due to reduced energy production in mitochondria. Additionally, affected white blood cells have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened immune system and recurrent infections. Dysfunctional mitochondria likely lead to other signs and symptoms of Barth syndrome.[5]
Common clinical manifestations include:[5][17][18]
- dilated cardiomyopathy (enlarged and weakened heart)
- muscle weakness
- recurrent infections
- short stature
- endocardial fibroelastosis
- growth retardation
- neutropenia
- organic aciduria (3-methylglutaconic acid)
Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.[17][18]
A c.348C>T mutation resulted in dilated cardiomyopathy with noncompaction of the ventricular myocardium.[19] A frame shift mutation of c.227delC displayed symptoms of neutropenia, cardiomegaly, and other common symptoms of Bath Syndrome.[20] Another a c.C153G mutation resulted in severe metabolic acidosis, cardiomegaly, and other major symptoms of Barth syndrome.[21]
In conclusion, tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL),[22] the signature lipid of the mitochondrial inner membrane. Therefore, a dysfunctioning tafazzin has been found to lead to an impaired mitochondrial respiratory chain. As a result, Barth syndrome patients exhibit defects in cardiolipin metabolism, including aberrant cardiolipin fatty acyl composition, accumulation of monolysocardiolipin (MLCL) and reduced total cardiolipin levels.[23][24] This may lead to acute metabolic decompensation and sudden death. Cardiac transplantation is the only possibility at the present time.[21]
## Dilated cardiomyopathy (DCM)
Some mutations in the TAZ gene cause dilated cardiomyopathy without the other features of Barth syndrome. Dilated cardiomyopathy is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently, often resulting in heart failure. The decreased blood flow can lead to swelling in the legs and abdomen, fluid in the lungs, and an increased risk of blood clots.[5]
## Isolated noncompaction of left ventricular myocardium (INVM)
Mutations in the TAZ gene can cause a heart condition called isolated noncompaction of left ventricular myocardium (INVM). This condition occurs when the lower left chamber of the heart (left ventricle) does not develop correctly. In INVM, the heart muscle is weakened and cannot pump blood efficiently. Abnormal heart rhythms (arrhythmias) can also occur. INVM frequently causes heart failure.[5]
## Cancer
Highly elevated TAZ activity has been linked to tumorigenesis and oncogenic activity. It has also been associated with and various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, and glioma.[6] In breast cancer, TAZ has been shown to be required for cancer cells to sustain self-renewal and create tumors.[25] Additionally, TAZ has been found to be highly expressed in gastric cancer cells resistant to cisplatin. This resistance was identified to be due to the acquired ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT). The findings that TAZ is involved in inducing EMT as well as its high levels in these cancer cells may point to its involvement in gastric cancer.[6][7] High expression of TAZ was also found in rectal cancer and thyroid neoplasms, indicating that TAZ may promote tumorigenesis and inhibit apoptosis.[8] In a study of 140 Swedish rectal cancer patients, high levels of TAZ was linked to rectal cancer development. Additionally, the levels of TAZ were connected to the radiotherapy response of the patients, potentially offering insight into cancer recurrence in patients.[26] A potential link between PI3K and TAZ indicates a possible association between PI3K signaling and TAZ as both were highly elevated in PTEN mutant cancer cells.[6]
# Interactions
TAZ has been shown to have protein-protein interactions with the following and more.[27][17]
- FUT11
- BTRC
- NAGA
- NID2
- ANKRD46
- VWDE
- ITGA8
# History
The protein was identified by Italian scientists Silvia Bione et al. in 1996.[11] Owing to the complex procedure required for the identification of tafazzin, the protein was named after "Tafazzi", a masochistic comic character in an Italian television show. | https://www.wikidoc.org/index.php/TAZ_gene | |
11625c48e52b1b361a586a2f58f6565108828e5f | wikidoc | TGF beta | TGF beta
# Overview
Transforming growth factor beta (TGF-β) is a protein that comes in three isoforms called TGF-β1, TGF-β2 and TGF-β3; it was also the original name for the founding member of this family that is now called TGF-β1. The TGF-β family is part of a superfamily of proteins known as the transforming growth factor beta superfamily, which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic and Vg-1. TGF beta controls proliferation, differentiation, and other functions in most cell types. It can also act as a negative autocrine growth factor.
TGF-β is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types. TGF-β acts synergistically with TGF-α in inducing cellular transformation (MIM 190170). It also acts as a negative autocrine growth factor. Specific receptors for TGF-β activation trigger apoptosis when activated. Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide.
TGF-β1, TGF-β2, and TGF-β3 all function through the same receptor signaling systems.
# The Structure of TGF-β
The peptide structures of the three members of the TGF-β family are highly similar. They are all encoded as large protein precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal signal peptide of 20-30 amino acids that they require for secretion from a cell, a pro-region (called latency associated peptide or LAP), and a 112-114 amino acid C-terminal region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage. The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs. TGF-β has nine cysteine residues that are conserved among its family; eight form disulphide bonds within the molecule to create a cysteine knot structure characteristic of the TGF-β superfamily while the ninth cysteine forms a bond with the ninth cysteine of another TGF-β molecule to produce the dimer. Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β molecules that is exposed at the surface of the molecule and is implicated in receptor binding and specificity of TGF-β.
# Functions
## Role in apoptosis
TGF-ß induces apoptosis in numerous cell types. TGF-ß can induce apoptosis in two ways: The SMAD pathway or the DAXX pathway.
