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Geriatric trauma in the State of Illinois: substance use and injury patterns. As the elderly population increases and they lead more active and healthy lifestyles, their exposure to the threats of injury multiply. Undoubtedly, the geriatric population will comprise a growing percentage of trauma patients. The role of alcohol and drug use in geriatric trauma has not been clearly defined. The purpose of this study is to determine the incidence of alcohol and illicit drug use in association with mechanism of injury in all elderly trauma patients presenting to level I and II trauma centers in the State of Illinois over 3 years. A retrospective analysis was performed on 3 years of data (January 1, 1994 to December 31, 1996), provided by the Illinois Department of Public Health as the Illinois Trauma Registry, which describes consecutive trauma patients presenting to level I and II trauma facilities in the State of Illinois. During the study period, there were a total of 134,846 trauma patient entries. Of these 32,382 (24.0%) were for patients 65 years of age or older. In those patients 65 and older, 1699 (5.2%) were tested for the presence of alcohol and 845 (49.7%) tested positive. Of the elderly patients who tested positive for alcohol, 71.8% were considered intoxicated (BAC >80 mg/dL). Urine toxicology screens were performed on 1785 (5.5%) elderly trauma patients, and 208 (11.6%) were positive. Besides alcohol, benzodiazipines and opiates were the most frequently detected drugs. For elderly patients under the influence of alcohol falls (49.5%) and motor vehicle crashes (36.7%) were the most common mechanism of injury. For geriatric patients testing negative for alcohol, motor vehicle crashes were a much more common mechanism of injury than falls (65.0% v 25.1%). Falls were a much more common cause of injury in elderly patients using alcohol than in those not using alcohol. Alcohol and substance abuse are possibly significant factors in geriatric trauma. Although only 5% of elderly trauma patients were tested for alcohol, nearly half had alcohol present on presentation to a trauma center, and the majority of these patients were intoxicated. Prospective studies are needed to determine the true incidence of alcohol use/abuse in the geriatric trauma population and the need for routine alcohol screening of these patients. Detection of alcohol abuse in elderly trauma patients could help identify individuals in need of counseling and rehabilitative treatment. It may also reduce future injuries in these patients.
Bright-light exposure during daytime sleeping affects nocturnal melatonin secretion after simulated night work. The guidelines for night and shift workers recommend that after night work, they should sleep in a dark environment during the daytime. However, staying in a dark environment during the daytime reduces nocturnal melatonin secretion and delays its onset. Daytime bright-light exposure after night work is important for melatonin synthesis the subsequent night and for maintaining the circadian rhythms. However, it is not clear whether daytime sleeping after night work should be in a dim- or a bright-light environment for maintaining melatonin secretion. The aim of this study, therefore, was to evaluate the effect of bright-light exposure during daytime sleeping on nocturnal melatonin secretion after simulated night work. Twelve healthy male subjects, aged 24.8 ± 4.6 (mean ± SD), participated in 3-day sessions under two experimental conditions, bright light or dim light, in a random order. On the first day, the subjects entered the experimental room at 16:00 and saliva samples were collected every hour between 18:00 and 00:00 under dim-light conditions. Between 00:00 and 08:00, they participated in tasks that simulated night work. At 10:00 the next morning, they slept for 6 hours under either a bright-light condition (>3000 lx) or a dim-light condition (<50 lx). In the evening, saliva samples were collected as on the first day. The saliva samples were analyzed for melatonin concentration. Activity and sleep times were recorded by a wrist device worn throughout the experiment. In the statistical analysis, the time courses of melatonin concentration were compared between the two conditions by three-way repeated measurements ANOVA (light condition, day and time of day). The change in dim light melatonin onset (ΔDLMO) between the first and second days, and daytime and nocturnal sleep parameters after the simulated night work were compared between the light conditions using paired t-tests. The ANOVA results indicated a significant interaction (light condition and3 day) (p = .006). Post hoc tests indicated that in the dim-light condition, the melatonin concentration was significantly lower on the second day than on the first day (p = .046); however, in the bright-light condition, there was no significant difference in the melatonin concentration between the days (p = .560). There was a significant difference in ΔDLMO between the conditions (p = .015): DLMO after sleeping was advanced by 11.1 ± 17.4 min under bright-light conditions but delayed for 7.2 ± 13.6 min after sleeping under dim-light conditions. No significant differences were found in any sleep parameter. Our study demonstrated that daytime sleeping under bright-light conditions after night work could not reduce late evening melatonin secretion until midnight or delay the phase of melatonin secretion without decreasing the quality of the daytime sleeping. Thus, these results suggested that, to enhance melatonin secretion and to maintain their conventional sleep-wake cycle, after night work, shift workers should sleep during the daytime under bright-light conditions rather than dim-light conditions.
Intestinal absorption, blood transport and hepatic and muscle metabolism of fatty acids in preruminant and ruminant animals. Current research on lipid metabolism in ruminants aims to improve the growth and health of the animals and the muscle characteristics associated with meat quality. This review, therefore, focuses on fatty acid (FA) metabolism from absorption to partitioning between tissues and metabolic pathways. In young calves, which were given high-fat milk diets, lipid absorption is delayed because the coagulation of milk caseins results in the retention of dietary fat as an insoluble clot in the abomasum. After weaning, the calves were fed forage- and cereal-based diets containing low levels of long-chain fatty acids (LCFA) but leading to high levels of volatile fatty acid (VFA) production by the rumen microflora. Such differences in dietary FA affect: i) the lipid transport system via the production of lipoproteins by the intestine and the liver, and (ii) the subsequent metabolism of lipids and FA by tissues. In preruminant calves, high-fat feed stimulates the secretion of triacylglycerols (TG)-rich lipoproteins (chylomicrons, very-low density lipoproteins (VLDL)). Diets rich in polyunsaturated FA (PUFA) stimulate the production of chylomicrons by the intestine (at peak lipid absorption) and of high density lipoproteins by the liver, leading to high blood concentrations of cholesterol. High levels of non-esterified FA (NEFA) uptake by the liver in high-yielding dairy cows in early lactation leads to TG infiltration of the hepatocytes (fatty liver). This is due to the low chronic capacity of the liver to synthesise and secrete VLDL particles. This abnormality in hepatic FA metabolism involves defects in apolipoprotein B synthesis and low availability of apolipoproteins and lipids for VLDL packaging. Fatty liver in calves is also caused by milk containing either soybean oil (rich in n-6 PUFA), or coconut oil (rich in C12:0 and C14:0). The ability of muscle tissue to use FA as an energy source depends on its mitochondrial content and, hence, on many physiological factors. The uptake and partitioning of LCFA between oxidation and storage in muscle is regulated by the activity of key intracellular enzymes and binding proteins. One such protein, carnitine palmitoyltransferase I (CPT I) controls the transport of LCFA into mitochondria. Metabolites derived from LCFA inhibit glucose oxidation, decrease the activity of CPT I and decrease the efficiency of ATP production by mitochondria. Most research on tissue lipid metabolism in ruminants is focused on: i) the partitioning of FA oxidation between intracellular peroxisomes and mitochondria in the liver and in muscles; (ii) the regulation of lipid metabolism by leptin, a recently discovered hormone secreted by mature adipocytes; and iii) the effects of activation of the nuclear receptors (PPARs and RXR) by LCFA or by phytol metabolites derived from chlorophyll.
Establishing the need for an engineering standard for agricultural hitch pins. Documented incidents have occurred in which failure or unintentional disengagement of agricultural hitch pins has contributed to property damage and personal injury. An examination of current hitch pin use on a convenience sample of farm operations in Indiana revealed a variety of non-standard, worn and damaged, and inappropriately sized hitch pins in use. Informal interviews with the farm operators confirmed that hitch pin misuse, failure, or disengagement is a relatively widespread problem that remains largely unaddressed. On-site observations also suggested a low use of hitch pin retaining devices or safety chains. A review of prior research revealed that little attention has been given to this problem, and currently no documentation allows for an estimate of the frequency or severity of losses associated with hitch pin misuse, failure, or disengagement. No specific engineering standards were found that directly applied to the design, appropriate selection, or loading capacity of agricultural hitch pins. Major suppliers of replacement hitch pins currently provide little or no information on matching hitch pin size to intended applications, and most replacement hitch pins examined were of foreign origin, with the overwhelming majority imported from China or India. These replacement hitch pins provided no specifications other than diameter, length, and, in some cases, labeling that indicated that the pins had been "heat treated. " Testing of a sample of 11 commercially available replacement hitch pins found variation along the length of the pin shaft and between individual pins in surface hardness, a potential predictor of pin failure. Examination of 17 commercially available replacement pins also revealed a variety of identifiers used to describe pin composition and fabrication methods, e.g., "heat treated." None of the pins examined provided any specifications on loading capacity. It was therefore concluded that there is a need to develop an agricultural hitch pin engineering standard that would reflect current agricultural applications and practices and that would be promoted to both original equipment manufacturers and manufacturers and suppliers of replacement hitch pins. The standard should address the design of composite pins, heat treating, surface hardening, loading capacity and labeling of such, incorporation of unintentional disengagement prevention devices, indicators of the need for replacement due to wear, and safety information that should be included in operator instructions. ASABE is the most appropriate organization to develop such a standard. It was also concluded that agricultural safety and health programs and professionals need to raise the awareness of farmers concerning the appropriate selection and use of agricultural hitch pins, including the need to replace non-standard pins with pins less likely to fail or disengage during use, the need to replace hitch pins with indications of potential failure, and the importance of using appropriate safety chains, especially during transport of equipment behind tractors and trucks on public roads.
Morphologic changes in the upper airway of children during awakening from propofol administration. The purpose of this study was to determine the morphologic changes that occur in the upper airway of children during awakening from propofol sedation. Children undergoing magnetic resonance imaging of the head underwent additional scans of the upper airway during deep sedation with propofol; this was repeated on awakening. Axial views were obtained at the most posterior sites of the pharynx at the levels of the soft palate and tongue. Measurements were then obtained of the anterior-posterior (A-P) diameter, transverse diameter, and cross-sectional areas at these levels. Data were obtained on 16 children, aged 10 months to 7 yr. In both sedated and awakening states, most children had the smallest cross-sectional area of the pharynx at the level of the soft palate. During the sedated state, at the soft palate level, the transverse diameter was most narrow in 11 children, the A-P diameter was most narrow in 1 child, and they were equal in 2 children. During the sedated state, at the level of the tongue, the transverse diameter was most narrow in 9 children, the A-P diameter was most narrow in 5 children, and they were equal in 2 children. During awakening, at the soft palate level, the transverse diameter was most narrow in none of the children, the A-P diameter was most narrow in 13 children, and they were equal in 1 child. At the level of the tongue, the transverse diameter was most narrow in 4 children, and the A-P diameter was most narrow in 12 children. During awakening, the A-P diameter of the pharynx at the level of the soft palate decreased in 12 children, increased in 1 child, and remained the same in 1 child. (P < 0.001). The transverse diameter increased in 11 children, decreased in 1 child, and remained the same in 2 children (P = 0.001). The cross-sectional area at the level of the soft palate increased in 4 children, decreased in 8 children, and stayed the same in 2 children (P = 0.5). During awakening, the A-P diameter of the pharynx at the level of the tongue decreased in 11 children, increased in 4 children, and remained the same in 1 child. (P = 0.01). The transverse diameter increased in 11 children and decreased in 5 children (P = 0.07). The cross-sectional area at the level of the tongue increased in 7 children, decreased in 7 children, and stayed the same in 2 children (P = 0.9). The dimensions of the upper airways of children change shape significantly on awakening from propofol sedation. When sedated, the upper airway is oblong shaped, with the A-P diameter larger than the transverse diameter. On awakening, the shape of the upper airway in most children changed such that the transverse diameter was larger. Cross-sectional areas between sedated and awakening states were unchanged. These changes may reflect the differential effects of propofol on upper airway musculature during awakening.
Scalpel versus electrosurgery for abdominal incisions. Scalpels or electrosurgery can be used to make abdominal incisions. The potential benefits of electrosurgery include reduced blood loss, dry and rapid separation of tissue, and reduced risk of cutting injury to surgeons, though there are concerns about poor wound healing, excessive scarring, and adhesion formation. To compare the effects on wound complications of scalpel and electrosurgery for making abdominal incisions. We searched the Cochrane Wounds Group Specialised Register (searched 24 February 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 2); Ovid MEDLINE (1950 to February Week 3 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 23 February 2012); Ovid EMBASE (1980 to 2012 Week 07); and EBSCO CINAHL (1982 to 17 February 2012). We did not apply date or language restrictions. Randomised controlled trials (RCTs) comparing the effects on wound complications of electrosurgery with scalpel use for the creation of abdominal incisions. The study participants were patients undergoing major open abdominal surgery, regardless of the orientation of the incision (vertical, oblique, or transverse) and surgical setting (elective or emergency). Electrosurgical incisions included those in which the major layers of abdominal wall, including subcutaneous tissue and musculoaponeurosis (a strong sheet of fibrous connective tissue that serves as a tendon to attach muscles), were made by electrosurgery, regardless of the techniques used to incise the abdominal skin and peritoneum. Scalpel incisions included those in which all major layers of abdominal wall including skin, subcutaneous tissue, and musculoaponeurosis, were incised by a scalpel, regardless of the techniques used on the abdominal peritoneum. We independently assessed studies for inclusion and risk of bias. One review author extracted data which were checked by a second review author. We calculated risk ratio (RR) and 95% confidence intervals (CI) for dichotomous data, and difference in means (MD) and 95% CI for continuous data. We examined heterogeneity between studies. We included nine RCTs (1901 participants) which were mainly at unclear risk of bias due to poor reporting. There was no statistically significant difference in overall wound complication rates (RR 0.90, 95% CI 0.68 to 1.18), nor in rates of wound dehiscence (RR 1.04, 95% CI 0.36 to 2.98), however both these comparisons are underpowered and a treatment effect cannot be excluded. There is insufficient reliable evidence regarding the effects of electrosurgery compared with scalpel incisions on blood loss, pain, and incision time. Current evidence suggests that making an abdominal incision with electrosurgery may be as safe as using a scalpel. However, these conclusions are based on relatively few events and more research is needed. The relative effects of scalpels and electrosurgery are unclear for the outcomes of blood loss, pain, and incision time.
Influence of age, sex and blood pressure on the principal endpoints of the Nordic Diltiazem (NORDIL) Study. The aim of the Nordic Diltiazem (NORDIL) Study was to compare patients with essential hypertension receiving calcium-antagonist-based treatment with diltiazem and similar patients receiving conventional diuretic/beta-blocker-based treatment, with respect to cardiovascular morbidity and mortality. To assess the influence of age, sex, severity of hypertension and heart rate on treatment effects, in a sub-analysis. The NORDIL study was prospective, randomized, open and endpoint-blinded. It enrolled, at health centres in Norway and Sweden, 10 881 patients aged 50-74 years who had diastolic blood pressure (DBP) of 100 mmHg or more. Systolic blood pressure (SBP) and DBP were decreased by 20.3/18.7 mmHg in the diltiazem group and by 23.3/18.7 mmHg in the diuretic/beta-blocker group - a significant difference in SBP (P < 0.001). The incidence of the primary endpoint - a composite of cardiovascular death, cerebral stroke and myocardial infarction - was similar for the two treatments. Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 patients in the conventional treatment group [relative risk (RR) 0.80, 95% confidence interval (CI) 0.65 to 0.99; P = 0.040], whereas there was a non-significant inverse tendency with respect to all myocardial infarction. There were significantly fewer cerebral strokes in patients receiving diltiazem in the subgroups with baseline SBP > 170 mmHg (n = 5420, RR 0.75, 95% CI 0.58 to 0.98; P = 0.032), DBP >/= 105 mmHg (n = 5881, RR 0.74, 95% CI 0.57 to 0.97; P = 0.030) and pulse pressure >/= 66 mmHg (n = 5461, RR 0.76, 95% CI 0.58 to 0.99, P = 0.041), and more myocardial infarctions in those with heart rate less than 74 beats/min (n = 5303, RR 1.13, 95% CI 1.01 to 1.87; P = 0.040). However, the tendencies for fewer strokes and greater incidence of myocardial infarction were present across subgroups when results were analysed for age, sex, severity of hypertension and heart rate, and treatment-subgroup interaction analyses were not statistically significant. Compared with a conventional diuretic/beta-blocker-based antihypertensive regimen, there were additional 25% reductions in stroke in the diltiazem-treated patients with blood pressure or pulse pressure greater than the medians, and an increase in myocardial infarction in those with heart rate less than the median. Such findings may be attributable to chance, but the consistency of, in particular, the stroke findings may also suggest an ability of diltiazem, beyond conventional treatment, to prevent cerebral stroke in hypertensive patients with the greatest cardiovascular risk.
Cardiovascular risk of essential hypertension: influence of class, number, and treatment-time regimen of hypertension medications. A number of observational studies have found that treated hypertensive patients, even those with controlled clinic blood pressure (BP), might have poorer prognosis than untreated hypertensives. Different trials have also shown that relatively low cardiovascular disease (CVD) risk cannot be achieved in high-risk hypertensive patients, leading to the belief they have a "residual CVD risk" that cannot be attenuated by conventional treatment. All these conclusions disregard the facts that the correlation between BP level and CVD risk is stronger for ambulatory than clinic BP and that the BP-lowering efficacy and effects on the 24-h BP pattern of different classes of hypertension medications exhibit statistically and clinically significant treatment-time (morning versus evening) differences. Accordingly, we evaluated the potential differential administration-time-dependent effects on CVD risk of the various classes of hypertension medications and the number of them used for therapy in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study, a prospective, open-label, blinded-endpoint trial on 2156 hypertensive patients (1044 men/1112 women), 55.6 ± 13.6 (mean ± SD) yrs of age, randomized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. Ambulatory BP was measured for 48 h at baseline, and again annually or more frequently (quarterly) when adjustment of treatment was necessary to achieve ambulatory, i.e., awake and asleep, BP control. CVD risk according to the number and classes of medications used at the final evaluation was calculated by comparison with that of 734 normotensive subjects who were identically followed and remained untreated. After a median follow-up of 5.6 yrs, CVD risk of hypertensive patients randomized to ingest all medications upon awakening was progressively higher with increase in the number of medications (adjusted hazard ratio [HR]: 1.75, 2.26, 3.02, and 4.18 in patients treated with 1, 2, 3, and ≥4 medications daily, respectively; p < .001 compared with normotensive subjects). CVD risk was markedly lower in patients ingesting ≥1 medications at bedtime (HR: .35, 1.45, .94, and 2.28 with 1, 2, 3, and ≥4 medications daily, respectively), and even lower in patients ingesting all medications at bedtime (HR: .35, .39, .87, and .79 with 1, 2, 3, and ≥4 medications daily, respectively). Patients ingesting ≥1 medications at bedtime evidenced significantly lower CVD risk than those ingesting all medications upon awakening, independent of class. Greater benefits were observed for bedtime compared with awakening treatment with angiotensin-II receptor blockers (ARBs) (HR: .29 [95% confidence interval, CI .17-.51]; p < .001) and calcium channel blockers (HR: .46 [95% CI: .31-.69]; p < .001). CVD risk was similar for all six classes of tested hypertension medications in patients randomized to ingest all of them upon awakening. Among patients randomized to ingest ≥1 medications at bedtime, however, ARBs were associated with significantly lower HR of CVD events than ingestion of any other class of medication also at bedtime (p < .017). We document significantly reduced CVD risk among hypertensive patients ingesting medications at bedtime, independent of the number of hypertension medications required to achieve proper ambulatory BP control. These findings challenge the current belief of "residual CVD risk," as a bedtime-treatment regimen of current hypertension medications, even in risk-high patients, can reduce such risk.
Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model. Inadequate blood supply of pedicle flaps results in partial necrosis, and prolonged ischemia during free-tissue transfer can result in partial or complete flap necrosis. Recent research in the field of cardiovascular surgery has shown that ischemic preconditioning (repeated brief episodes of coronary artery occlusion followed by reperfusion) improves myocardial muscle survival when the heart is subsequently subjected to prolonged ischemia. Preconditioning of skin or myocutaneous flaps as either pedicle or free flap models has never been studied. The goal of this investigation was to measure the effect of ischemic preconditioning on myocutaneous and skin flap survival areas and total necrosis rates after variable periods of global ischemia. In 220 rats, 100 transverse rectus abdominis myocutaneous flaps and 120 dorsal cutaneous flaps were randomized into treatment and control groups. The treatment flaps underwent preconditioning by three cycles of 10 minutes of pedicle clamping followed by 10 minutes of reperfusion for a total preconditioning period of 1 hour. The control flaps were perfused without clamping for 1 hour. Both control and treatment flaps then underwent global ischemia for 0, 2, 4, 6, 10, or 14 hours by pedicle clamping. Flap survival area was measured on the fifth postoperative day. Statistical analysis was performed with analysis of variance, student's t tests, and probit analysis. Preconditioning improved survival areas of pedicle myocutaneous flaps (0-hour group) from 47 +/- 16 percent (mean percent area surviving +/- SD) to 63 +/- 5 percent. This difference was statistically significant (t test, p < 0.04). There was no statistically significant improvement in pedicle skin flap survival. For free flap models (flaps undergoing global ischemia), preconditioning increased the survival areas of skin and myocutaneous flaps (analysis of variance, p < 10(-5)). For the skin flap model, statistical significance of the survival area difference was reached at 6, 10, and 14 hours of ischemia (t test, p < 10(-4)). The magnitude of this effect was higher in the myocutaneous flap model and reached statistical significance at 2, 4, 6, and 10 hours of ischemia (p < 10(-3)). Preconditioned flap survival areas were increased by two to five times that of non-preconditioned flaps at these ischemia times. Preconditioning lowered total necrosis rates at all ischemia times for both flap models. The critical ischemia time when 50 percent of skin flaps became totally necrotic (CIT50) improved from 6.9 to 12.4 hours by preconditioning. Similarly, preconditioning improved the CIT50 of myocutaneous flaps from 3.6 to 9.2 hours. For the first time, statistically significant improvements of partial necrosis areas and total necrosis rates have been demonstrated through intraoperative ischemic preconditioning of skin and myocutaneous flaps. In clinical practice, application of this technique may lead to improved survival during pedicled or free transfer of myocutaneous flaps and free transfer of skin flaps.
Factors contributing to the modulation of norepinephrine uptake by synaptosomes from mouse brain cortex. The mode of inheritance of the synaptosomal mechanism for uptake of norepinephrine (NE) was studied in two inbred strains of mice, BALB/cBY and C57BL/6BY, along with the reciprocal F1 hybrids and 7 recombinant inbred strains, CXBD, CXBE, CXBG,CXBH,CXBI,CXBJ and CXBK. All these strains were also tested in the open field as a measure of response to mild stress, since stress had been shown to affect the kinetic constants of synaptosomal uptake. The two parental strains show a significant difference in Km for NE uptake similar to that previously reported between BALB/cJ and C57BL/10J, and no significant difference in V max. The F1 hybrids resemble C57BL/6BY, and the recombinant inbred strains show no significant differences from either parent with only minor exceptions. This makes further genetic analysis impossible with the data available at this time. A high positive correlation exists between Km and Vmax (r=0.89). The affinity for NE uptake and the number of uptake sites available seem to be modulated in a coordinated fashion. When the data on Km for all strains tested are pooled, a bimodal distribution is apparent. There are two populations with means of 2.25 and 4.03 x 10-7 M, respectively. Analysis of open field ambulation enables the strains to be divided into a high (C57BL/6BY, BXCF1, CXBF1, CXBD, CXBE, and CXBK) and a low group (BALB/cBY, CXBG, CXGH, CXGI and CXBJ). There is a significant negative interstrain correlation (r=0.87) between open field ambulation and Km for NE uptake. If we take open field ambulation as an index of reactivity to stress (high ambulation-low reactivity and vice versa), then we can regroup the data on NE uptake into two categories: 78% of the mice from the highly reactive strains presents high Km for NE uptake, while only 35% of the non-reactive mice show high Km. The bimodal distribution is apparent in both cases and the means of both high Km groups are identical; the same is true of the means for both low Km groups of strains of mice. It appears that Km for NE uptake does not vary along a continuum but it presents two discrete values. This would be suggestive of the existence of two distinct conformational states for the presumably proteinic uptake site. Stress presumably causes a switch from the high affinity conformation to the low affinity conformation. Thus a higher percentage of individuals from strains highly reactive to stress shows low affinity for NE uptake.
What is the Likelihood of Subsequent Arthroplasties after Primary TKA or THA? Data from the Osteoarthritis Initiative. Osteoarthritis is common and debilitating, in part because it often affects more than one large weightbearing joint. The likelihood of undergoing more than one total joint arthroplasty has not been studied in a heterogeneous, multicenter population in the United States. We used prospectively collected data of patients with osteoarthritis from the multicenter Osteoarthritis Initiative (OAI) project to ask (1) What is the likelihood of a subsequent THA or TKA after primary TKA or THA? (2) What risk factors are associated with undergoing contralateral TKA after primary TKA? Longitudinally maintained data from the OAI were used to identify 332 patients who underwent primary TKA and 132 patients who underwent primary THA for osteoarthritis who did not have a previous TKA or THA in this retrospective study. OAI was a longitudinal cohort study of knee osteoarthritis conducted at five centers in the United States (Columbus, OH, USA; Pittsburgh, PA, USA; Baltimore, MD, USA; Pawtucket, RI, USA; and San Francisco, CA, USA). In this study, the mean follow-up time was 4.0 ± 2.3 years, with 24% (112 of 464) followed for less than 2 years. The primary outcome was the cumulative incidence of subsequent arthroplasty calculated using the Kaplan-Meier method. Age, BMI, gender, and contralateral Kellgren-Lawrence grade, medial joint space width, and hip-knee-ankle angles were modeled as risk factors of contralateral TKA using Cox proportional hazards. Using the Kaplan-Meier method, at 8 years the cumulative incidence of contralateral TKA after the index TKA was 40% (95% CI 31 to 49) and the cumulative incidence of any THA after index TKA was 13% (95% CI 5 to 21). The cumulative incidence of contralateral THA after the index THA was 8% (95% CI 2 to 14), and the cumulative incidence of any TKA after index THA was 32% (95% CI 15 to 48). Risk factors for undergoing contralateral TKA were younger age (HR 0.95 for each year of increasing age [95% CI 0.92 to 0.98]; p = 0.001) and loss of medial joint space width with a varus deformity (HR 1.26 for each 1 mm loss of joint space width at 1.6 varus [1.06 to 1.51]; p = 0.005). Patients who underwent TKA or THA for osteoarthritis had a high rate of subsequent joint arthroplasties in this study conducted at multiple centers in the United States. The rate of subsequent joint arthroplasty determined in this study can be used to counsel patients in similar settings and institutions, and may serve as a benchmark to assess future osteoarthritis disease-modifying interventions. Level III, therapeutic study.
Dynamics of HIV infection of CD4+ T cells. We examine a model for the interaction of HIV with CD4+ T cells that considers four populations: uninfected T cells, latently infected T cells, actively infected T cells, and free virus. Using this model we show that many of the puzzling quantitative features of HIV infection can be explained simply. We also consider effects of AZT on viral growth and T-cell population dynamics. The model exhibits two steady states, an uninfected state in which no virus is present and an endemically infected state, in which virus and infected T cells are present. We show that if N, the number of infectious virions produced per actively infected T cell, is less a critical value, Ncrit, then the uninfected state is the only steady state in the nonnegative orthant, and this state is stable. For N > Ncrit, the uninfected state is unstable, and the endemically infected state can be either stable, or unstable and surrounded by a stable limit cycle. Using numerical bifurcation techniques we map out the parameter regimes of these various behaviors. oscillatory behavior seems to lie outside the region of biologically realistic parameter values. When the endemically infected state is stable, it is characterized by a reduced number of T cells compared with the uninfected state. Thus T-cell depletion occurs through the establishment of a new steady state. The dynamics of the establishment of this new steady state are examined both numerically and via the quasi-steady-state approximation. We develop approximations for the dynamics at early times in which the free virus rapidly binds to T cells, during an intermediate time scale in which the virus grows exponentially, and a third time scale on which viral growth slows and the endemically infected steady state is approached. Using the quasi-steady-state approximation the model can be simplified to two ordinary differential equations the summarize much of the dynamical behavior. We compute the level of T cells in the endemically infected state and show how that level varies with the parameters in the model. The model predicts that different viral strains, characterized by generating differing numbers of infective virions within infected T cells, can cause different amounts of T-cell depletion and generate depletion at different rates. Two versions of the model are studied. In one the source of T cells from precursors is constant, whereas in the other the source of T cells decreases with viral load, mimicking the infection and killing of T-cell precursors.(ABSTRACT TRUNCATED AT 400 WORDS)
Control of oxidation-reduction potentials in flavodoxin from Clostridium beijerinckii: the role of conformation changes. X-ray analyses of wild-type and mutant flavodoxins from Clostridium beijerinckii show that the conformation of the peptide Gly57-Asp58, in a bend near the isoalloxazine ring of FMN, is correlated with the oxidation state of the FMN prosthetic group. The Gly-Asp peptide may adopt any of three conformations: trans O-up, in which the carbonyl oxygen of Gly57 (O57) points toward the flavin ring; trans O-down, in which O57 points away from the flavin; and cis O-down. Interconversions among these conformers that are linked to oxidation-reduction of the flavin can modulate the redox potentials of bound FMN. In the semiquinone and reduced forms of the protein, the Gly57-Asp58 peptide adopts the trans O-up conformation and accepts a hydrogen bond from the flavin N5H [Smith, W. W., Burnett, R. M., Darling, G. D., & Ludwig, M. L. (1977) J. Mol. Biol. 117, 195-225; Ludwig, M. L., & Luschinsky, C. L. (1992) in Chemistry and Biochemistry of Flavoenzymes III (Müller, F., Ed.) pp 427-466, CRC Press, Boca Raton, FL]. Analyses reported in this paper confirm that, in crystals of wild-type oxidized C. beijerinckii flavodoxin, the Gly57-Asp58 peptide adopts the O-down orientation and isomerizes to the cis conformation. This cis form is preferentially stabilized in the crystals by intermolecular hydrogen bonding to Asn137. Structures for the mutant Asn137Ala indicate that a mixture of all three conformers, mostly O-down, exists in oxidized C. beijerinckii flavodoxin in the absence of intermolecular hydrogen bonds. Redox potentials have been manipulated by substitutions that alter the conformational energies of the bend at 56M-G-D-E. The mutation Asp58Pro was constructed to study a case where energies for cis-trans conversion would be different from that of wild type. Intermolecular interactions with Asn137 are precluded in the crystal, yet Gly57-Pro58 is cis, and O-down, when the flavin is oxidized. Reduction of the flavin induces rearrangement to the trans O-up conformation. Redox potential shifts reflect the altered energies associated with the peptide rearrangement; E(ox/sq) decreases by approximately 60 mV (1.3 kcal/mol). Further, the results of mutation of Gly57 agree with predictions that a side chain at residue 57 should make addition of the first electron more difficult, by raising the energy of the O-up conformer that forms when the flavin is reduced to its semiquinone state. The ox/sq potentials in the mutants Gly57Ala, Gly57Asn, and Gly57Asp are all decreased by approximately 60 mV (1.3 kcal/mol). Introduction of the beta-branched threonine side chain at position 57 has much larger effects on the conformations and potentials. The Thr57-Asp58 peptide adopts a trans O-down conformation when the flavin is oxidized; upon reduction to the semiquinone, the 57-58 peptide rotates to a trans O-up conformation resembling that found in the wild-type protein. Changes in FMN-protein interactions and in conformational equilibria in G57T combine to decrease the redox potential for the ox/sq equilibrium by 180 mV (+4.0 kcal/mol) and to increase the sq/hq potential by 80 mV (-1.7 kcal/mol). A thermodynamic scheme is introduced as a framework for rationalizing the properties of wild-type flavodoxin and the effects of the mutations.
NTP Toxicology and Carcinogenesis Studies of 2-Chloroethanol (Ethylene Chlorohydrin) (CAS No. 107-07-3) in F344/N Rats and Swiss CD-1 Mice (Dermal Studies). Toxicology and carcinogenesis studies of 2-chloroethanol (99% pure), an industrial chemical and an intermediate in the synthesis of ethylene oxide, were conducted by dermal application of 2-chloroethanol dissolved in 70% ethanol:30% water (v/v) solutions to groups of 50 F344/N rats of each sex at doses of 0, 50, or 100 mg/kg for 103 weeks or to groups of 50 Swiss CD-1 mice of each sex at doses of 0, 7.5, or 15 mg per animal for 104 weeks (0, 253, or 630 mg/kg at week 1; 0, 180, 411 mg/kg at week 100). The control groups received skin applications of the vehicle; the mouse studies also included untreated control groups of 50 male and 50 females. 2-Chloroethanol solutions were applied to the clipped interscapular area of the animals once daily, 5 days per week for the test period. Rats received a volume of 0.18-0.22 ml of solution; mice received 0.10 ml of solution. In the 13-week studies, mortality was observed in male and female rats receiving 20 mg per day and higher. In the 104-week studies, the survival of high dose male mice was lower (P<0.05) than that of the vehicle controls (vehicle control, 26/50; 7.5 mg, 16/50; 15 mg, 12/50). Body weights of dosed mice were unaffected by 2-chloroethanol. The survival and body weight gain data suggest that the male and female rats and female mice could have tolerated a higher dose of 2-chloroethanol. Male mice probably could not have tolerated a higher dose than was applied to the skin. Seven high dose male mice died within 3 days of the start of dosing; all of these had inflammation at the site of dermal application. Five also had ulceration at the site of dermal application, and five had lung congestion, inflammation, or hemorrhage. Marginal increases were found in the incidence of lymphomas or leukemias (combined) as well as in the incidence of alveolar/bronchiolar adenomas or carcinomas (combined) in low dose male mice. Since there was no dose-related trend for these tumor incidences and because the increases were observed in only one sex, the increases were not considered to be related to the dermal application of 2-chloroethanol. 2-Chloroethanol was mutagenic in Salmonella typhimurium strains TA100 and TA1535 (but not TA1537 or TA98) in either the presence or the absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. 2-Chloroethanol did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these 2-year studies. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenicity of 2-chloroethanol for male and female F344/N rats given 50 or 100 mg/kg per day or for male and female Swiss CD-1 mice given 7.5 or 15 mg per animal per day. Synonyms: ethylene chlorohydrin; chloroethanol; glycol chlorohydrin; b-chloroethanol
Chromophore/DNA interactions: femto- to nanosecond spectroscopy, NMR structure, and electron transfer theory. The mechanism of photoinduced hole injection into DNA has been studied using an integrated approach that combines NMR structural analysis, time-resolved spectroscopy, and quantum-chemical calculations. A covalently linked acridinium derivative, the protonated 9-amino-6-chloro-2-methoxyacridine (X+), is replacing a thymine and separated from either guanine (G) or the easier to oxidize 7-deazaguanine (Z) by one adenine.thymine (A.T) base pair. The key features of this donor/acceptor system are the following: (i) In more than 95% of the duplexes, X+ is located in a central, coplanar position between the neighboring A.T base pairs with its long axis in parallel showing minimal twist and tilt angles (<15 degrees). The complementary adenine base is turned out into the extrahelical space. In a minority of less than 5%, X+ is found to be still attached to the duplex. X+ is most probably associated with one of the phosphates, since it is neither intercalated between more remote base pairs nor bound to sugars or grooves. This minority characterized by an excited state lifetime >10 ns gives rise to a small background signal in time-resolved measurements and contributes predominantly to steady-state fluorescence spectra. (ii) Although the intercalation mode of X+ is well defined, the NMR structure reveals that there are two conformations of X+ with respect to the arrangement of its methoxy substituent. In one conformation, the methoxy group is in the plane of the chromophore, while, in the other extraplanar conformation, the methoxy group forms an angle of 70 degrees with the acridinium ring. The fluorescence decay of 5'-ZAX and 5'-GAX tracts can be fitted to a biexponential function with similar amplitudes, reflecting the oxidation dynamics of G and Z, with the slower rate being determined by larger thermal activation energy. The attribution of biexponential electron transfer (ET) dynamics to the bimodal orientation of the methoxy group at the acridinium is supported by quantum-chemical calculations. These predict a larger free energy change for hole transfer in the nonplanar conformation as compared to the planar one, whereas the difference in the electronic couplings is negligible. (iii) Kinetic studies of the directionality of the 1(X+)* induced hole injection reveal similarly fast decay components in both directions of the duplex, that is, in 5'-ZAX and 5'-XAZ, with the amplitude of the fast component being significantly reduced in 5'-XAZ. The NMR structure shows that local structural deviations from B-DNA are much more pronounced in the 3'-5' direction than in the 5'-3' direction. According to quantum-chemical calculations, the directionality of charge injection is not a universal feature of the DNA duplex but depends critically on the rotation angle of the aromatic plane of the acridinium within the pi stack. The arrangement of X+ in 5'-ZAX and 5'-XAZ corresponds to a conformation with weak directionality of the electronic couplings. The increased disorder in the 3'-5'direction favors slow hole transfer components at the expense of the fast ones. (iv) A comparison of the hole transfer in 5'-GAX and 5'-ZAG shows that classical Marcus theory can explain the ratio of the charge shift rates of more than 2 orders of magnitude on the basis of a free energy difference between G and Z of 0.3 eV. Both NMR structures and quantum-chemical calculations justify the appreciable neglect of differences of electronic couplings as well as in the reorganization energy in 5'-GAX and 5'-ZAG. Despite the attractive concept for the behavior of floppy DNA oligonucleotides, in this acridinium/DNA system, there is no evidence for conformational gating, that is, for fluctuations in the electronic couplings that permit the ET to occur.
A National Database Analysis Comparing the Nationwide Inpatient Sample and American College of Surgeons National Surgical Quality Improvement Program in Laparoscopic vs Open Colectomies: Inherent Variance May Impact Outcomes. Clinical and administrative databases each have fundamental distinctions and inherent limitations that may impact results. This study aimed to compare the American College of Surgeons National Surgical Quality Improvement Program and the Nationwide Inpatient Sample, focusing on the similarities, differences, and limitations of both data sets. All elective open and laparoscopic segmental colectomies from American College of Surgeons National Surgical Quality Improvement Program (2006-2013) and Nationwide Inpatient Sample (2006-2012) were reviewed. International Classification of Diseases, Ninth Revision, Clinical Modification coding identified Nationwide Inpatient Sample cases, and Current Procedural Terminology coding for American College of Surgeons National Surgical Quality Improvement Program. Common demographics and comorbidities were identified, and in-hospital outcomes were evaluated. A national sample was extracted from population databases. Data were derived from the Nationwide Inpatient Sample database: 188,326 cases (laparoscopic = 67,245; open = 121,081); and American College of Surgeons National Surgical Quality Improvement Program: 110,666 cases (laparoscopic = 54,191; open = 56,475). Colectomy data were used as an avenue to compare differences in patient characteristics and outcomes between these 2 data sets. Laparoscopic colectomy demonstrated superior outcomes compared with open; therefore, results focused on comparing a minimally invasive approach among the data sets. Because of sample size, many variables were statistically different without clinical relevance. Coding discrepancies were demonstrated in the rate of conversion from laparoscopic to open identified in the National Surgical Quality Improvement Program (3%) and Nationwide Inpatient Sample (15%) data sets. The prevalence of nonmorbid obesity and anemia from National Surgical Quality Improvement Program was more than twice that of Nationwide Inpatient Sample. Sepsis was statistically greater in National Surgical Quality Improvement Program, with urinary tract infections and acute kidney injury having a greater frequency in the Nationwide Inpatient Sample cohort. Surgical site infections were higher in National Surgical Quality Improvement Program (30-day) vs Nationwide Inpatient Sample (8.4% vs 2.6%; p < 0.01), albeit less when restricted to infections that occurred before discharge (3.3% vs 2.6%; p < 0.01). This is a retrospective study using population-based data. This analysis of 2 large national databases regarding colectomy outcomes highlights the incidence of previously unrecognized data variability. These discrepancies can impact study results and subsequent conclusions/recommendations. These findings underscore the importance of carefully choosing and understanding the different population-based data sets before designing and when interpreting outcomes research.
Surveys of Food Intake Just after the Nuclear Accident at the Fukushima Daiichi Nuclear Power Station. As a result of the nuclear accident at the Fukushima Daiichi nuclear power station (FDNPS) after the Great East Japan Earthquake on March 11, 2011, volatile radionuclides including iodine-131 were released into the environment and contaminated open-field vegetables, raw milk, tap water, etc. It is important for the health care of residents to correctly comprehend the level of their exposure to radioactive substances released following the accident. However, an evaluation of the internal exposure doses of residents of Fukushima Prefecture as a result of the ingestion of foods, which is indicated in the report issued by United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)1 is based on a number of assumptions. For instance, the estimation assumes that foods were ingested as usual, without regard to the places to which residents were evacuated after the accident, the places where food shipment restrictions were imposed, and so forth. The present report aims to improve the accuracy of estimation of the amount of food actually ingested at evacuation areas, in order to reduce as much as possible the level of uncertainty in conventional values estimated directly after the accident, which were in fact values based on conservative assumptions. More concretely, as basic source material to more accurately estimate internal exposure doses from food ingestion, various patterns of evacuation and dietary habits at the time of the accident of the residents of 13 municipalities in Fukushima Prefecture who were evacuated during the period from directly after the accident of March 11, 2011 until the end of March are clarified in this report. From survey results, most of the food that evacuees took immediately after the accident was confirmed to have been sourced from either stockpiles prepared before the accident, or relief supplies from outside of the affected areas. The restriction orders of food supplies such as contaminated vegetables and milk, and tap water intake were implemented within several days after the major release of radionuclides on March 15, 2011. In addition, collapse in supply chains, i.e., damage to distribution facilities, lack of transportation vehicles or electricity, and the closure of retail stores, contributed to a situation where food or supplies contaminated with iodine -131 were not consumed in large quantities in general, even before the food restriction order. Since people consumed tap water and water from other sources before the implementation of restriction orders in affected areas, we surveyed the status of water as a potential route of internal exposure.
Human placental sterylsulfatase. Interaction of the isolated enzyme with substrates, products, transition-state analogues, amino-acid modifiers and anion transport inhibitors. The enzymatic properties of a homogeneous sterylsulfatase preparation isolated from human term placenta were studied. The enzyme exhibited both arylsulfatase and sterylsulfatase activity: it catalysed the hydrolysis of sulfuric acid esters of (in the order of decreasing specific activity) non-steroidal phenols, of a phenolic steroid, and of neutral 3 beta-, 21- and (though at a very low rate) 17 beta-hydroxysteroids. However, among all the substrates tested only the 3-sulfates of phenolic and neutral steroids exhibited high affinity towards the sulfatase. Vitamin D3 sulfate was not hydrolysed by the sterylsulfatase but strongly inhibited its activity. The products of the catalytic reaction, free steroids or phenols as well as the sulfate anion or analogues thereof, likewise interfered with the enzyme's activity. Ki values of unconjugated steroids were ten- to hundredfold higher than Km values of the respective sulfoconjugates. Inorganic sulfate only slightly inhibited the sulfatase activity; its inhibitory potency, however, increased in a time-dependent manner when it was preincubated with the enzyme prior to assay. In contrast to sulfate, the hypothetical transition-state analogues sulfite and vanadate acted as strong inhibitors of the sulfatase activity. According to the results of an analysis of the effect of pH on sterylsulfatase kinetics, enzyme constituents with pK values of approximately 5.8 and 8.0 are involved in a general acid-base catalysed reaction. Treatment of the sulfatase with amino-acid side chain modifying reagents directed against arginine, cysteine, cystine, serine or tyrosine residues did not result in significant alteration of its activity. Diethyl-pyrocarbonate known to react primarily with histidyl groups, however, rapidly inactivated the enzyme; this inactivation reaction was markedly retarded in the presence of substrate. Histidine thus appears to be essential for the catalytic activity of the sulfatase. Taken together, the present results reveal a considerable similarity between the catalytic mechanism of human placental sterylsulfatase and the ones already proposed for the lysosomal arylsulfatases A and B. Taurocholate, salicylate, ouabain, and 4,4'-substituted stilbene-2,2'-disulfonates are well known inhibitors of carrier-mediated transport of anions across cellular membranes. With the exception of ouabain, these compounds likewise turned out to inhibit the enzymatic hydrolysis of steryl sulfates; the pattern of dose dependences of their interference with the sulfatase activity resembles the one reported for inhibition of anion transport. Since the sterylsulfatase in vivo strongly is associated with cellular membranes including the plasma membrane of the syncytiotrophoblast, this finding supports the speculation that similar molecular structures may be involved in both placental transport and hydrolysis of anionic steryl sulfates.
Intraoperative local fibrinolysis as emergency therapy after early coronary artery bypass thrombosis. Acute graft occlusion early postoperatively after coronary artery bypass grafting (CABG) is a rare but dramatic complication, frequently making resuscitation necessary. Emergency reoperation with reanastomosing of the concerning grafts is the normal procedure to restrict the otherwise unavoidable myocardial damage. Mortality in these cases is up to 50%. Due to this unsatisfying situation, we perform since 1995 in such cases an adjuvant intraoperative intracoronary installed fibrinolysis with recombinant tissue type plasminogen activator (rt-PA; alteplase). Between 1/1994 and 8/1998, 4231 patients underwent CABG. In 18 of these patients, emergency reoperation within the first 12 h after CABG due to clinical signs of acute myocardial infarction was necessary. In nine of the patients (group II) additionally intraoperative rt-PA lysis of the involved vessel/s has been performed. When the peripheral anastomosis was reopened and the thrombotic material was removed, we inserted for this a left atrial-catheter (LA-catheter) of 1.2 mm in diameter, into the coronary artery. Then we administered within 3-5 min, up to 100 mg rt-PA (t1/2: 5-9 min.) locally into the vessel. All patients were treated postoperatively with acetylsalicyl acid (ASA) and heparine. In group I (n = 9; seven males, two females) without thrombolytic therapy, 78% of the patients (n = 7) could not have been prevented from large myocardial infarction despite emergency reoperation. Three of these patients died during or early after reintervention. In group II with fibrinolytic therapy (n = 9) three of the patients developed Q-wave myocardial infarction following reoperation. None of the patients died. Creatinkinase maximum were in group I significantly higher than in group II (group I: CK = 1254 units/I, CK-MB = 197 units/l; group II: CK = 502 units/l, CK-MB = 61 units/l; P < 0.01). Postoperative bleeding was considerable elevated in both groups. In group I, 832 ml/24 h (375-1420 ml), in group II 1164 ml/24 h (520-1560 ml). Lysis-associated complications were not observed. Reoperation of patients with acute thrombotic bypass occlusion after CABG is characterized by a high mortality and morbidity. If additionally fibrinolysis is performed, a sufficient myocardial perfusion seems to be restored. A short half-life in combination with the presented non-systemic application technique of rt-PA seem to prevent unpredictable bleeding. Rt-PA lysis apparently contributes very effectively to the restoration of the macro- and microcirculation within the infarct-related area. Thrombolytic therapy during cardiac surgery with rt-PA is feasible, its application easy and harmful complications are not seen.
[The spatial organization of centrosome-attached and free microtubules in 3T3 fibroblasts]. Microtubules spatial organization is essential for different cellular processes to proceed normally. It is supposed traditionally, that the fibroblasts have radial microtubule array consisting of long microtubules running from the centrosome. However, the detailed analysis of the microtubule array in the internal cytoplasm has never been performed. In the current study we used laser photobleaching for the analysis of the spatial organization of microtubules in the internal cytoplasm of cultured 3T3 fibroblasts. Cells were injected with Cy-3-labeled tubulin, and then in the bleached zone growth of microtubules in the centrosome region and in the peripheral parts of cytoplasm was analyzed. In most cases microtubules growth in the bleached zone occurred rectilinearly, on the distance up to 5 microm they seldom bend more than 10-15 degrees. We considered a growing fragment of the microtubule as a vector with the beginning in the point of occurrence and with the end in a point where growth terminated (or the end point after 30 s if microtubule's persistent growth proceeded longer). We defined the direction of microtubules growth in different parts of the cell using these vectors and measured the angle of their deviation from the vector of comparison. In the area of the centrosome we directed the vector of comparison inside of the bleached zone from the centrosome to the beginning of the growing microtubule segment; in fibroblast lamella and in fibroblast trailing part we used, the vector of comparison was directed along the long axis of the cell from its geometrical center to periphery. The microtubules growing immediately from the centrosome grew along the cell radius. However at a distance of 10 microm from the centrosome radially growing microtubules gave 40% from the overall number, and at a distance of 20 microm--only 25%. The rest of microtubules grew in different directions, with the preferred angle between their growth direction and cell radius around 90 degrees. Fibroblast lamella and trailing part 80% of all microtubules grew along the cell long axis or at the angle no more than 20 degrees, and 10-15% of microtubules grew along cell axis but towards the centrosome. Thus, in 3T3 fibroblasts the radial system of microtubules is perturbed starting from the distance of several microns from the centrosome. In the internal cytoplasm the microtubule system is completely disordered, and in the stretched parts of the polarized cell (lamella, trailing edge) the microtubule system again becomes well organized--microtubules are preferentially oriented along the long cell axis. From the results obtained we conclude that orderliness of microtubules at the periphery of the fibroblast is not a consequence of their growth from the centrosome, but their orientation is preset by local factors.
Transmission dynamics of intramammary infections with coagulase-negative staphylococci. A field trial was conducted on 2 US dairy herds to evaluate the transmission dynamics of coagulase-negative staphylococci (CNS) during the lactation period. Quarter milk cultures positive for CNS were classified as intramammary infection (IMI) or incidental isolation (transient colonization). The average proportion of quarters with CNS IMI was 0.114 in farm 1 and 0.09 in farm 2, and corresponding estimates for quarters with transient colonization of CNS were 0.122 and 0.088 throughout the 13-mo study period. Transmission parameters were obtained both for IMI caused by CNS and for CNS-positive quarters classified as the combination of transient colonization and IMI. Transmission between cows and between quarters in the same cow was assessed. The transmission parameters (β) for IMI caused by CNS were 0.0066 (farm 1) and 0.0111 (farm 2). Corresponding estimates of β when IMI and transient colonization of CNS were assessed jointly were 0.0256 (farm 1) and 0.0253 (farm 2). On farm 1, risk of transmission for CNS IMI between quarters in the same cow was 2 times greater than that between quarters from cow to cow. Transmission of CNS was considered contagious in one farm but no distinction between contagious and environmental transmission could be made in the other. We hypothesize that between-farm variation may be related to diversity between prevailing CNS species or by differences in management. In the current study, estimates of the basic reproduction number (R(0)) at the farm level for CNS IMI were 0.59 and 0.84 in farms 1 and 2, respectively. This shows that the transmission of CNS from IMI during the lactation period would to be too low to maintain the observed herd prevalence of CNS IMI. The R(0) values for the combination of transient colonization and IMI by CNS were 1.13 and 1.17 in farms 1 and 2, respectively. This indicates potential for sustained endemic infection of CNS throughout lactation. However, prevailing CNS species may also differ between transient colonization and IMI. Therefore, not only CNS originating from IMI or incidental isolation events, but also CNS IMI occurring from the period outside the lactation pen are essential for maintenance of the observed herd prevalence of CNS IMI throughout lactation in this study. The effect of IMI originating outside the lactation pen was verified in simulations with reduced entry of infectious quarters to the lactation pens. Measures against CNS IMI would probably increase in efficiency if prevention of infection during the dry period and early lactation were further emphasized in herd health programs.
Effect of insulin and metformin on methylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A of rat offspring with gestational diabetes mellitus. To discuss the effect of insulin and metformin on a methylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A (PPARGC1A) of rat offspring with gestational diabetes mellitus (GDM). A total of 45 pregnant rats received the intraperitoneal injection of streptozotocin to establish the pregnant rat model of GDM. A total of 21 pregnant rats with GDM were randomly divided into three groups, with 7 rats in each group, namely the insulin group, metformin group and control group. Rats in the insulin group received the abdominal subcutaneous injection of 1 mL/kg recombinant insulin glargine at 18:00 every day. Rats in the metformin group received the intragastric infusion of metformin hydrochloride at 18:00 every day, with the first dose of 300 mg/kg. The doses of two groups were adjusted every 3 d to maintain the blood glucose level at 2.65-7.62 mmol/L. Rats in the control group received the intragastric infusion of 1 mL normal saline at 18:00 every day. After the natural delivery of pregnant rats, 10 offspring rats were randomly selected from each group. At birth, 4 wk and 8 wk after the birth of offspring rats, the weight of offspring rats was measured. The blood glucose level of offspring rats was measured at 4 wk and 8 wk, while the level of serum insulin, triglyceride and leptin was measured at 8 wk. The weight of offspring rats at birth in the insulin group and metformin group was significantly lower than the one in the control group (P < 0.05), and there was no significant difference at 4 wk and 8 wk among three groups (P > 0.05). The fasting blood glucose and random blood glucose in the insulin group and metformin group at 4 wk and 8 wk were all significantly lower than ones in the control group (P < 0.05); there was no significant difference between the insulin group and metformin group (P > 0.05). The expression of PPARGC1A mRNA in the insulin group and metformin group was significantly higher and the methylation level of PPARGC1A was significantly lower than the one in the control group (P < 0.05); but there was no significant difference between the insulin group and metformin group (P > 0.05). Insulin and leptin at 8 wk in the insulin group and metformin group were significantly higher, while triglyceride was significantly lower than the one in the control group (P < 0.05); triglyceride level in the insulin group was significantly higher than the one in the metformin group (P < 0.05). There was no significant difference in insulin and leptin level between the insulin group and metformin group (P > 0.05). GDM can induce the methylation of PPARGC1A of offspring rats to reduce the expression of PPARGC1A mRNA and then cause the disorder of glycolipid metabolism when the offspring rats grow up; the insulin or metformin in the treatment of pregnant rats with GDM can reduce the methylation level of PPARGC1A and thus improve the abnormal glycolipid metabolism of offspring rats.
Results of total cavopulmonary connection in the treatment of patients with a functional single ventricle. Total cavopulmonary connection was proposed as a modification of the Fontan procedure that might have greater benefits than previous methods. To assess this procedure we reviewed case histories of 38 patients (aged 17 months to 30 years) who underwent Fontan procedures with cavopulmonary anastomoses between January 1987 and December 1989. The group included 32 patients with univentricular heart, 2 with pulmonary atresia and intact ventricular septum, 3 with tricuspid atresia, and 1 with hypoplastic left heart syndrome. One or more previous palliative procedures were performed in 34 patients, including 19 systemic-pulmonary shunts, 16 pulmonary artery bandings, 7 atrial septectomies/septostomies, 7 Glenn shunts, and 1 patent ductus arteriosus ligation. Preoperative hemodynamics showed a pulmonary artery pressure of 12 mm Hg (range 6 to 22 mm Hg), pulmonary-systemic flow ratio of 1.6 (range 0.37 to 3.0), left ventricular end-diastolic pressure 9 mm Hg (range 3 to 15 mm Hg), and systemic arterial oxygen saturation of 82% (range 67% to 94%). Concomitant with cavopulmonary connection, 13 patients underwent additional procedures, including 9 atrioventricular valve annuloplasties, 4 Damus-Stansel-Kaye procedures, and 2 resections of subaortic membranes. Modifying the Fontan procedure in this fashion was particularly useful in the management of 2 patients with pulmonary atresia and intact ventricular septum who had right ventricular-dependent coronary blood flow. Cavopulmonary anastomosis and atrial septectomy were performed in both patients, with resultant inflow of oxygenated blood to the right ventricle and coronary arteries. Excellent postoperative results were noted in each. Postextubation hemodynamics for the entire group included a mean right atrial pressure of 13 mm Hg (range 11 to 17 mm Hg), a mean left atrial pressure of 6 mm Hg (range 3 to 12 mm Hg), and a room air oxygen saturation of 96% (range 92% to 98%). Seven patients had pleural effusions, 3 required postoperative pacemaker placement, and 2 required reoperation for tamponade. A venous assist device was required in one patient on the second postoperative day, but the patient was weaned successfully within 24 hours. One early death (2.6%) occurred in a patient who had intractable ventricular fibrillation 2 days after operation. There was one late cardiac death (2.7%) caused by ventricular failure and one late noncardiac death. These results demonstrate that total cavopulmonary connection provides excellent early definitive treatment, with low morbidity and mortality, for a variety of complex congenital heart lesions.
Emergence of complex chemistry on an organic monolayer. In many origin-of-life scenarios, inorganic materials, such as FeS or mineral clays, play an important role owing to their ability to concentrate and select small organic molecules on their surface and facilitate their chemical transformations into new molecules. However, considering that life is made up of organic matter, at a certain stage during the evolution the role of the inorganic material must have been taken over by organic molecules. How this exactly happened is unclear, and, indeed, a big gap separates the rudimentary level of organization involving inorganic materials and the complex organization of cells, which are the building blocks of life. Over the past years, we have extensively studied the interaction of small molecules with monolayer-protected gold nanoparticles (Au NPs) for the purpose of developing innovative sensing and catalytic systems. During the course of these studies, we realized that the functional role of this system is very similar to that typically attributed to inorganic surfaces in the early stages of life, with the important being difference that the functional properties (molecular recognition, catalysis, signaling, adaptation) originate entirely from the organic monolayer rather than the inorganic support. This led us to the proposition that this system may serve as a model that illustrates how the important role of inorganic surfaces in dictating chemical processes in the early stages of life may have been taken over by organic matter. Here, we reframe our previously obtained results in the context of the origin-of-life question. The following functional roles of Au NPs will be discussed: the ability to concentrate small molecules and create different local populations, the ability to catalyze the chemical transformation of bound molecules, and, finally, the ability to install rudimentary signaling pathways and display primitive adaptive behavior. In particular, we will show that many of the functional properties of the system originate from two features: the presence of metal ions that are complexed in the organic monolayer and the multivalent nature of the system. Complexed metal ions play an important role in determining the affinity and selectivity of the interaction with small molecules, but serve also as regulatory elements for determining how many molecules are bound simultaneously. Importantly, neighboring metal ion complexes also create catalytic pockets in which two metal ions cooperatively catalyze the cleavage of an RNA-model compound. The multivalent nature of the system permits multiple noncovalent interactions with small molecules that enhances the affinity, but is also at the basis of simple signal transduction pathways and adaptive behavior.
Mortality outcomes after busulfan-containing conditioning treatment and haemopoietic cell transplantation in patients with Gilbert's syndrome: a retrospective cohort study. Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative conditioning and haemopoietic cell transplantation would have different mortality outcomes depending on whether or not they had laboratory evidence of Gilbert's syndrome. In this retrospective cohort study, we used clinical and laboratory data of patients who had haemopoietic cell transplantation from Jan 1, 1991, to Dec 31, 2011. Patients were included if they had received high-dose conditioning regimens of cyclophosphamide plus total body irradiation (CY/TBI), busulfan plus cyclophosphamide (BU/CY), busulfan plus melphalan plus thioTEPA (BUMELTT), or melphalan before transplant. Patients were excluded if their original consent forms to report transplant outcomes were not signed, if consent was withdrawn, or if they were a prisoner. Patients with Gilbert's syndrome were defined as having laboratory values before the start of conditioning therapy for unconjugated serum bilirubin concentrations of at least 17·1 μmol/L (≥1 mg/dL), normal conjugated serum bilirubin, and no evidence of hepatitis, cholestasis, or haemolysis. We assessed the association of Gilbert's syndrome with overall mortality and non-relapse mortality using adjusted Cox regression models at day 200 after transplantation. Our study cohort was 3379 patients-1855 (55%) allograft and 1524 (45%) autograft recipients. 211 (6%) patients had Gilbert's syndrome and 3168 (94%) did not have this condition. Most patients were adults (median age 45·8 years [IQR 33·2-55·5]) with haematological malignancies. For overall mortality 664 (20%) patients had died by day 200 after transplant (47 [22%] of 211 who had Gilbert's syndrome vs 617 [19%] of 3168 who did not have Gilbert's syndrome), and for non-relapse mortality 499 (92%) patients had died before relapse was recorded (38 [18%] who had Gilbert's syndrome vs 461 [15%] who did not have Gilbert's syndrome). The effect of Gilbert's syndrome on the risk of overall mortality and non-relapse mortality by transplant day 200 varied between the conditioning regimens and donor groups. In patients conditioned with a myeloablative regimen that contained busulfan (n=1131), those with Gilbert's syndrome (n=60) were at a significantly increased risk of death and non-relapse mortality by day 200 compared with those without Gilbert's syndrome (n=1071; hazard ratio [HR] 2·30, 95% CI 1·47-3·61, p=0·00030; and 2·77, 1·71-4·49, p<0·0001). In patients who received CY/TBI or melphalan conditioning regimens, those with Gilbert's syndrome had similar outcomes to those without Gilbert's syndrome (overall mortality at day 200 HR 0·90, 95% CI 0·60-1·34, p=0·60; non-relapse mortality at day 200: 0·90, 0·56-1·45, p=0·65). Analyses of causes of death and busulfan disposition provided no mechanistic explanation for the differences in mortality. Overall mortality and non-relapse mortality at day 200 after transplant were significantly worse in patients with Gilbert's syndrome who received busulfan-containing myeloablative conditioning regimens, compared with non-Gilbert's syndrome patients. Patients with Gilbert's syndrome should receive busulfan-containing myeloablative conditioning regimens with caution. US National Institutes of Health.
Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults. Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure. This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3-N-acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC0-∞, AUC0-t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC0-∞, AUC0-t, or Cmax between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use. Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed. At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.
[Morphodynamic response of the pineal gland to an initial stress attack--the effect of morphine]. The possible participation of a stimulated ACTH secretion in the promotion of the pineal gland reactive response under conditions of injection stress was studied. Morphine was used as a pharmacological mimicry of the stress-induced ACTH outflow in the post-injection period of 10-45 min. In animals subjected to injection stress (administration of the physiological solution), in the 10-th min. light pinealocytes exhibited a significant rise in the relative volume of the GER field and the Gogli apparatus, as well as bouquets of presecretory or secretory forms of the cell processes and frequent extrusion of lipid droplets. From 20-th min. on, the relative volume of their membranous elaborative compartment gradually decreased, the cell processes were missing and the lipid droplet extrusion was rare. The rich arbourisation of the GER tubules, the active appearance of the Golgi apparatus and a more abundant occurrence of lipid droplets--a picture which persisted even in 30 min.--showed that the intensified elaborative activity of dark pinealocytes, a minor cell population, was of longer duration in comparison with light pinealocytes. The subsequent fall in their stress-reactive response points out that the function of light and dark pinealocytes is driven by different regulative systems. Based on the principle that the function is the reflection of morphometabolic changes, in can be concluded that 10 min. after the injection act, the pineal gland has a short-term crescendo of its stress-reactive response. The morphine injection did not cause any significant changes in both pinealocyte populations in 10 min. A considerable increase of the relative volume of the constituents of the membrane elaborative compartment was found in light pinealocytes in the next observational periods, i.e., in the 20-th and the 30-th min. The lack of any conspicuous signs of an enhanced secretory activity, in contrast with frequent findings of lipid droplets and prosecretory granules, shows that the facilitation of the elaborative activity leads more to a restitution and increase of the pinealocyte potential than to a stimulation of their current secretion. Characteristic of this period was a frequent finding of newly generated lipid droplets. Their presence within the fields of GER tubules, as well as the communication of the lumens of these tubules with the matrix of the arising lipid droplet suggest a close connection of lipid droplets with the pinealocyte peptidergic activity Unexpected was the finding of a conglomerate of fasciculated lamellae--structures of a so far unknown function.(ABSTRACT TRUNCATED AT 400 WORDS)
Eye injuries in Singapore--don't risk it. Do more. A prospective study. The purpose of this study was to characterise and describe the epidemiology of all eye injuries presenting to the National University Hospital (NUH). A prospective study was conducted over a 7-week period (11/4/2005 to 29/5/2005) on all ophthalmic trauma patients seen by the Department of Ophthalmology in NUH. Data on patient presentation, source of injury and intervention were collected via a standardised interview and examination, and documented using a validated datasheet. A total of 133 patients, and 139 eyes, were included in the study. The average age was 33.5 years, with a range of 5 years to 88 years, and 84.2% (n = 112) were men. Close to half (46.6%, n = 62) of the patients studied were non-Singaporeans. 56.4% (n = 75) of all eye injuries were work-related and only 5% (n = 7) of eyes were open-globe injuries. Common sources of eye trauma included: Use of high-powered tools in activities such as grinding, welding and hammering (38.3%, n = 51), human-inflicted injuries (12.0%, n =16) and road traffic accidents (8.3%, n = 11). Of the work-related eye injuries, 29.3% (n = 22) reported to having used personal protective equipment (PPE) at the time of injury, 38.7% (n = 29) had been issued PPE but had not used them, while 32% (n = 24) reported that PPE had not been issued. An initial visual acuity of 6/12 or better was found in 63.0% (n = 88) of patients and a reading of 6/60 or worse was found in 10.0% (n =14). Superficial foreign bodies (22.4%, n = 55) were the most common clinical finding, followed by periorbital bruise (12.2%, n = 30), lid ecchymoses (6.9%, n = 17), orbital fractures (6.5%, n = 16), lid laceration (6.1%, n = 15) and corneal abrasions (5.7%, n = 14). There is a broad spectrum of causes, mechanisms and severity of ophthalmic injuries seen in the hospital, of which work-related trauma makes up a significant proportion. The patients who suffer occupational injuries are a well-defined group: Young, non-Singaporean males, working with power tools in the construction industry are at particular risk. Although preventive strategies are in place for this high-risk group, the lack of awareness and compliance limit their effectiveness. The adequacy and functionality of PPE should be emphasised. In addition, preventive efforts are equally important in domestic, recreational, sports and transport settings. Eye trauma research and prevention can be further aided by a collaborative registry of eye injuries. A long-term islandwide database of all ophthalmic injuries is recommended.
The role of the primary care physician in the Israeli health care system as a 'gatekeeper'--the viewpoint of health care policy makers. The aim of the study was to determine the attitudes of policy makers in the health care system in Israel to a change in the role of primary care physicians (PCP) and to ascertain the conditions under which they would be ready to adopt the model of PCP as gatekeeper. The study design was qualitative, with analyses of in-depth structured interviews of 20 policy makers from the Ministry of Health, the Sick Funds' central administrations and the Israel Medical Association (IMA) central office. The majority of the respondents claim that they want highly trained PCPs (family physicians, pediatricians and internals) to play a central role in the health care system. They should be co-ordinators, highly accessible and should be able to weigh cost considerations. However, only about half of the respondents support a full gatekeeper model and most of them think that the gatekeeper concept has a negative connotation. They also feel that it would be difficult to implement regulations regarding primary care. The barriers to implementation of the gatekeeper model, as cited by the respondents include loss of faith in PCPs by the general population, dearth of PCPs with adequate training, low stature, lack of availability on a 24-h basis, resistance by specialists, strong competition between the sick funds including promises of direct access to specialists, the medical care habits of the general population many of whom do not settle for only one opinion, and a declared anti-gatekeeper policy by one of the sick funds. Ways to overcome these obstacles include implementation of fundholding clinics, patient education on the importance of having a personal physician, appropriate marketing by family medicine and primary care advocates, and continued training in primary care. Israeli health care policy makers have an ambivalent attitude to strengthening the role of primary care. In theory, they profess support for placing primary care physicians in a central role in the health care system. However, in practice almost half oppose the full gatekeeper model. Therefore, introduction of a gatekeeper model into the Israeli health care system should be implemented gradually, based on incentives rather than regulations. Furthermore, the idea should be marketed by the primary care physicians' professional organizations, the Ministry of Health and the sick funds to physicians as well as to patients, in order to garner their support. In light of the broad consensus that competent primary care physicians are the basis for implementation of the gatekeeper model, board certification should be gradually required by employers of primary care physicians. The process of training physicians currently working in the system should be encouraged and supported by the Ministry of Health. Given the existing opposition of policy makers to giving primary care physicians exclusive referral rights to specialists, the current policy of direct access to a limited number of specialties should be continued but not extended to other specialties.
Prostate cancer screening: results of a prospective trial in Canton Aargau, Switzerland. Prostate cancer is the most commonly diagnosed cancer in Swiss men and the second leading cause of cancer related death among them (e.g. CH: 1,267 in year 1998). With the population at risk constantly growing these absolute numbers are expected to further increase. While there is no question that aggressive treatment of localised tumour is required for definitive cure of prostate cancer, the application of screening for early stage disease remains controversial. Since 1998 the Clinic of Urology in Kantonsspital Aarau has participated in the ERSPC (European Randomised Study of Screening for Prostate Cancer) study, which is designed to provide data on prostate cancer screening within a prospective randomised controlled setting. Men aged between 55 and 70 years were enrolled in the study. From n = 18,361 men invited by a letter to participate, 7,124 (38.8%) agreed and gave their informed consent to be randomised in either a PSA measurement (n = 3,562, group 1) or a control group (n = 3,562, group 2). Men in group 1 with a PSA level ?3.0 ng/ml, n = 372 (10.5%) then underwent ultrasound guided transrectal sextant biopsy of the prostate. Prostate cancer was detected at presentation in every fourth man biopsied (n = 89). Neither the free-to-total PSA ratio nor the PSA density could significantly spare biopsies while sustaining a high sensitivity level. The overall cancer detection rate amounted to 2.5% in PSA tested men. In 7% (n = 5) distant disease was already present. 93% of men with clinically organ confined disease underwent prostatectomy (n = 59) or radiotherapy (n = 22), whilst only (n = 3) chose to follow a policy of watchful waiting. In 92% the histology of the prostatectomy specimens revealed aggressive cancer characteristics according to the criteria of Epstein et al. Although the clinically relevant tumour characteristics and the relatively low cancer detection rate of 2.5% (less than the lifetime mortality risk of 3% and the morbidity risk of 8%) seem to justify screening in terms of adequate diagnosis and treatment, follow-up until 2008 is needed to prove the benefit in mortality for the prostate cancer screening group over the control group. Furthermore, information from the ongoing ERSPC study is needed in order to assess uncertainties i.e. the degree of overdiagnosis caused by repeated screening and the quality of life adjusted gain in life years. For daily practice a "PSA grey zone" of 4-10 ng/ml can no longer be postulated as only 70% of men in this range presented with organ confined disease. Once the PSA level exceeds 4.0 ng/ml. prostate biopsy should be performed immediately.
Outcome of eyes developing retinal detachment during the Early Treatment for Retinopathy of Prematurity Study (ETROP). To report the structural and visual outcomes of eyes in which retinal detachment developed from retinopathy of prematurity (ROP) in the Early Treatment of Retinopathy of Prematurity (ETROP) Study. Method Infants in the ETROP Study with bilateral high-risk prethreshold ROP had 1 eye randomized to early treatment, with the fellow eye managed conventionally. In infants with asymmetric disease, the eye with high-risk prethreshold ROP was randomized to early treatment or conventional management. When a retinal detachment was detected, observation or vitreoretinal surgery (ie, scleral buckling and/or vitrectomy) was provided at the discretion of the individual investigator. At 9 months corrected age, retinal examinations were performed and visual acuities were assessed by masked testers using grating acuity. The ETROP Study enrolled 401 patients with high-risk prethreshold ROP. Retinal detachments occurred in 89 eyes of 63 patients. Follow-up was available for 78 eyes of 56 patients. The detachments were bilateral in 21 patients (38%) and were classified as stage 4A in 30 eyes, stage 4B in 14 eyes, and stage 5 in 16 eyes. Detachments were not classified in 18 eyes. Twelve eyes of 11 patients were observed and 66 eyes of 52 patients underwent vitreoretinal surgery. Attachment of the macula at 9 months persisted or was achieved in 17 (30%) of 56 eyes after vitrectomy with or without scleral buckle, in 6 (60%) of 10 eyes after scleral buckle only, and in 2 (17%) of 12 eyes followed up without surgery. Favorable visual acuity (> or =1.85 cycles/degree) was found in 13 (17%) of the 78 eyes. All 6 eyes that maintained normal visual acuity (> or =3.70 cycles/degree) had a stage 4A detachment (1 of 6 managed by observation, 3 of 6 by scleral buckle, and 2 of 18 by vitrectomy). Eleven eyes with stage 5 detachment underwent vitreoretinal surgery, resulting in 6 with no light perception, 3 with light perception only, and 2 with detection of only the low vision card. In the ETROP Study, the outcome of retinal detachment owing to ROP was generally poor. Vitreoretinal surgery for retinal detachment was associated with macular attachment in 16 of 48 eyes. Normal acuity was maintained after surgical repair of stage 4A retinal detachment in 5 (21%) of 24 eyes. Vitreoretinal surgery for stage 5 disease was associated with some structural successes but poor functional outcomes.
Molecular Detection of Phytophthora ramorum, the Causal Agent of Sudden Oak Death in California, and Two Additional Species Commonly Recovered from Diseased Plant Material. ABSTRACT Sudden oak death is a disease currently devastating forest ecosystems in several coastal areas of California. The pathogen causing this is Phy-tophthora ramorum, although species such as P. nemorosa and P. pseudo-syringae often are recovered from symptomatic plants as well. A molecular marker system was developed based on mitochondrial sequences of the cox I and II genes for detection of Phytophthora spp. in general, and P. ramorum, P. nemorosa, and P. pseudosyringae in particular. The first-round multiplex amplification contained two primer pairs, one for amplification of plant sequences to serve as an internal control to ensure that extracted DNA was of sufficient quality to allow for polymerase chain reaction (PCR) amplification and the other specific for amplification of sequences from Phytophthora spp. The plant primers amplified the desired amplicon size in the 29 plant species tested and did not interfere with amplification by the Phytophthora genus-specific primer pair. Using DNA from purified cultures, the Phytophthora genus-specific primer pair amplified a fragment diagnostic for the genus from all 45 Phytophthora spp. evaluated, although the efficiency of amplification was lower for P. lateralis and P. sojae than for the other species. The genus-specific primer pair did not amplify sequences from the 30 Pythium spp. tested or from 29 plant species, although occasional faint bands were observed for several additional plant species. With the exception of one plant species, the resulting amplicons were smaller than the Phytophthora genus-specific amplicon. The products of the first-round amplification were diluted and amplified with primer pairs nested within the genus-specific amplicon that were specific for either P. ramorum, P. nemorosa, or P. pseudo-syringae. These species-specific primers amplified the target sequence from all isolates of the pathogens under evaluation; for P. ramorum, this included 24 isolates from California, Germany, and the Netherlands. Using purified pathogen DNA, the limit of detection for P. ramorum using this marker system was approximately 2.0 fg of total DNA. However, when this DNA was spiked with DNA from healthy plant tissue extracted with a commercial miniprep procedure, the sensitivity of detection was reduced by 100- to 1,000-fold, depending on the plant species. This marker system was validated with DNA extracted from naturally infected plant samples collected from the field by comparing the sequence of the Phytophthora genus-specific amplicon, morphological identification of cultures recovered from the same lesions and, for P. ramorum, amplification with a previously published rDNA internal transcribed spacer species-specific primer pair. Results were compared and validated with three different brands of thermal cyclers in two different laboratories to provide information about how the described PCR assay performs under different laboratory conditions. The specificity of the Phytophthora genus-specific primers suggests that they will have utility for pathogen detection in other Phytophthora pathosystems.
The risks of spontaneous preterm delivery and perinatal mortality in relation to size at birth according to fetal versus neonatal growth standards. The aim of this study was to test the null hypothesis that size at birth relative to fetal or neonatal growth standards is not a significant variable related to the risk of spontaneous preterm delivery. This was a hospital-based cohort study of consecutive births at a tertiary care perinatal center from January 1, 1985, to December 31, 1996. A total of 37,377 pregnancies met the following inclusion criteria: (1) singleton gestation, (2) 25 to 40 weeks' gestation, and (3) no anomalies. Neonates were divided into 5 birth weight categories according to either fetal (uncorrected for sex) or neonatal (corrected for sex) growth standards, as follows: (1) intrauterine growth restriction, birth weight <3rd percentile; (2) borderline intrauterine growth restriction, birth weight > or = 3rd percentile and <10th percentile; (3) appropriate for gestational age, birth weight from 10th percentile through 90th percentile; (4) borderline large for gestational age, birth weight >90th percentile but < or = 97th percentile, and (5) large for gestational age, birth weight >97th percentile. Logistic regression analysis was used to estimate the independent effect of birth weight category on the risk of preterm delivery after spontaneous onset of labor, with the appropriate-for-gestational-age group serving as a reference. When fetal growth standards were applied, there was a significant increase in the risk of spontaneous preterm delivery when birth weight was outside the appropriate-for-gestational-age range (odds ratios of 2.5, 1.4, 1.2, and 1.9 for intrauterine growth restriction, borderline intrauterine growth restriction, borderline large-for-gestational age, and large-for-gestational-age groups, respectively). In contrast, when neonatal growth standards were applied, the risks of spontaneous preterm delivery in intrauterine growth restriction, borderline intrauterine growth restriction, and large-for-gestational-age groups were significantly lower (odds ratios of 0.5, 0.7, and 0.7 for intrauterine growth restriction, borderline intrauterine growth restriction, and large-for-gestational-age groups, respectively) because of an underestimation in the number of fetuses with abnormal size at birth delivered prematurely. With both fetal and neonatal growth standards there was a 5-to 6-fold greater risk of perinatal death for both preterm and term fetuses with intrauterine growth restriction. Fetal growth standards are more appropriate in predicting the impact of birth weight category on the risk of spontaneous preterm delivery than are neonatal growth standards. When fetal standards are applied, the risks of preterm birth in both extreme abnormal birth weight categories (intrauterine growth restriction and large for gestational age) are 2- to 3-fold greater than the risk among appropriate-for-gestational-age infants.
[A retrospective view of tumor immunology]. The story of tumor immunology includes periods of hope followed by ones of disenchantment as far as clinical applications are concerned. In antiquity, cancer was considered "contrary to Nature", a concept which was confirmed by Ehrlich at the beginning of our century when the layed down the foundations of immunology. The latter was defined as the defence against all "non-self" intruders, including cancer, as opposed to the protection of "self". This concept was further accentuated by the theory immune surveillance proposed by Burnet in 1969 which implicated a destruction of nascent neoplastic cells by T lymphocytes. To increase host defence was the basis of tumor immunotherapy with BCG, levamisol and other adjuvants. The appearance of the nude mouse, athymic, and yet free of spontaneous tumors, led to a new paradigm, the network theory proposed by Jerne. This was based on immunological homeostasis implicating that both "self" and "non-self" can be rejected and tolerated. Cancer gradually ceased to be considered as "contrary to Nature". As for the proposed viral etiology of cancer which was the basis of the National Cancer Act signed by Nixon in 1971, this led to various breakthroughs and Nobel Prizes (Table 1), to discoveries such as reverse transcriptase, cellular oncogenes, tumor suppressor genes, which gave a new explanation for neoplastic transformation. The latter can now be considered as the consequence of a cascade of molecular events which include oncogene expression, anti-oncogene deletion, etc... converting, step by step, for instance, a polyp into a colon cancer and its metastases. The availability of monoclonal antibodies capable of attacking tumor cells did not lead to the expected success because of the complexity of the immune system. Attempts at a better understanding of the latter have led to a subdivision of the T lymphocyte CD4 population into Th1 and Th2. Th1 favor rejection (tumoral, fetal or of transplants) through the elaboration of IL-2, IFN and TNF while Th2 led to tolerance or acceptation through the production of IL-4, IL-5 and IL-10: both functions neutralize each other establishing a "normal" equilibrium Th1 vs Th2. This could explain the state of "tumor dormancy" or tumors in situ which are apparently quite frequent. That any immunological stimulation would cause these dormant tumors to proliferate is the basis of the immunostimulation theory proposed by Prehn and supported by the clinical observations of Stewart. This new concept has led some authors to propose that instead of destroying the tumor cells an attempt be made to maintain them in a state of dormancy in congenial company with normal cells.