### SMAD pathway
The SMAD pathway is the classical signaling pathway that TGF-ß family members signal through.
In this pathway TGF-ß dimers binds to a type II receptor which recruits and phosphorylates a type I receptor.
The type I receptor then recruits and phosphorylates a receptor regulated SMAD (R-SMAD). SMAD3, an R-SMAD, is implicated in inducing apoptosis.
The R-SMAD then binds to the common SMAD (coSMAD) SMAD4 and forms a heterodimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes, including those to activate the Mitogen-activated protein kinase 8 pathway.
This then triggers apoptosis.
### DAXX pathway
TGF-ß may also trigger apoptosis via the death associated protein 6 (DAXX adapter protein).
DAXX has been shown to associate with and bind to the type II TGF-ß receptor kinase.
## Role in cell cycle
TGF-ß plays a crucial role in the regulation of the cell cycle.
## Role in heart disease
A study at the Saint Louis University School of Medicine has found that cholesterol suppresses the responsiveness of cardiovascular cells to TGF-ß and its protective qualities, thus allowing atherosclerosis to develop. It was also found that statins, drugs that lower cholesterol levels, enhance the responsiveness of cardiovascular cells to the protective actions of TGF-ß, thus helping prevent the development of atherosclerosis and heart disease.
# Types
The primary three are:
- TGF beta 1 - TGFB1 (OMIM 190180)
- TGF beta 2 - TGFB2 (OMIM 190220)
- TGF beta 3 - TGFB3 (OMIM 190230)
- TGFβ4 precursor was discovered as a gene upregulated during pre-menstrual phase in the endometrail stroma(Kothapalli et al. 1997) and called EBAF (endometrial bleeding associated factor). Later independently discovered to be involved in vertebrate embryonic left right asymmetry determination, and given the name lefty2 (also called Lefty A). | TGF beta
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Transforming growth factor beta (TGF-β) is a protein that comes in three isoforms called TGF-β1, TGF-β2 and TGF-β3; it was also the original name for the founding member of this family that is now called TGF-β1. The TGF-β family is part of a superfamily of proteins known as the transforming growth factor beta superfamily, which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic and Vg-1. TGF beta controls proliferation, differentiation, and other functions in most cell types. It can also act as a negative autocrine growth factor.
TGF-β is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types. TGF-β acts synergistically with TGF-α in inducing cellular transformation (MIM 190170). It also acts as a negative autocrine growth factor. Specific receptors for TGF-β activation trigger apoptosis when activated. Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide.
TGF-β1, TGF-β2, and TGF-β3 all function through the same receptor signaling systems.
# The Structure of TGF-β
The peptide structures of the three members of the TGF-β family are highly similar. They are all encoded as large protein precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal signal peptide of 20-30 amino acids that they require for secretion from a cell, a pro-region (called latency associated peptide or LAP), and a 112-114 amino acid C-terminal region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage.[1] The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs.[2] TGF-β has nine cysteine residues that are conserved among its family; eight form disulphide bonds within the molecule to create a cysteine knot structure characteristic of the TGF-β superfamily while the ninth cysteine forms a bond with the ninth cysteine of another TGF-β molecule to produce the dimer.[3] Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β molecules that is exposed at the surface of the molecule and is implicated in receptor binding and specificity of TGF-β.
# Functions
## Role in apoptosis
TGF-ß induces apoptosis in numerous cell types. TGF-ß can induce apoptosis in two ways: The SMAD pathway or the DAXX pathway.
### SMAD pathway
The SMAD pathway is the classical signaling pathway that TGF-ß family members signal through.
In this pathway TGF-ß dimers binds to a type II receptor which recruits and phosphorylates a type I receptor.
The type I receptor then recruits and phosphorylates a receptor regulated SMAD (R-SMAD). SMAD3, an R-SMAD, is implicated in inducing apoptosis.
The R-SMAD then binds to the common SMAD (coSMAD) SMAD4 and forms a heterodimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes, including those to activate the Mitogen-activated protein kinase 8 pathway.
This then triggers apoptosis.
### DAXX pathway
TGF-ß may also trigger apoptosis via the death associated protein 6 (DAXX adapter protein).
DAXX has been shown to associate with and bind to the type II TGF-ß receptor kinase.
## Role in cell cycle
TGF-ß plays a crucial role in the regulation of the cell cycle.
## Role in heart disease
A study at the Saint Louis University School of Medicine has found that cholesterol suppresses the responsiveness of cardiovascular cells to TGF-ß and its protective qualities, thus allowing atherosclerosis to develop. It was also found that statins, drugs that lower cholesterol levels, enhance the responsiveness of cardiovascular cells to the protective actions of TGF-ß, thus helping prevent the development of atherosclerosis and heart disease. [2]
# Types
The primary three are:
- TGF beta 1 - TGFB1 (OMIM 190180)
- TGF beta 2 - TGFB2 (OMIM 190220)
- TGF beta 3 - TGFB3 (OMIM 190230)
- TGFβ4 precursor was discovered as a gene upregulated during pre-menstrual phase in the endometrail stroma(Kothapalli et al. 1997) and called EBAF (endometrial bleeding associated factor). Later independently discovered to be involved in vertebrate embryonic left right asymmetry determination, and given the name lefty2 (also called Lefty A). | https://www.wikidoc.org/index.php/TGF-beta |
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