Ultrasound monitoring of blood flow and echotexture of the corpus luteum and uterus during early pregnancy of beef heifers. The aim was to characterize changes in the ultrasound characteristics of the CL and uterus in pregnant, inseminated nonpregnant, and cyclic beef heifers and to correlate findings with systemic progesterone (P4) concentrations with the intention of identifying possible markers for early identification of pregnancy. Heifers were randomly selected for artificial insemination after estrus synchronization. Ultrasound examinations of the CL and uterus were carried out by transrectal ultrasonography using a high-resolution ultrasound scanner equipped with a 12 MHz linear array probe on Days 7, 11, 14, 16, and 18 after artificial insemination (Day 0; i.e., estrus). Cross-sectional B-mode images of the CL were captured for calculation of CL tissue area and echotexture. Images of the CL and associated blood flow were captured and stored for analysis of luteal blood flow area and ratio. Longitudinal B-mode images of the uterine horns were captured just beyond the bifurcation of the uterine horns and stored for analysis of contrast and homogeneity (MaZda v4.6; Technical University of Lodz, Institute of Electronics, Poland). A total of three images were captured for each structure of interest. Serum concentrations of P4 were determined from blood samples collected at each ultrasound examination. After pregnancy diagnosis by ultrasound, heifers were retrospectively allocated as being pregnant (embryonic heartbeat on Day 28; n = 14) or nonpregnant (interestrous interval 18-21 days; n = 8) and their data were compared with noninseminated cyclic heifers (n = 10). Corpus luteum tissue area did not appear to change between pregnant, nonpregnant, or cyclic control groups between Days 7 and 18 (P > 0.05). No significant differences in CL echotexture characteristics were found between groups at any time point. There were no significant differences between pregnant, nonpregnant, and cyclic control groups for CL blood flow area (P > 0.05). However, CL blood flow ratio decreased significantly (P < 0.05) in both inseminated nonpregnant and cyclic heifers between Days 14 and 18, whereas it remained unchanged in pregnant heifers (P > 0.05). Uterine homogeneity was not significantly different between groups at any time point (P > 0.05). However, uterine contrast was significantly greater (P < 0.05) in pregnant compared with cyclic control heifers on Days 16 and 18. Concentrations of P4 were lower (P < 0.05) in nonpregnant and control heifers than in pregnant heifers from Days 16 to 18. In conclusion, there were differences between nonpregnant and cyclic heifers compared with pregnant heifers in P4 concentrations from Day 16. On Day 18, the CL and uterine characteristics were different between the nonpregnant and pregnant heifers. Ultrasound measures of CL blood flow and uterine echotexture may be useful to establish pregnancy status. Further investigation is required to identify if pregnancy diagnosis can be made on Day 18 or at a later day postpartum.
Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. Testosterone use in older men is increasing, but its long-term effects on progression of atherosclerosis are unknown. To determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels. Testosterone's Effects on Atherosclerosis Progression in Aging Men (TEAAM) was a placebo-controlled, double-blind, parallel-group randomized trial involving 308 men 60 years or older with low or low-normal testosterone levels (100-400 ng/dL; free testosterone <50 pg/mL), recruited at 3 US centers. Recruitment took place between September 2004 and February 2009; the last participant completed the study in May 2012. One hundred fifty-six participants were randomized to receive 7.5 g of 1% testosterone and 152 were randomized to receive placebo gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium; secondary outcomes included sexual function and health-related quality of life. Baseline characteristics were similar between groups: patients were a mean age of 67.6 years; 42% had hypertension; 15%, diabetes; 15%, cardiovascular disease; and 27%, obesity. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference adjusted for age and trial site, 0.0002 mm/year; 95% CI, -0.003 to 0.003, P = .89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (adjusted mean difference, -10.8 Agatston units/year; 95% CI, -45.7 to 24.2; P = .54). Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone. Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit and prostate-specific antigen levels increased more in testosterone group. Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men. clinicaltrials.gov Identifier: NCT00287586.
[Effectiveness and efficacy of self-measurement of capillary blood glucose in patients with type 2 diabetes mellitus]. The efficacy of self-measurement of capillary blood glucose (SMBG) in patients with type 2 diabetes mellitus is not fully established. The objectives of the study were: a) to verify the efficacy of the SMBG in patients with type 2 diabetes mellitus in the primary care set; b) to investigate the possible causes that explain the lack of effectiveness of the method, in their case, and c) to deduce the predictive variables that permit to select good utilizador of the SMBG. Clinical trial controlled and randomized carried out in the environment of the primary care, on type 2 diabetic patients. The patients were assigned, of random form and stratified, according to the type of treatment for diabetes that received, in 2 groups: SMBG group (SMBG-G) and control group (CG). The period of monitoring was of 12 months. The efficacy of the SMBG was analyzed, and also its effectiveness. 100 patients were included in the study. Out of them, 51 were assigned to SMBG-G and 49 to CG. The SMBG was efficient in the 21.6% of SMBG-G and in 14.3% patients of the CG (p = 0.44). The SMBG efficacy was greater in patients with combined treatment and in those who received only insulin (50% in both cases). No improvement was observed in patients on treatment with diet (p = 0.006). The effectiveness for the cut off from value the HbA1c was of 59.2% and of 29.58% for the totality of the European criteria of metabolic control. The independent predictor variables of the SMBG efficacy were: the evolution years number of the diabetes mellitus and a deficient control of the illness at the start of the study. The global precision of the mathematical model obtained was of 88.24% with sensibility of 54.5%, especificity of 97.5%, positive predictor value of 85.7% and negative predictive value of 11.4% (p < 0.001). The area under the ROC curve was of 89.9% (p < 0.001) (95% confidence interval, 81.2-98.5%). According to the ROC curve, the point of cut that better the SMBG efficacy discriminated was that of 74% (sensibility: 72.7%; especificity: 77.5%). SMBG is a tool that, although can improve the metabolic control of type 2 diabetes, requires a careful selection of patients and, therefore, cannot be utilized in an indiscriminate way. The time of evolution of the illness and fundamentally, the presence of a deficient metabolic control of the disease should be the factors that determine a good selection. Therefore, its extended use among the type 2 diabetic population, without a prior selection, does not seem to be justified.
A novel polymorphism of human CYP2A6 gene CYP2A617 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo. Cytochrome P450 (CYP) 2A6 is a major CYP responsible for the metabolism of nicotine and coumarin in humans. We identified a novel allele, designated CYP2A617 , which contains A51G (exon 1), C209T (intron 1), G1779A (exon 3), C4489T (intron 6), G5065A (V365M, exon 7), G5163A (intron 7), C5717T (exon 8), and A5825G (intron 8). We developed a genotyping method by polymerase chain reaction-restriction fragment length polymorphism for the CYP2A617 allele, targeting the G5065A mutation. The allele frequency in black subjects (n = 96) was 9.4% (95% confidence interval [CI], 5.3%-13.5%). The allele was not found in white subjects (95% CI, 0%-0.9%; n = 163), Japanese subjects (95% CI, 0%-1.6%; n = 92), and Korean subjects (95% CI, 0%-0.7%; n = 209). To examine the effects of the amino acid change in the CYP2A617 allele on the enzymatic activity, we expressed a wild-type or variant (V365M) CYP2A6 together with NADPH-CYP reductase in Escherichia coli . For coumarin 7-hydroxylation, the apparent Michaelis-Menten constant value of variant CYP2A6 (1.06 +/- 0.11 micromol/L) was significantly (P < .005) higher than that of wild type (0.60 +/- 0.05 micromol/L). The maximum velocity values of the wild-type and variant CYP2A6 were 0.61 +/- 0.06 and 0.64 +/- 0.07 pmol . min -1 . pmol -1 CYP, respectively. For nicotine C -oxidation, the apparent Michaelis-Menten constant values of the wild-type or variant CYP2A6 were 31.6 +/- 2.9 micromol/L and 31.3 +/- 3.1 micromol/L, respectively. The maximum velocity value of variant CYP2A6 (0.72 +/- 0.21 pmol . min -1 . pmol -1 CYP) was significantly (P < .05) lower than that of the wild type (1.80 +/- 0.42 pmol . min -1 . pmol -1 CYP). Thus the intrinsic clearance values for coumarin 7-hydroxylation and nicotine C -oxidation by the variant were both significantly (P < .05) decreased to 40% to 60% compared with the wild type. Furthermore, cotinine/nicotine ratios after 1 piece of nicotine gum was chewed, used as an index of in vivo nicotine metabolism, were significantly (P < .05) decreased in heterozygotes of the CYP2A617 allele (5.4 +/- 2.7, n = 12) compared with homozygotes of the wild type (11.5 +/- 10.5, n = 37). A subject with CYP2A617 / CYP2A6*17 revealed the lowest cotinine/nicotine ratio (1.8). We found a novel allele in black subjects that affects the nicotine metabolism in vitro and in vivo.
A phase II trial of mitomycin C, 5'-deoxy-5-fluorouridine, etoposide and medroxyprogesterone acetate (McVD-MPA) as a salvage chemotherapy to anthracycline-resistant tumor in relapsed breast cancer and its mechanism(s) of antitumor action. To assess the therapeutic efficacy in the combination of mitomycin C (MMC), 5'-deoxy-5-fluorouridine (5'-DFUR), etoposide (VP-16) and medroxyprogesterone acetate (MPA) (McVD-MPA) to anthracycline-resistant tumor as a salvage chemotherapy, a phase II trial was conducted in patients with relapsed breast cancer. Fifty-five patients were enrolled in this trial and 54 were assessable, who had all previously been treated with an anthracycline regimen. The treatment schedule was designed with the intravenous administration of MMC (6 mg/m2) on day 1 followed by peroral administration of VP-16 (75 mg/m2) on day 2, 4, 6 and the peroral administration of 5'-DFUR (600 mg/m2) and MPA (400 mg/m2) on day 1 through 21 in one cycle. The overall tumor response rate was 40.7% (22/54) including 16.6% (9 cases) in complete response and 24.0% (13 cases) in partial response, and the long no change (NC) was observed in 18.5% (10/54) out of 44.4% (24/54) in NC. Of the patients with primary resistance to anthracycline 30.0% responded to McVD-MPA therapy. Bone and liver metastases responded in 50.0% and 50.0%, whereas soft tissue and lung metastases responded in 36.8% and 35.2%, respectively. The mean time to response and response duration were 2.7 and 15.6 months, respectively. The overall survival of the patient treated with the McVD-MPA was superior to the non-treatment of second line therapy, and the median survival between McVD-MPA and non-treatment was 86 days and 50 days, respectively. The major adverse effect was observed in hematological toxicity (31.7%) such as leukopenia and thrombocytopenia and non-hematological toxicity of gastrointestinal events (31.7%), the toxicity was less than grade 2, and was tolerable during the treatment. In the experiment of MDA-MB-231 breast cancer cell line that was overexpressed with P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP), the mechanism(s) by which McVD-MPA induces the antitumor effect to anthracycline-resistant tumor may be explained at least in part as follows: i) The treatment of MMC suppressed the expression of P-gp and MRP in a dose-and time-dependent manner, connecting the increase of the intracellular concentration of VP-16; ii) The treatment of MMC enhanced the expression of thymidine phosphorylase to increase the production of 5-FU from 5'-DFUR in the antiangiogenic effect of MPA. These results indicate that the combination chemotherapy of the McVD-MPA may be an effective regimen to anthracycline-resistant tumor as a salvage chemotherapy to prolong the survival in the patient with relapsed breast cancer.
Surgical pulmonary embolectomy and catheter-based therapies for acute pulmonary embolism: A contemporary systematic review. Mortality in acute pulmonary embolism (PE) is believed to be principally due to the subgroup of PEs that are massive. Systemic thrombolysis is the therapeutic mainstay for acute massive PE, despite evidence suggesting limited survival benefits. Both catheter-based therapies (CBT) and surgical pulmonary embolectomy (SE) are well-accepted alternatives to treat acute PE. However, the comparative effectiveness of these approaches is difficult to study. We conducted a systematic review of CBT and SE for acute PE. The PubMed database was queried for CBT- and SE-related publications between January 1998 and June 2017. A minimum of 10 patients undergoing intervention(s) was required for inclusion, and studies must not have excluded patients with massive PE. End points examined included hospital mortality, and additionally for CBT, procedural success rate. A total of 75 studies (41 of CBT, 34 of SE) were identified, with 1650 patients undergoing CBT and 1101 undergoing SE. Patients undergoing SE were more critically ill than those undergoing CBT (massive PE, 545 out of 975 [55.9%] for SE vs 742 out of 1553 [47.8%] for CBT). Cardiopulmonary resuscitation (CPR) was required in 217 out of 1015 patients undergoing SE (21.4%) versus 38 out of 983 patients undergoing CBT (4.0%). The hospital mortality of SE was 14.0%, versus 5.6% for CBT, in the entire patient group. However, the hospital mortality of SE in patients with pre-SE CPR was 46.3%, whereas it was 6.8% in those patients without pre-SE CPR. Although CPR was associated with an increased risk of mortality both for CBT and SE, it accounted for all of the mortality effect on SE (the adjusted odds ratio for CPR in a random effects model with treatment considered was 9.79 (95% confidence interval, 4.98-19.17; P < .0001). The adjusted odds ratio for mortality for SE relative to CBT was 1.36 (95% confidence interval, 0.80-2.32; P = .84). Moreover, CBT was associated with a procedural failure rate of 8.3%. Both CBT and SE were associated with satisfactory published outcomes. SE is associated with greater absolute postprocedure mortality than CBT, but has been undertaken in more critically ill populations. The markedly higher incidence of CPR in SE accounts for the differential mortality between the patients undergoing SE and those undergoing CBT. Decision making with respect to best therapy must take into account potential needs for periprocedure artificial mechanical right ventricle and lung support, institutional experience and outcomes, anticipated therapeutic efficacy and benefit, and approach-specific risks.
Modulation of substance P-ergic system in the rat spinal cord by an opioid antagonist. Substance P- and opioid peptide-immunoreactive nerve terminals functionally interact in the spinal cord as two opposing systems in the regulation of the nociceptive pathway. In order to determine how SP-ergic system adapts to chronic opioid receptor blockade, the effects of naltrexone on SP level, SP receptor and the second messenger system coupled to the SP receptor were examined in the rat spinal cord. Male Sprague-Dawley rats were treated with naltrexone or vehicle for seven days by constant minipump infusion. Animals were sacrificed on day 8, spinal cords rapidly removed, segmentally sectioned and used to determine SP and inositol 1,4,5-trisphosphate [ins(1,4,5)P3] tissue contents, and to examine the regulation of their respective receptors in in vitro receptor binding assays. Following chronic naltrexone treatment, SP content in the lumbosacral segment of the spinal cord was increased by 53% over matched control values. The binding capacity (Bmax) of SP receptors, determined using [125I]BHSP, in lumbosacral synaptosomal membranes was significantly increased by 92%, but the binding affinity (Kd) remained unchanged. In addition, the concentration of [Sar9, Met(O2)11]SP, an NK-1 receptor-specific agonist, required to inhibit half of [125I]BHSP binding (IC50) in lumbosacral synaptosomal membranes was significantly decreased, but the IC50s for SP, the endogenous ligand for the SP receptor, and [Pro7]NK B, an NK-3 receptor-specific agonist, were unaltered by chronic blockade of opioid receptors. The data suggest that although naltrexone does not directly interact with tachykinin receptors, it acts indirectly on SP-ergic neurons to cause a change in the apparent affinity of NK-1 receptor (as reflected by a change in IC50 value). Formation of cellular ins(1,4,5)P3 in the lumbosacral cord, quantified by a highly sensitive and selective radioreceptor assay, was significantly increased by 34% relative to matched controls. A time course study indicated that increases in ins(1,4,5)P3 contents over the time studied corresponded qualitatively with increases in SP level in the lumbosacral cord. With [3H]ins(1,4,5)P3 as a ligand, Scatchard analyses of the concentration dependent saturation curves showed that the density of intracellular ins(1,4,5)P3 receptors was also increased by 119%, with no change in binding affinity. The data suggest that ins(1,4,5)P3 formation, possibly coupled to functional SP receptor activation, and ins(1,4,5)P3 receptors, which mediate ins(1,4,5)P3-induced alterations in intracellular Ca2+ flux, are increased in the lumbosacral cord by chronic blockade of opioid receptors. Taken together, the data support the concept of a role for endogenous opioids in the regulation of SP receptor activity in the spinal cord.
Use and cost of hospital and community service provision for children with HIV infection at an English HIV referral centre. To describe the use of hospital and community services for children infected with HIV and estimate the cost per patient-year by stage of HIV infection during the era of antiretroviral monotherapy. Data on the use of hospital services were collected from case notes; the use of statutory and nonstatutory community services was recorded through diaries and interviews. Total cost estimates were calculated from unit costs from relevant hospital departments and community organisations. Children managed at St. Mary's Hospital (London, England) between 1 January 1986 and 31 December 1994, some of whom used statutory and nonstatutory community services in South East England between 1 November 1994 and 31 May 1996. 118 children with positive HIV antibody status. Mean inpatient days, outpatient visits, tests and procedures performed, drugs prescribed, community services used, associated unit costs and average cost estimates per patient-year by stage of HIV infection (1995/1996 values), and lifetime costs. Service provision during the study period was predominantly hospital-based. The use of services increased for different stages of HIV infection and increased with increasing severity of HIV infection. A shift from an inpatient-based to an outpatient-based service was seen between the periods 1986 to 1991 and 1992 to 1994. As symptoms evolved, children used more hospital inpatient services, with an accompanying shift in the use of community services from general services, such as schooling, to increased use of nurses, social care and home help. The estimated total cost of hospital and community care was 18,600 Pounds per symptomatic non-AIDS patient per year and 46,600 Pounds per AIDS patient per year. Similar estimates for children with indeterminate HIV infection and asymptomatic infection amounted to 8300 Pounds and 4800 Pounds per patient-year, respectively. Nondiscounted lifetime costs for hospital care amounted to 152,400 Pounds (44,300 Pounds to 266,800 Pounds) compared with discounted lifetime costs of 122,700 Pounds (42,000 Pounds to 182,200 Pounds); nondiscounted lifetime costs for community care amounted to 24,300 Pounds (7900 Pounds to 41,600 Pounds) compared with discounted lifetime costs of 21,000 Pounds (6800 Pounds to 32,000 Pounds). The continued emphasis on the use of hospital services may be due to the small number of children infected with HIV, most of whom lived in the London metropolitan area where specialist care was concentrated in a few centres. A shift from an inpatient- to an outpatient-based service was observed over time; the advent of the use of combination antiretroviral therapy in this population may further facilitate a shift in service provision and promote shared care between specialist centres, local hospital and community-based services.
Phase I trial using adaptive control dosing of hexamethylene bisacetamide (NSC 95580). Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m2/day. Because our previous trial had shown wide interpatient variability in HMBA pharmacokinetics and excess toxicity at HMBA plasma concentrations greater than 2 mM (HMBA doses between 24 and 33.6 g/m2/day), we attempted to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA. In all courses, a plasma sample was assayed daily and infusion rates were adjusted to achieve an HMBA plasma concentration of 1.5-2.0 mM (300-400 mg/liter). The patients included 12 men and 1 woman with a median age of 56 years (range, 34-76) and median Karnofsky performance status of 90% (range, 60-100). All patients had received prior chemotherapy and 9 patients had also received radiation therapy. The linear adaptive control algorithm was reasonably precise, with a mean absolute error of 0.28 (SE 0.04) mM. However, adjustments in infusion rate systematically overshot the desired change in steady state concentration, probably due to nonlinear clearance of HMBA. For levels within 24 h of a change in infusion rate, this resulted in significant bias, with a mean error of 0.24 (SE 0.09) mM. The mean absolute error was 0.40 (SE 0.06) mM. A second adaptive control algorithm, using a pharmacokinetic model with parallel first-order (renal) clearance and Michaelis-Menten (nonrenal) clearance and using Bayesian parameter estimation with a priori estimates based on our previous phase I trial, proved to be much more precise than the linear method and was unbiased when applied retrospectively to the same observations, with a mean error (within 24 h of a change in infusion rate) of 0.02 (SE 0.06) mM and a mean absolute error of 0.22 (SE 0.03) mM. Toxicity was reversible in all cases. Neurotoxicity, consisting of hallucinations, agitation, somnolence, or confusion, was seen in 2 patients. Four patients complained of insomnia or anxiety. Mild asymptomatic acidosis was seen in 3 patients. Other toxicity included grade 1-2 nausea and vomiting (10 patients), grade 2 diarrhea (2 patients), grade 3 thrombocytopenia (3 patients), grade 1-3 leukopenia (3 patients), and oral herpes simplex infection (4 patients). Mild reversible renal insufficiency (measured by creatinine clearance) was seen in 8 patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Evaluation of Wound Closure Rates Using a Human Fibroblast-derived Dermal Substitute Versus a Fetal Bovine Collagen Dressing: A Retrospective Study. Diabetic foot ulcers (DFUs) are associated with an increased risk for serious and costly outcomes such as osteomyelitis, amputation, and hospitalization. A retrospective study was conducted to evaluate the proportion of patients healed and time to healing of DFUs treated with a human fibroblast-derived dermal substitute (HFDS) or a fetal bovine collagen dressing (FBCD). Data from patients with a DFU who received the first treatment in 2014 were extracted from the electronic record database of 93 wound care centers. Baseline demographics (eg, age, gender, body mass index, and number of wounds); wound location, size, and duration; and wound-specific information such as wound size and number of and interval between applications were obtained. Study criteria stipulated patients who received at least one treatment in 2014 with HFDS or FBCD on a DFU with location coded as foot, toe, heel, metatarsal head, toe web space, toe amputation site, or transmetatarsal amputation site; ulcer size ≥1 cm2 to <20 cm2; and ulcer area reduction ≤50% in the 28 days before the first treatment with HFDS or FBCD were eligible for inclusion. Wounds that received an alternate skin substitute treatment up to 28 days before or concurrent with the first HFDS or FBCD treatment or if patient data that lacked baseline or follow-up wound area measurement were excluded. Deidentified data were extracted directly into data files and transferred to a third-party data management and statistical group for analysis. The frequency of DFUs achieving wound closure (defined as area ≤0.25 cm2) by weeks 12 and 24 and median time to wound closure of wounds that healed were analyzed. Baseline characteristics were compared using 2-sample t tests for continuous variables and 2-tailed Fisher's exact tests for difference in proportions between treatments. Frequency of and median time to wound closure were determined by Cox proportional hazards analysis. The frequency of wounds closed at 12 and 24 weeks, median time to wound closure, hazard ratio with 95% confidence interval, and P value were estimated from the Cox model. Statistical significance was defined as P <.05. Records showed 206 patients with 208 DFUs received treatment (108 HFDS, mean age 60.2 years, mean wound duration 8.8 months; 100 FBCD, mean age 65.2 years, mean wound duration 12.8 months) and were included. Mean number of treatment applications was 4.5 and 2.4 for HFDS and FBCD, respectively. After 12 and 24 weeks 44 (41%) and 69 (64%) of HFDS-treated wounds, respectively, and 21 (21%) and 43 (43%) of FBCD-treated wounds, respectively, were healed (at 12 weeks, P = .03; at 24 weeks, P = .03, log rank 2-tailed test, unadjusted). Median time to wound closure for HFDS and FBCD was 14.6 and 25 weeks, respectively (P = .03; log rank, 2-tailed test; Kaplan-Meier analysis). HFDS treatment significantly increased the probability of wound healing compared to FBCD treatment in the Cox proportional hazards analysis after adjusting for treatment terms, baseline wound area, baseline wound duration, baseline wound depth, wound location, and patient age at first treatment (HR = 1.77; 95% CI: 1.06-2.97; P = .03). DFU wounds are more likely to heal when treated with HFDS than with FBCD as used by facilities in this database. Studies examining the efficacy, cost-effectiveness, and patient-centered outcomes of these treatments is warranted. .
p27(Kip1) Knockout mice are protected from diabetic nephropathy: evidence for p27(Kip1) haplotype insufficiency. High glucose up-regulates the mesangial cell expression of p27(Kip1), an inhibitor of cyclin-dependent kinases/cyclin complexes. Previous in vitro studies using cultured mesangial cells from p27(Kip1-/-) mice demonstrated that these cells do not undergo high glucose-mediated cellular hypertrophy. Since glomerular hypertrophy is an early feature of diabetic nephropathy and may precede the development of glomerulosclerosis, interference with p27(Kip1) expression may attenuate diabetic nephropathy. However, it is unclear whether deletion of p27(Kip1) protects the kidneys of diabetic nephropathy in vivo. Type 1 diabetes mellitus was induced in p27(Kip1+/+), p27(Kip1+/-), and p27(Kip1-/-) mice by injection of streptozotocin (STZ). Mice were studied for 6 weeks. Animals injected with citrate buffer only served as controls. At the end of the experiments, urine was collected, albuminuria was determined with an enzyme-linked immunosorbent assay (ELISA), and blood glucose concentrations were measured. Kidneys were perfusion-fixed for quantitative morphologic analysis with glutaraldehyde and for immunohistochemical studies with formaldehyde. Glomerular cell number and volume were analyzed. Glomerulosclerosis, tubulointerstitial, and vascular damage indices were semiquantitatively assessed according to standard methodology. Quantitative glomerular parameters (cell numbers and volumes of endothelial, mesangial, and epithelial cells) were measured on semithin sections. Expression of transforming growth factor-beta1 (TGF-beta1), laminin, and collagen type IV were determined by immunohistochemical staining. In contrast to animals only injected with citrate buffer, mice that received STZ developed hyperglycemia. There was no significant difference in the degree of hyperglycemia among p27(Kip1+/+), p27(Kip1+/-), and p27(Kip1-/-) mice. Diabetic p27(Kip1+/+), but not control p27(Kip1+/+) animals, developed albuminuria. Albuminuria was significantly reduced in diabetic p27(Kip1+/-) and more profoundly in p27(Kip1-/-) animals. Diabetic p27(Kip1+/+) mice revealed a significant increase in mean glomerular volume at 6 weeks. The volumes of mesangial and endothelial cells and podocytes all increased, whereas cell numbers were reduced, consistent with cell hypertrophy. Glomerular, endothelial, mesangial and podocyte hypertrophy were reduced in diabetic p27(Kip1+/-) and p27(Kip1-/-) animals. Diabetic p27(Kip1) (+/+) animals had significantly increased glomerulosclerosis, tubulointerstium, and vascular damage indices compared to nondiabetic p27(Kip1+/+) controls. Diabetic p27(Kip1-/-) mice exhibited significantly less structural damage than diabetic wild-type animals. Diabetic p27(Kip1+/-) animals revealed intermediate glomerulosclerosis, tubulointerstium, and vascular damage values. Immunohistological stainings demonstrated increases in TGF-beta1, collagen type IV, and laminin expression in kidneys of diabetic p27(Kip1+/+) animals compared to nondiabetic p27(Kip1+/+) controls. Staining intensity for type IV collagen and laminin, but not for TGF-beta1, was significantly lower in diabetic p27(Kip1-/-) mice. Deletion of p27(Kip1) attenuates the functional and morphologic features of diabetic nephropathy. Although deletion of p27(Kip1) abolished some parameters of diabetic glomerular hypertrophy, the significant reduction of TGF-beta1 expression in the tubulointerstitium indicates that other protective mechanisms could be operative. The p27(Kip1) gene is haplo-insufficient because diabetic p27(Kip1)+/- mice exhibited an intermediate degree of functional and structural renal injury. Our data shows that p27(Kip1) plays an important role in diabetic nephropathy.
Feasibility study of Nestorone-ethinylestradiol vaginal contraceptive ring for emergency contraception. The Nestorone/ethinylestradiol (NES/EE) vaginal ring is being developed as a regular contraceptive method by the Population Council. This ring is designed to release NES 150 microg/day and EE 15 microg/day during 1 year. Here, we report a Phase I clinical trial to determine the usefulness of this ring for emergency contraception. To that end, we tested the ability of this ring to interfere with ovulation when it is inserted during the follicular phase. Forty-eight women protected from the risk of pregnancy by nonhormonal methods were divided into three groups, which differed by the size of the dominant follicle at the time of ring insertion: 12-14 mm (n = 16), 15-17 mm (n = 18) and >or=18 mm (n = 14) diameter. The NES/EE ring was left in the vagina for 7 consecutive days, after which it was removed. The growth of the leading follicle and plasma levels of estradiol, progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the ensuing 5 days after ring insertion were determined. Afterwards, steroid hormones were measured twice a week, until menses took place. All women had a control cycle before the ring cycle, and the range of maximum follicular diameter assigned to each volunteer was the same for the control and the ring cycle at the time when placebo was ingested or the ring inserted. During the 5-day period after ring insertion with follicles 12-17 mm, ovulation was absent in 25 of 34 cycles (p < .01 vs. control), and ovulatory dysfunction (absent, blunted or mistimed LH peak) occurred in 8 of the 9 remaining cycles (33/34 ovulatory processes altered; p < .005 vs. control). After ring insertion with follicles >or=18 mm in diameter, ovulation did not occur in 2 of 14 cycles or was dysfunctional in 7 of the 12 remaining cycles (9/14 ovulatory processes altered; p<.025 vs. control). Altogether, 87.5% of ring cycles (42/48) had either no ovulation or ovulatory dysfunction in the 5-day study period, in contrast to 39.6% (19/48 cycles) in control cycles (p < .001). Among follicles that failed to rupture within the 5-day study period, none ruptured later on in the ring-treated cycles, while 9 of 16 did so in control cycles. Sixty-two percent of ring-treated cycles were shorter than 24 days. Nausea, vaginal discharge and abdominal pain were the most frequently reported adverse events during ring use. Interference with 87.5% of ovulatory processes, without ovulation occurring later in the cycle and shortening of cycle length, suggests the NES/EE ring may be used as an emergency contraceptive method, with the potential advantage of providing continuing contraception after it has performed its emergency function.
Infarct-size limitation by preconditioning is enhanced by dipyridamole administered before but not after preconditioning: evidence for the role of interstitial adenosine level during preconditioning as a primary determinant of cardioprotection. Although the importance of adenosine (Ado)-receptor activation in preconditioning (PC) has been established, it is unclear whether cardioprotection afforded by PC is determined by the Ado level during PC ischemia or by that during sustained ischemia. Accordingly, we tested whether the PC effect is modified by augmenting the increase in the interstitial Ado level during PC or by that during sustained ischemia. In the first series of experiments, the effect of 0.25 mg/kg dipyridamole (DIP) on the interstitial Ado level was assessed by in vivo microdialysis in the rabbit heart. Dialysate Ado during 2-min ischemia was 70% higher in the heart pretreated with 0.25 mg/kg of DIP than in the untreated controls, indicating that DIP was capable of enhancing an ischemia-induced increase of interstitial Ado. In the second series of experiments, myocardial infarction was induced in the rabbit by 30-min coronary artery occlusion and 3-h reperfusion. Infarct size was determined by tetrazolium staining and expressed as percentage of area at risk (%IS/AR). Rabbits were subjected to one of nine treatments before the 30-min ischemia: no treatment, DIP (0.25 mg/kg, i.v.), PC with 2-min ischemia, DIP before 2-min PC, DIP after 2-min PC, PC with 3-min ischemia, DIP before 3-min PC, DIP after 3-min PC, or 8-sulfophenyltheophylline (SPT) after 3-min PC. DIP alone did not modify %IS/AR (38.8 +/- 5.8% vs. 41.2 +/- 4.7%), but administration of DIP before 2-min PC significantly enhanced the infarct size-limiting effect (14.6 +/- 2.1% with DIP vs. 32.1 +/- 4.7% without DIP). Although the 3-min PC per se could achieve significant infarct limitation, the effect of DIP on 3-min PC was not significant (14.7 +/- 1.9% with DIP vs. 20.5 +/- 1.8% without DIP). On the other hand, the effect of DIP administered after PC was very slight (only 7% reduction of %IS/AR) and statistically insignificant, regardless of the duration of PC ischemia. However, infarct limitation by 3-min PC was inhibited by SPT given after the PC (%IS/AR = 34.5 +/- 3.2), as reported previously. These results suggest that the interstitial Ado level during PC ischemia, not the level during sustained ischemia, is a primary determinant of the extent of cardioprotection by PC and that the threshold for Ado-receptor activation required during sustained ischemia is much lower than that for triggering PC.
Statin use and other factors associated with mortality after major lower extremity amputation. Above-knee amputations (AKAs) and below-knee amputations (BKAs) are associated with high postoperative mortality rates. In this study, we examined factors associated with 30-day, 90-day, and 1-year mortality in patients who underwent a major lower extremity amputation. We queried a prospectively collected institutional database for all patients who underwent AKA or BKA with primary or secondary closure, during a 5-year period, between November 2009 and November 2014. Predictors of 30- and 90-day mortality were determined by multivariable logistic regression, and risk indexes for 1-year mortality were determined with Cox proportional hazards model. We identified 811 patients who underwent AKA (n = 325) or BKA (n = 486). The 30-day mortality was 8.4% (AKA, 13.5%; BKA, 4.9%; P < .001) and 90-day mortality was 15.4% (AKA, 24.3%; BKA, 9.45%; P < .001). Predictors of 30-day mortality included AKA (odds ratio [OR], 3.09; 95% confidence interval [CI], 1.76-5.53), emergency operation (OR, 2.86; 95% CI, 1.56-5.14), chronic obstructive pulmonary disease (OR, 3.09; 95% CI, 1.07-7.81), end-stage renal disease (ESRD) on hemodialysis (HD; OR, 2.35; 95% CI, 1.24-4.33), and chronic kidney disease stages 3 (OR, 1.84; 95% CI, 1.00-3.37) and 4 (OR, 2.33; 95% CI, 1.01-4.98). Predictors of 90-day mortality included age (OR, 1.02; 95% CI, 1.00-1.04), ESRD on HD (OR, 2.56; 95% CI, 1.55-4.22), AKA (OR, 2.61; 95% CI, 1.70-4.05), history of coronary artery bypass grafting (OR, 2.04; 95% CI, 1.06-3.87), and medium-intensity or high-intensity statin (OR, 0.46; 95% CI, 0.29-0.73). One-year survival for the overall cohort was 73.7% (95% CI, 70.8%-76.8%). Predictors of 1-year mortality included AKA (hazard ratio [HR], 2.07; 95% CI, 1.54-2.77), coronary artery bypass grafting (HR, 1.57; 95% CI, 1.07-2.32), age >70 years (HR, 1.39; 95% CI, 1.02-1.88), gangrene (HR, 1.44; 95% CI, 1.07-1.94), ESRD on HD (HR, 1.96; 95% CI, 1.42-2.70), chronic obstructive pulmonary disease (HR, 2.54; 95% CI, 1.52-4.25), Caucasian race (HR, 1.62; 95% CI, 1.18-2.22), history of open lower extremity revascularization (HR, 0.71; 95% CI, 0.51-1.00) and undergoing bilateral amputations (HR, 2.10; 95% CI, 1.06-4.15). In the year after amputation, medium-intensity statin (HR, 0.64; 95% CI, 0.47-0.87) and high-intensity statin (HR, 0.56; 95% CI, 0.33-0.95) conferred a mortality benefit. Low-intensity statins did not confer protection from mortality. At 1 year after amputation, only 44.7% of patients were receiving appropriate statin therapy. AKA and BKA have historically been associated with high mortality rates. Medium-intensity and high-intensity statin therapies were associated with a mortality benefit at 1 year. We have identified initiation of statin therapy in this high-risk population as a gap in patient care.
Environmental fate and microbial degradation of aminopolycarboxylic acids. Aminopolycarboxylic acids (APCAs) have the ability to form stable, water-soluble complexes with di- and trivalent metal ions. For that reason, synthetic APCAs are used in a broad range of domestic products and industrial applications to control solubility and precipitation of metal ions. Because most of these applications are water-based, APCAs are disposed of in wastewater and reach thus sewage treatment plants and the environment, where they undergo abiotic and/or biotic degradation processes. Recently, also natural APCAs have been described which are produced by plants or micro-organisms and are involved in the metal uptake by these organisms. For the two most widely used APCAs, nitrilotriacetate (NTA) and ethylenediaminetetraacetate (EDTA), transformation and mineralisation processes have been studied rather well, while for other xenobiotic APCAs and for the naturally occurring APCAs little is known on their fate in the environment. Whereas NTA is mainly degraded by bacteria under both oxic and anoxic conditions, biodegradation is apparently of minor importance for the environmental fate of EDTA. Photodegradation of iron(III)-complexed EDTA is supposed to be mostly responsible for its elimination. Isolation of a number of NTA- and EDTA-utilising bacterial strains has been reported and the spectrum of APCAs utilised by the different isolates indicates that some of them are able to utilise a range of different APCAs whereas others seem to be restricted to one compound. The two best characterised obligately aerobic NTA-utilising genera (Chelatobacter and Chelatococcus) are members of the alpha-subgroup of Proteobacteria. There is good evidence that they are present in fairly high numbers in surface waters, soils and sewage treatment plants. The key enzymes involved in NTA degradation in Chelatobacter and Chelatococcus have been isolated and characterised. The two first catabolic steps are catalysed by a monooxygenase (NTA MO) and a membrane-bound iminodiacetate dehydrogenase. NTA MO has been cloned and sequenced and its regulation as a function of growth conditions has been studied. Under denitrifying conditions, NTA catabolism is catalysed by a NTA dehydrogenase. EDTA breakdown was found to be initiated by a MO also which shares many characteristics with NTA MO from strictly aerobic NTA-degrading bacteria. In contrast, degradation of [S,S]-ethylenediaminedisuccinate ([S,S]-EDDS), a structural isomer of EDTA, was shown to be catalysed by an EDDS lyase in both an EDTA degrader and in a NTA-utilising Chelatococcus strain. So far, transport of APCAs into cells has only been studied for EDTA and the results obtained give strong evidence for an energy-dependent carrier system and Ca(2+) seems to be co-transported with EDTA. Due to their metal-complexing capacities, APCAs occur in the environment mostly in the metal-complexed form. Hence, the influence of metal speciation on various degradation processes is of utmost importance to understand the environmental behaviour of these compounds. In case of biodegradation, the effect of metal speciation is rather difficult to assess at the whole cell level and therefore only limited good data are available. In contrast, the influence of metal speciation on the intracellular enzymatic breakdown of APCAs is rather well documented but no generalising pattern applicable to all enzymes was found.
Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (Oncorhynchus mykiss). The pregnane X receptor (PXR) belongs to the nuclear hormone receptor (NR) superfamily and is commonly described as a xenophore or a pharmacophore, as it can be activated by a wide array of xenobiotics, including numerous pharmaceuticals and other environmental pollutants. The PXR regulates expression of e.g. cytochrome P450 3A (CYP3A) and the P-glycoprotein (P-gp) that are involved in excretion of lipophilic xenobiotics and endobiotics. A full length PXR cDNA was isolated from rainbow trout liver and it was expressed in a descending order of magnitude in liver>intestine>kidney>heart. A rainbow trout PXR reporter assay was developed and a suite of pharmaceuticals and other xenobiotics were screened. However, no specific activation of rainbow trout PXR was observed with the substances tested. Interactions of prototypical PXR agonists on PXR signaling in rainbow trout were further investigated in cells of hepatic origin exposed in vitro and in juvenile rainbow trout exposed in vivo. The rainbow trout hepatoma cell line (RTH-149), displayed 600 times lower expression of CYP3A mRNA compared to primary cultures of hepatocytes, and did not respond to treatment with either pregnenolone 16α-carbonitrile (PCN), ketoconazole (KCZ) or rifampicin (RIF), which implies a non-functional PXR in this cell line. Exposure of hepatocytes to PCN and lithocholic acid (LA), resulted in a weak concentration-dependent induction of CYP3A and P-gp mRNA levels, though, exposure to the higher concentration of LA (50 μM) decreased PXR mRNA levels. Exposure to dexamethasone (DEX) resulted in a decrease in PXR mRNA, without affecting CYP3A mRNA levels in hepatocytes in vitro. Injections of rainbow trout in vivo with 1 mg LA/kg fish resulted in a slight (albeit not significant) increase in CYP3A mRNA levels without affecting PXR mRNA levels. Although, injection with 10mg omeprazole (OME)/kg fish had no effect on PXR and CYP3A mRNA levels, a 60% inhibition of CYP3A enzyme activities was evident. An in vitro screening of the chemicals used showed that OME and RIF acted as weak CYP3A inhibitors whereas LA and DEX did not affect the CYP3A activity. In contrast, PCN acted as an activator of the CYP3A enzyme activity in vitro. Taken together, these data show that some prototypical PXR agonists weakly affect PXR activation in rainbow trout. Besides, some of these agonists have a stronger effect on the CYP3A catalyst. This study demonstrates the importance of investigation effects of pharmaceuticals on the PXR signaling pathway in non-target animals such as fish.
Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease. In 1,049 patients with stable ischemic heart disease (IHD), brain natriuretic peptide (BNP) and amino terminal pro-brain natriuretic peptide (NTproBNP) correlated closely (r = 0.09, p < 0.001) and were similarly related to left ventricular ejection fraction (LVEF) (r = -0.50 and -0.46, respectively), age (0.44 and 0.47), and creatinine clearance (-0.51 and -0.51). Receiver-operating characteristic curves for detection of LVEF <30% were similar (area under the curves = 0.83 and 0.80, both p < 0.001), and both peptides had strong negative predictive value (95% and 94%). Both independently predicted all-cause mortality and/or heart failure with closely overlapping event-free survival curves; BNP and NTproBNP display strong, near-identical test performance in ruling about severely reduced LVEF and in prediction of all-cause mortality or heart failure in stable IHD. The aim of this work was to test B-type natriuretic peptides for assessment of function and prognosis in stable ischemic heart disease (IHD) and to compare brain natriuretic peptide (BNP) with amino terminal pro-brain natriuretic peptide (NTproBNP), including the relative effects of age and renal function on test performance. Brain natriuretic peptide and NTproBNP are emerging diagnostic and prognostic markers in heart failure and acute coronary syndromes. Their performance in assessing function and prognosis in stable IHD is unknown. Whether one marker is superior and the relative effects of age and renal function on test performance are uncertain. In 1,049 patients with stable IHD, left ventricular ejection fraction (LVEF) was measured by radionuclide scanning and creatinine clearance estimated by the Cockroft-Gault equation. Age, gender, and body mass index were recorded. Twelve-month all-cause mortality or admission with heart failure was prospectively recorded; BNP and NTproBNP were measured by radioimmunoassay. Brain natriuretic peptide and NTproBNP correlated closely (r = 0.90, p < 0.001) and had similar relationships to LVEF (r = -0.50 and -0.46, respectively, both p < 0.001), age (0.44 and 0.47, both p < 0.001), and creatinine clearance (-0.51 and -0.51, both p < 0.001). Areas under receiver-operating characteristic curves for detection of LVEF <30% were similar (0.83 and 0.80, both p < 0.001) with strong negative predictive values for both (95% and 94%). Both markers independently predicted the clinical end point with closely overlapping event-free survival curves. In stable IHD, BNP and NTproBNP display strong and near-identical test performance in ruling out severely reduced LVEF and in prediction of all-cause mortality or heart failure despite significant effects of age, gender, and renal function on levels of both markers.
Strontium: new drug. Postmenopausal osteoporosis: too many unknowns. (1) Strontium ranelate is marketed in the European Union for the treatment of postmenopausal osteoporosis. Strontium, a cation closely related to calcium, was already used for this purpose in the 1950s but was abandoned because it caused bone mineralization disorders (mainly due to the high doses used at the time). (2) Strontium has only been compared with placebo: there are no clinical trials versus a diphosphonate. (3) On the basis of bone mineral density, two dose-finding studies suggested that, in women who are also taking calcium and vitamin D, the effective minimal dose of strontium is 1 g/day for primary prevention and 2 g/day for secondary prevention. (4) In secondary prevention, a randomised, double-blind trial (SOTI) involving 1649 postmenopausal women who had already had an osteoporotic fracture and were also taking calcium + vitamin D, showed that 2 g strontium daily reduced the risk of symptomatic vertebral fractures compared with placebo (11.3% versus 17.4%) after three years of treatment. (5) Another randomised, double-blind trial (TROPOS) involved 5091 women with osteoporosis of the femur. After three years of treatment with calcium, vitamin D, and either 2 g/day strontium or placebo, the risk of non vertebral osteoporotic fracture was lower in the strontium arm (10.9% versus 9.1%; relative risk 0.85, 95% confidence interval 0.71-1.01), although the difference was only just significant (p = 0.05). This trial failed to show that strontium reduced the risk of femoral fracture. A retrospective subgroup analysis raised the possibility of a preventive effect on hip fracture in patients aged over 74 years, but again the difference had only borderline significance (relative risk 0.64, confidence interval 0.412-0.997). (6) The SOTI and TROPOS studies were subsequently pooled for analysis. A retrospective subgroup analysis of women aged over 80 suggested some efficacy on non vertebral fractures, but this remains to be confirmed in a comparative trial with relevant outcome measures. (7) The reports of these trials include little information on the adverse effects of strontium. Strontium caused a 50% increase in the risk of venous thromboembolism (including pulmonary embolism). Strontium also increased serum creatine kinase activity in 30% of patients. Strontium can affect mental functions, and this effect needs to be quantified. Neurological and muscular adverse effects were inadequately documented, although disorders of this type were observed in animals. (8) The long-term adverse effects of strontium on bone (osteomalacia, pathological fractures, etc.) are unknown. Data from experimental studies and dialysis patients with renal failure raise the possibility of these adverse effects. (9) In practice, there are too many unknowns surrounding the potential risks of strontium while there is not enough evidence of clinical advantages over diphosphonates.
Screening of colorectal cancer. Cost-effectiveness analyses have shown that the cost per year of life saved by screening with any of the tests recommended is reasonable by US standards. Although the specific results vary among analyses, in general the marginal cost-effectiveness of this screening is less than $25,000 per year of life saved. Screening for CRC was among the highest ranked services in an analysis of the value of preventive services based on the burden of disease prevented and cost-effectiveness. Although the up-front costs vary by screening modality, the long-term cost-effectiveness is similar across screening tests, so that decisions about which options to include--in the long run and from the perspective of society--do not need to be affected heavily by costs. Costs increase out of proportion to benefits with shorter intervals between screening examinations. Screening has provided great opportunities. Screening can prevent CRC by polypectomy and find early-stage cancers for treatment with less morbidity. Screening can reduce the burden of treating advanced cancers and can identify families at increased risk. Screening also has provided a better understanding of the biology of CRC. Screening for CRC should be part of a complete prevention program that includes a healthy lifestyle and familial risk assessment. Individuals with increased familial risk require special screening approaches, whereas individuals with average risk can have more standard screening. The average-risk individuals can be stratified further into persons who require intensive follow-up and persons who require less intensive or no follow-up at all. We are beginning to learn how to apply screening and surveillance approaches based on risk stratification for a more cost-effective approach to conserve resources and reduce complications and costs. Chemoprevention can be added to the program when substantial benefit of agents has been demonstrated. We have a better understanding of the biology of CRC and the technology to intervene in that biology to make a difference in the lives of many people. We have the concepts and technology to reduce substantially the mortality for CRC and even prevent it entirely. Newer screening tests or others yet to be developed may, with time, replace the modern options. Screening should take place with the tests currently available and not wait until something better comes along. In this way, needless suffering and loss of life can be avoided for this leading cause of cancer death. Screening may become even more successful if the promise of new technologies is confirmed and they enter clinical practice. In the last analysis, the best test is the one that gets done and gets done immediately.
[The Significance of Early Reposition in Patients with Visible Malposition of the Upper Ankle Joint]. Background: Protracted dislocation of the upper ankle joint can lead to substantial damage to the surrounding soft tissue, possibly followed by local complications and longer hospitalisation. Although reposition is usually easy to conduct, it is commonly recommended that this should only be performed by an experienced specialist, as long as there is no neurovascular restriction. There are however no exact data or studies on this problem. The aim of the present study is to examine whether early reposition is of benefit for subsequent treatment. Methods: Retrospective study of all patients in a supra-regional trauma centre during the period from January 2009 to July 2015, with either prehospital reposition of the ankle joint because of visible malposition or documented visible malposition on arrival at hospital. Patients with relevant concomitant injuries elsewhere were excluded. Data on the duration of dislocation were matched with diagnostic findings at the time of hospital admission, the kind of primary care, local complications and the time of hospitalisation, using linear regression analysis and ANOVA calculations. Results: Of a total of 391 patients with a dislocation or a fracture dislocation of the ankle joint within this period, 132 fulfilled the inclusion criteria. These patients were divided into 5 groups on the basis of the time of dislocation. Time to reposition was less than one hour for 39 patients, between one and two hours for 29 patients, between two and six hours for 41 patients, between six and 24 hours for 13 patients and more than 24 hours for 10 patients, all with a visible dislocation. The results on admission showed a significant increase in skin bruises and tension bullae with increasing time of dislocation. A longer time of dislocation was associated with more two stage surgical procedures with external fixators and a decreasing number of single stage procedures. While there was immediate definitive treatment of 79.5 % of the patients in the first group, this figure decreased continuously to 10.0 % in the last group. The number of local complications increased significantly in every group with the duration of dislocation. In particular, the incidence of severe swelling, wound healing disorders, skin necrosis and the need for revision surgery and plastic reconstruction exhibit a significant linear increase within the groups (p < 0.05). The incidence of severe swelling rose from 10.3 % in the first group, to 31.0 % in the second group, to 100 % in the last group. The incidence of wound healing disorders rose from 7.7 to 13.8 to 80 % and the incidence of skin necrosis from 2.6 to 3.5 to 30.0 %. The duration of hospitalisation also exhibited a significant linear increase with group affiliation (p < 0.001), from 8.3 days in the first group to 12.5 days in the second group and 30.5 days in the last group. Conclusion: This study shows the importance of conducting reposition of the ankle joint as soon as possible if there is visible malposition, in order to avoid local complications and longer hospitalisation. If there is visible malposition of the ankle joint, the best procedure is immediate - ideally prehospital - reposition and in-axis splinting, in order to preserve soft tissue.
Predictors of repeat pregnancy in a program for pregnant teens. To describe repeat pregnancy among adolescents and to compare those who experienced a repeat pregnancy to those who did not. Retrospective case control of all adolescents who entered and exited the Teen Mother & Child Program, a multidisciplinary clinic for pregnant and parenting teens and their children, between 1985 and 2000. Repeat pregnancy. Over the 16-yr study period, 1838 teens entered and exited the program with the mean time in the program of 1.9 yrs. 194 (10.6%) teens went on to have a second pregnancy, and 4 of those had a third pregnancy. Ninety-two percent (n=175) of these pregnancies resulted in a live birth. The mean interval between delivery of the initial child and delivery of the second child was 21.8 months (range 5.4-53.2). Teens repeating (R) were compared to those who did not repeat (NR). R were younger at entry and older at exit from the program (both P<0.0001). R were more likely to be Hispanic (P=0.009) or have a partner who was Hispanic (P=0.02). R were more likely to have experienced a poor initial pregnancy outcome (miscarriage, stillbirth) (P=0.03). R were more likely than NR to be in a stable relationships with the father of the baby (i.e., married or engaged) (P=0.03). Self-report of physical and sexual abuse, depression, and substance abuse were common, but did not differ between R and NR. However, R were more likely than NR to self-report suicide gestures/attempts and to have a significant psychiatric history (P=0.01, P=0.004). Only 24% of R and 26% of NR had completed high school by the time of exit from the program. Ten percent of adolescents served by comprehensive multidisciplinary teen pregnancy program experienced a repeat pregnancy while in the program. Compared to nonrepeaters, adolescents who experienced a repeat pregnancy were younger, were more frequently Hispanic, and were more likely to be in a stable relationship with the baby's father. Many of the program's clients have psychosocial factors reported in the literature to be associated with repeat pregnancy. A history of suicide gestures/attempts and a significant psychiatric history were more common in those who had a repeat pregnancy. Disappointingly, only about 25% of the adolescents completed high school by the time they exited the program whether they experienced a repeat pregnancy or not. Although directing interventions (e.g., mental health services, counseling those who miscarried) to teens who appear to be at highest risk for a repeat pregnancy may decrease their risk of repeating, all teens in our program would likely benefit from such services.
Is there a territorial differentiation in the prevalence of peptic ulcer among rural population in Poland? The aim of this study was to determine the prevalence of peptic ulcer among rural population in various regions of Poland and to analyse the conditions influencing the prevalence of the disease. For organizational reasons, the division of the territory of Poland into eight regions was adopted for the study. The study covered a representative group of 6,512 rural inhabitants, comprising 3,107 males (47.7%) and 3405 women (52.3%), aged 20-64, selected by two-stage stratified sampling. At the first stage of the study all health centres (3,286) were classified into 150 groups and in each group two prevention-treatment regions were selected by means of stratified sampling. The second-stage samples were selected based on communes where the health centres classified for the study were located. People selected for the study were subject to examinations which covered: a specially designed questionnaire form, detailed physical examination, and the necessary specialist tests. The obtained results were recorded in a questionnaire form, which additionally contained questions concerning detailed demographic and social data, hazardous factors present in the working environment, as well as data pertaining to housing conditions, nutrition and habits. Among the rural population under study, peptic ulcer was found in 8.0% of males and 2.9% of females, gastric ulcer was observed in 1.2% of people under study, duodenal ulcer - in 3.2%, gastric and duodenal ulcer - in 0.2%, whereas patients who underwent surgical procedures due to peptic ulcer constituted 0.7% of respondents. Territorial differences were noted in the prevalence of peptic ulcer among Polish rural population. The highest peptic ulcer incidence rates were observed in Macroregion I (western Poland) - where the disease was diagnosed in 7.2% of people under study (Northern Region - 8.1%, Southern Region - 7.4%, and South-Western Region - 6.4%), while the lowest rates were noted in Macroregion II (central and eastern Poland), where peptic ulcer occurred among 4.7% of respondents (South-Eastern Region - 4.4%, North-Eastern Region - 4.5%, Middle-Eastern Region - 4.7%, Middle- Western Region - 4.8%, and Central Region - 5.1%). In regions where the highest incidence rates were noted, the greatest numbers of divorcees, widows and widowers were observed. An analysis by occupational groups showed that in these regions there were more unskilled and skilled workers, employees of services, and the largest number of people performed non-agricultural occupations. Cigarette smoking habit was also more prevalent in these regions.
Common femoral artery endarterectomy for occlusive disease: an 8-year single-center prospective study. Only a few operative or interventional studies have addressed the issue of isolated arterial occlusive disease at the femoral bifurcation, the early and late results reportedly being favorable in the former, controversial in the latter. The purpose of this study was to analyze the peri-operative (30-day) and long-term outcomes of isolated surgical endarterectomy in patients with occlusive disease at the common femoral artery (CFA), providing a baseline for comparison with emerging endovascular procedures. Over an 8-year period, all consecutive patients referred to our institution for claudication, rest pain, nonhealing ulcer(s), or minor tissue loss, with imaging findings of CFA occlusive disease (isolated or with additional infrainguinal lesions in the ipsilateral limb) amenable to endarterectomy of the CFA (isolated or combined with a profundoplasty or with the endarterectomy of the superficial or deep femoral artery first tract, not >1 cm long) were enrolled in the study. We excluded all patients with major tissue loss for which a contemporary infrainguinal revascularization was performed because treating the inflow disease alone would not be sufficient to heal the ischemic wound(s) owing to the presence of concomitant femoral and/or distal lesions, inadequate collateralization, or poor runoff. Descriptive demographic data, risk factors, clinical manifestations, and operative details were recorded. Primary patency (PP), assisted PP (APP), and limb salvage (LS) rates, freedom from additional proximal or distal revascularization in the ipsilateral limb, and survival were assessed using Kaplan-Meier life tables. Univariate and multivariate analyses were performed to identify which factors could influence CFA segment patency or other parameters. In all, 117 patients were enrolled and underwent 121 CFA endarterectomies, 60.3% for claudication and 39.7% for critical limb ischemia (CLI); 30 patients were excluded because they underwent a contemporary infrainguinal revascularization. All procedures were performed with patients under regional anesthesia and took an average operating time of 1.3 +/- 0.7 hours. There were no perioperative deaths or major complications, but 8 (6.6%) local complications. A complete follow-up (mean 4.2 years) was obtained in 111 patients (115 limbs). The 7-year PP, APP, and LS rates were 96%, 100%, and 100%, respectively; the 7-year rates of freedom from further revascularization and survival were 79% and 80%, respectively. Operative endarterectomy in patients with claudication or CLI for occlusive CFA disease proved safe, effective, and durable, and should provide a baseline for comparison with endovascular treatment. Proponents of endovascular procedures as a routine alternative treatment option should bear this in mind.
Physico-chemical properties of a novel (-)-hydroxycitric acid extract and its effect on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological changes over a period of 90 days. Garcinia cambogia-derived (-)-hydroxycitric acid (HCA) is a popular and natural supplement for weight management. HCA is a competitive inhibitor of the enzyme ATP citrate lyase, which catalyzes the conversion of citrate and coenzyme A to oxaloacetate and acetyl coenzyme A (acetyl CoA) in the cytosol. Acetyl CoA is used in the synthesis of fatty acids, cholesterol and triglycerides, and in the synthesis of acetylcholine in the central nervous system. Studies have demonstrated the efficacy of a novel 60% calcium-potassium salt of HCA derived from Garcinia cambogia (HCA-SX, Super CitriMax) in weight management. Results have shown that HCA-SX promotes fat oxidation, enhances serotonin release and availability in the brain cortex, normalizes lipid profiles, and lowers serum leptin levels in obese subjects. Acute oral, acute dermal, primary dermal irritation and primary eye irritation toxicity, as well as Ames bacterial reverse mutation studies and mouse lymphoma tests have demonstrated the safety of HCA-SX. However, no detailed long-term safety of HCA-SX or any other HCA extract has been previously assessed. We evaluated the dose- and time-dependent effects of HCA-SX in Sprague-Dawley rats on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry over a period of 90 days. Furthermore, a 90-day histopathological evaluation was conducted. The animals were treated with 0, 0.2, 2.0 and 5.0% HCA-SX of feed intake and were sacrificed on 30, 60 or 90 days of treatment. The body weight and selected organ weights were assessed and correlated as a % of body weight and brain weight at 90 days of treatment. A significant reduction in body weight was observed in treated rats as compared to control animals. An advancing age-induced marginal increase in hepatic lipid peroxidation was observed in both male and female rats, while no such difference in hepatic DNA fragmentation was observed as compared to the control animals. Furthermore, selected organ weights individually and as a % of body weight and brain weight at 90 days of treatment exhibited no significant difference between the groups. No difference was observed in hematology and clinical chemistry or the histopathological evaluation. Taken together, these results show that 90 day treatment of HCA-SX results in a reduction in body weight, and does not cause any changes in major organs or in hematology, clinical chemistry, and histopathology.
Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate. In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226. Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Gilead Sciences.
[The introduction of Western psychiatry into Korea (II). Psychiatric education in Korea during the forced Japanese annexation of Korea (1910-1945)]. In the second report in our series on the historical investigation on the introduction of western psychiatry into Korea, authors deal with the status of psychiatric education during the Japanese forced annexation of Korea. The first lecture on psychiatry in Korea under the title "Mental Diseases" was held in Dae-han-eui-won around 1910. In 1913, the Department of Psychiatry branched off from the Department of Internal Medicine of Chosen-sotoku-fu-iing, the Colonial Governmental Clinic, the successor of Dae-han-eui-won. The chairman, Professor Suiju Sinji; and the Korean assistant Sim Ho-seop administered the psychiatric ward with 35 beds. Since 1913, an Australian missionary psychiatrist, Dr. McLaren began to teach neurology and psychiatry at Severance Union Medical College and established a Department of Psychiatry in 1923. Dr. McLaren was a faithful Christian and open minded toward Oriental religious thought such as in Buddhism and Taoism. He devoted himself to the humanitarian care of mentally ill patients and served there until 1937 when he had to leave the land due to Japanese persecution. His disciple, Dr. Lee Jung Cheol succeeded the chair of the Psychiatric Department of Severance Medical College and served until 1939. In 1916, Keijo (Seoul) Medical College was established and in 1928, Keijo Teikoku Daigaku (Imperial University). From 1929 to 1941, the Department of Neurology and Psychiatry of Keijo Imperial University grew under the chairmanship of Professor Kubo Kioji followed by Professor Watanabe until 1945. Many assistants including a few Koreans were gathered to the Department for training and research. The main textbook used for the psychiatric education for medical students in Korea was on Kraepelinian German Psychiatry translated and edited by Japanese psychiatrists. Lectures and clerkships for Neurology and Psychiatry were allocated generally in the curriculum for senior students for weekly 1-3 hours. Postgraduate professional training for the psychiatrists was carried out according to the tutorial system under the supervision of professors and staff. In regard to a wide range of references discovered in the library of the Department of Neurology and Psychiatry, Keijo Imperial University the trainees seem to have had opportunity to contact with diverse subspecialties of psychiatry and also to exercise specific laboratory examinations in the setting of the German linik". Comparisons of psychiatry in Korea and Japan during Japanese occupation suggest the following conclusions: 1. Extreme discrimination against Korean trainees in their academic careersprobably due to colonial policy. After 35 years of Japanese occupation of Korea only ten Korean neuro-psychiatrists and neurologists were left; 2. Somewhat narrow academic interests of psychiatrists in Korea in research fields focusing on neuropathology and opium addiction etc and the lackness of the interest in social psychiatric issues: for example, the rights of the mentally ill patient or non-restraining care systems as seen in Japanese psychiatry in Japan. 3. Extremely limited number of psychiatry teaching staffs in Korea. For a long time Keijo Imperial University's Department of Neurology and Psychiatry was the only center for training psychiatrists in Korea.
Paramedic judgment of the need for trauma team activation for pediatric patients. To determine the value of paramedic judgment in determining the need for trauma team activation (TA) for pediatric blunt trauma patients. A prospective, observational study was conducted at the ED of Children's Hospital Medical Center of Akron between July 12, 1996, and February 28, 1997, in cooperation with Akron Fire Department emergency medical technician-paramedics (EMT-Ps). The ED provides on-line and off-line medical control for pediatric transports. Patients with minor or no identifiable injuries are released at the scene with the instructions to see a physician. The remainder are transported to the ED. The decision for TTA is based on ED trauma protocols as well as emergency physician judgment of injury severity in combination with the judgment of the treating paramedic. During the study, EMT-Ps were asked (before physician input) whether, based solely on their judgment, a patient needed TTA. Patients 0-14 years old who were involved in motor vehicle crashes, bike crashes, or falls from a height of >10 feet were included in the study. TTA was defined as necessary if the patient was admitted to the intensive care unit (ICU) or operating room (OR) for nonorthopedic surgical procedures. Out-of-hospital, ED, and hospital records were reviewed. Coroners' records as well as medical records of all trauma admissions during the study period were reviewed to ensure that the patients released at the scene were not mistriaged. One hundred ninety-two patients met study criteria. Eighty-five patients (44%) were transported to the ED, of whom 12 had TTA. EMT-Ps requested TTA for 10 of these patients, and 2 patients had TTA per ED trauma protocol. Two of the patients who were judged by EMT-Ps to need TTA were admitted to the ICU/OR, and neither of the patients identified by ED trauma protocol to require TTA were admitted to the ICU/OR. Two initially stable patients who did not have TTA deteriorated after arrival to the ED. Both were admitted to the ICU. The sensitivity and specificity of paramedic judgment of the need for TTA for pediatric blunt trauma patients were 50% (95% CI 9.2-90.8) and 87.7% (95% CI 78.0-93.6), respectively. The positive and negative predictive values were 16.7% (95% CI 2.9-49.1) and 97.3% (95% CI 89.6-99.5). None of the patients released at the scene was mistriaged based on the review of the coroners' and trauma admission records. Results of this investigation indicate that a small percentage of pediatric blunt trauma patients require TTA. EMT-P judgment alone of the need for TTA for pediatric blunt trauma patients is not sufficiently sensitive to be of clinical use. The low sensitivity is explained by the deterioration in the clinical condition of 2 initially stable patients. The paramedic disposition decisions from the scene were always accurate. Nontransport by emergency medical services (EMS) may be acceptable in some uninjured pediatric trauma patients. Injured pediatric trauma patients who appear to be stable may deteriorate shortly after injury. However, if a pediatric patient appears injured, transport from the scene and examination by a trauma specialist are needed. Finally, the role of paramedic judgment must be further defined by larger studies with urban, rural, and suburban EMS systems before it can be used as a sole predictor of TTA.
Trends and determinants of antiresorptive drug use for osteoporosis among elderly women. It has been established that women who have had a first osteoporotic fracture are at a significantly greater risk of future fractures. Effective antiresorptive treatments (ART) are available to reduce this risk, yet little information is available on trends in ART drug use among the elderly. The objective is to estimate the rate ratio (RR) of having an ART prescription filled among elderly women and its relation to selected determinants from 1995 through 2001. A cohort design was used. Through random sampling, we selected 40% of the women aged 70 years and older listed in the Régie de l'assurance maladie du Québec (RAMQ) health database. The women were grouped into four cohorts (for 1995, 1996, 1998 and 2000). January 1 was established as the index date within each cohort (1995, 1996, 1998 and 2000). The dependent variable was the RR of having at least one prescription of ART drugs filled during the year following the index date among women with and without prior use. ART users were divided in two groups: bone-specific drugs (bisphosphonates, calcitonin, raloxifen) and HRT (hormone replacement therapy). The independent variable was whether or not (control) there had been an osteoporotic-related fracture. The RR was determined for having at least one prescription of bone-specific drugs or of HRT filled during the year following the index date using a Cox regression adjusted for age, chronic disease score (CDS) and prior bone mineral density (BMD) test. Crude rates of BMD testing (per 500 person-years) ranged from 20.4 (1995) to 41.1 (2000) in women who had had an osteoporotic-related fracture, and from 4.4 to 15.3 in controls. The crude rate of women (per 100 person-years) who had had an osteoporotic-related fracture and who took at least one bone-specific drug during follow-up ranged from 1.9 in 1995 to 31 in 2000 among those with prior osteoporotic-related fracture, and from 0.5 in 1995 to 11 in 2000 for controls; the corresponding figures for HRT ranged 6.7 in 1995 to 13 in 2000, and from 8.4 in 1995 to 11 in 2000 respectively. BMD test is the only major factor affecting the adjusted RR of having a prescription filled for bone-specific drugs (RR of 10.44; 6.91-15.79 in 1995 and RR of 3.68; 3.30-4.10 in 2000) or HRT (RR of 2.08; 1.64-2.64 in 1995 and RR of 1.44; 1.17-1.77 in 2000), particularly among women who had not had prior use. The fact of having a fracture status does significantly affect the RR of having at least one bone-specific drug prescription filled only among women without prior use (RR of 1.71; 1.26-2.33 in 1996 and RR of 1.77; 1.44-2.19 in 2000). The fact of being younger did not affect the RR of having at least one prescription of bone-specific drugs filled, but being younger increased the RR of filling a prescription of HRT. Significant change was seen over time in the number of BMD tests ordered and ART use. Effective osteoporosis interventions are not optimal in the treatment of elderly women in a Canadian health-care system who have had an osteoporotic fracture, given that approximately 25% of women who had had an osteoporotic-related fracture were users of ART.
[Analysis on risk factors of endotracheal cuff under inflation in mechanically ventilated patients]. To investigate the prevalent condition of endotracheal cuff pressure and risk factors for under inflation. A prospective cohort study was conducted. Patients admitted to the Department of Critical Care Medicine of Fuxing Hospital Affiliated to Capital Medical University, who were intubated with a high-volume low-pressure endotracheal tube, and had undergone mechanical ventilation for at least 48 hours, were enrolled. The endotracheal cuff pressure was determined every 8 hours by a manual manometer connected to the distal edge of the valve cuff at 07 : 00, 15 : 00, and 23 : 00. Measurement of the endotracheal cuff pressure was continued until the extubation of endotracheal or tracheostomy tube, or death of the patient. According to the incidence of under inflation of endotracheal cuff, patients were divided into the incidence of under inflation lower than 25% group (lower low cuff pressure group) and higher than 25% group (higher low cuff pressure group). The possible influencing factors were evaluated in the two groups, including body mass index (BMI), size of endotracheal tube, duration of intubation, use of sedative or analgesic, number of leaving from intensive care unit (ICU), the number of turning over the patients, and aspiration of sputum. Logistic regression analysis was used to determine risk factors for under-inflation of the endotracheal cuff. During the study period, 53 patients were enrolled. There were 812 measurements, and 46.3% of them was abnormal, and 204 times (25.1%) of under inflation of endotracheal cuff were found. There were 24 patients (45.3%) in whom the incidence of under inflation rate was higher than 25%. The average of under inflation was 7 (4, 10) times. Compared with the group with lower rate of low cuff pressure, a longer time for intubation was found in group with higher rate of low cuff pressure [hours: 162 (113, 225) vs. 118 (97, 168), Z=-2.034, P=0.042]. There were no differences between the two groups in other factors, including size of endotracheal tube, the time from intubation to first measurement of endotracheal cuff pressure, number of leaving from ICU during admission, use of sedative agent or analgesic, and the number of body turning and aspiration (all P>0.05). No risk factor was found resulting from under inflation of the endotracheal cuff by logistic regression analysis. No significant difference was found in the incidence of ventilator associated pneumonia, duration of mechanical ventilation, successful rate of weaning on 28th day, or 28-day mortality after weaning from mechanical ventilation, and ICU mortality between the two groups. However, patients in the group of higher rate of low cuff pressure had a longer ICU stay compared with that in the group of lower rate of low cuff pressure group [days: 13 (8, 21) vs. 10 (6, 18), Z=-2.120, P=0.034]. Abnormal endotracheal cuff pressure is common in critically ill patients with intratracheal intubation. Duration of intubation is associated with under inflation of the cuff, and it calls for strengthening monitoring and management.
[Insulin, glucagon and growth hormone responses during glucose, arginine and insulin tolerance tests in children with hyperthyroidism]. There are many reports of glucose intolerance in adult patients with hyperthyroidism but few reports of glucose intolerance in hyperthyroid children. In this study, we measured plasma levels of glucose, insulin, glucagon and growth hormone in hyperthyroid children and control subjects by the use of three kinds of tolerance tests: an oral glucose tolerance test, an arginine tolerance test and an insulin tolerance test. In the oral glucose tolerance test, mean fasting glucose levels (79.6 +/- 1.4 mg/dl) rose to maximum levels (157.3 +/- 4.3 mg/dl) at 30 min in hyperthyroid children which were significantly higher than the levels in control subjects (p less than 0.01). The maximum levels of glucose fell slowly and returned to fasting levels at 180 min. In this test, plasma insulin levels increased from basal levels (12.7 +/- 1.9 microU/ml) to maximum levels (120.8 +/- 22.1 microU/ml) at 30 min in the prepubertal age group of hyperthyroidism. On the other hand, in the pubertal age group of hyperthyroidism, maximum levels of insulin were observed at 60 min, but not at 30 min. These maximum levels of insulin of both hyperthyroid age groups were significantly higher than those in the control subjects (p less than 0.05, p less than 0.01 respectively). There was no difference in insulin-glucose ratio at 30 min (delta IRI/delta BG) and insulinogenic index (I.I.) at 0 to 60 min between these two groups of hyperthyroid children and control subjects. However, I.I. at 0 to 120 min and 0 to 180 min decreased significantly in the pubertal age group of hyperthyroidism as compared with those in the control group (p less than 0.05, p less than 0.02 respectively). In the oral glucose tolerance test, plasma glucagon levels decreased from basal levels (74.1 +/- 4.3 pg/ml) to minimum levels (36.4 +/- 4.7 pg/ml) at 90 min in hyperthyroidism, which were significantly lower than those in the controls (p less than 0.05). However, there was no difference in -epsilon delta IRG/epsilon delta BG (cumulative glucagon response/cumulative glucose response) between the subjects with hyperthyroidism and the controls. On the other hand, lower responses of blood glucose, insulin, glucagon and growth hormone to arginine were observed in subjects with hyperthyroidism than in the controls. Moreover in the insulin tolerance test, there was no difference in glucagon and growth hormone response between the subjects with hyperthyroidism and the controls. Thus our conclusions are as follows: A marked increase in blood glucose after oral glucose load was observed in spite of normal insulin-glucose ratio in hyperthyroid children, suggesting the existence of peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
Influence of follicle size, methods of retrieval on oocytes yield and morphology in Egyptian Jennies ovaries with special reference to maturation rate in vitro. This work was designed to evaluate the ovarian follicular development, oocytes morphology, methods of oocytes reterival, and the effect of different in vitro maturation (IVM) media on cumulus cell expansion and nuclear maturation of Jennies oocytes. Experiment 1, the number of small (<6 mm), medium (6 to 9 mm) and large size (>10 mm) ovarian follicles was recorded. Cumulus-oocyte-complexes (COCs) were reterived and classified into 4 Grades based on their cumulus-cells investment and the homogenous of the ooplasm. In Experiment 2, COCs were recovered by using 18-G, 20-G needle or slicing and scraping of ovarian follicles to determine the number and morphology of the recovered COCs. In Experiment 3, Grade A and B COCs were IVM in DMEM-HG, DMEM-LG, DMEM-F12, TCM199, TCM199-F12 or CR1aa media supplemented with 10% FCS+10 μg FSH/mL+10 IU hCG/mL+50 μg/mL gentamicin. Maturation was performed for 36 h at 38.5 °C under 5% CO2 in humidified air. After IVM, cumulus cell expansion and oocytes nuclear canfiguration were determined. An average of 6.40±0.26 follicles was recorded per Jenny ovary, representing 3.37±0.46, 1.89±0.14 and 1.14±0.16, for the small, medium and large size follicles, respectively. Oocyte recovery was higher (P<0.05) in large and medium size follicle than in the small one (62%, 60% and 45.1%, respectively). Small size follicles produced higher (P<0.05) percentage of Grade A COCs than large or medium size follicles. A higher number of oocytes was recovered by slincing and scraping of follicles (4.86±0.67), then aspiration of follicles using 18-G needle (3.14±0.36 COCs/ovary, P<0.05). Aspiration using 18-G needle or slicing and scraping of follicles using produced a significantly higher (P<0.05) percentage of Grade A COCs compared to aspiration of follicles using 20-G needle (56.6%, 46.7% and 32.0%, respectively, P<0.05). IVM of COCs in CR1aa and TCM 199-F12 media significantly increased (P<0.05) Grade 3 cumulus-cell expansion compared with TCM199, DMEM-F12, DMEM-LG and DMEM-HG (65.5% and 64.0%, 52.8%, 32.1%, 0.0% and 7.4%, respectively). The proportion of IVM oocytes reaching the M II stage was significantly higher (P<0.05) for oocytes matured in TCM199-F12 or CR1aa media than TCM199, DMEM-HG, DMEM-LG, DMEM-F12 (69.1% and 62.2%, 55.7%, 45.8%, 39.0% and 40.7%, respectively). The proportion of degenerated oocytes IVM in TCM199-F12 (10.3%), CR1aa (11.3%) or TCM199 (13.1%) was lower (P<0.05) than that matured in DMEM-HG, DMEM-LG or DMEM-F12 media (23.7%, 29.3% and 22.9%, respectively). Slicing and scraping or aspiration of follicles using 18-G needle increased the number and percentage of Grade A Jennies oocytes. TCM199-F12, CR1aa and TCM199 medi are more suitable for IVM of Jenny oocytes by promoting cumulus cells expansion and nuclear maturation to M II stage.
Treatment of malaria and related symptoms using traditional herbal medicine in Ethiopia. Medicinal plants have always been an integral part of different cultures in Ethiopia in the treatment of different illnesses including malaria and related symptoms. However, due to lack of proper documentation, urbanization, drought, acculturation and deforestation, there is an increased risk of losing this traditional knowledge. Hence, the use of the indigenous knowledge should be well documented and validated for potential future use. To gather and document information on medicinal plants which are used in the traditional treatment of malaria and related symptoms in Ethiopia. First, an ethnomedicinal survey of plants was conducted in 17 districts of Jimma zone, the Oromia national regional state of Ethiopia. Jimma zone is malarious and rich in natural flora. A total of 115 traditional healers were interviewed using a semi-structured questionnaire containing personal data of the respondents, and information on medicinal plants used to treat malaria and related symptoms. In addition, a literature search using Medline/PubMed, Google Scholar, ScienceDirect and HINARI was conducted on the indigenous use, in-vitro/in-vivo anti-malarial activity reports, and the chemical characterization of medicinal plants of Ethiopia used against malaria. From ethnomedicinal survey, a total of 28 species of plants used in the traditional treatment of malaria and related symptoms in Jimma Zone were collected, identified and documented. In addition, the literature search revealed that 124 medicinal plant species were reported to be traditionally used in the treatment of malaria in Ethiopia. From both ethnomedicinal survey and the literature search, Asteraceae and Fabaceae were the most represented families and Allium sativum L., Carica papaya L., Vernonia amygdalina Del., Lepidium sativum L. and Croton macrostachyus Del. were the most frequently reported plant species for their anti-malarial use. The dominant plant parts used in the preparation of remedies were leaves. About 54% of the medicinal plants documented in the survey have been reported as an anti-malarial plant in the literature search. Furthermore, the in-vitro and in-vivo anti-plasmodial activity reports of extracts from some of plant species were found to support the traditional claim of the documented plants. Moreover, literatures indicate that several secondary metabolites isolated from certain plant species that are traditionally used for the treatment of malaria and related symptoms in Ethiopia demonstrate strong anti-plasmodial activity. The result of the current study showed that traditional knowledge is still playing an important role in the management of malaria and related symptoms in Ethiopia. Allium sativum L., Carica papaya L., Vernonia amygdalina Del., and Lepidium sativum L. are the most commonly reported species as anti-malarial plants and the traditional claim of some species was supported by known anti-plasmodial activity and bioactivity reports. The finding of this study is important in the rational prioritization of plant species which are potentially used for investigating new compounds, which could be efficacious for malaria treatment.
Effects of different types of solid feeds on health status and performance of Swiss veal calves. I. Basic feeding with milk by-products. The objective of this study was to identify a suitable alternative to the current practice of complementing the feeding of milk by-products with straw. The influence of 5 different types of solid feeds on health and performance of Swiss veal calves was investigated in 2 production cycles of 200 veal calves each with a mean initial age of 40 days (d). The calves were housed in groups of 40 in stalls with outside pen. Liquid feeding consisted of a milk by-product combined with an additional skim milk powder ad libitum. Groups were assigned to 1 of the 5 following experimental solid feeds provided ad libitum: mix (composition: soy flakes, corn, barley, wheat, oat, barley middling, plant oil, molasses), whole plant corn pellets, corn silage, hay, and wheat straw as control. Daily dry matter intake per calf averaged 2.25 kg of the liquid food, 0.16 kg of straw, 0.33 kg of mix, 0.47 kg of corn silage, 0.38 kg of corn pellets, and 0.39 kg of hay. No significant differences (P > 0.05) among groups were found in calf losses that amounted to 4.8 % (68 % because of gastrointestinal disorders). Four percent of the calves were slaughtered prematurely. Daily doses of antibiotics were higher in the mix (36.9 d, P < 0.01) and in the corn silage groups (35 d, P < 0.01) compared to control. Compared to the 4 other groups, calves of the straw group showed the highest prevalence of abnormal ruminal content (73 %, P < 0.05), of abnormal ruminal papillae (42 %, P < 0.05), of abomasal fundic lesions (13.5 %, P < 0.1), and the lowest number of chewing movements per bolus (45, P < 0.05). The hemoglobin concentration averaged 85 g/l at the beginning and 99 g/l at the end of the fattening period with no significant differences among groups (P > 0.1). The duration of the fattening period averaged 114 d, slaughter age 157 d, and carcass weight 122 kg. The average daily weight gain (ADG) was highest in the control group straw (1.35 kg), and lowest in the hay group (1.22 kg, P < 0.01). The number of carcasses classified as C, H, and T (very high to medium quality) was lower in the hay group compared to straw (P < 0.01). No significant differences between groups were found in meat color (P > 0.1): 73 % of the carcasses were assessed as pale (267/364), 18 % as pink (66/364), and 9 % (31/364) as red. The results reveal that whole-plant corn pellets are most consistent with an optimal result combining the calves' health and fattening performance. Therefore, it can be recommended as an additional solid feed for veal calves under Swiss conditions.
Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients. prostaglandin (PG) biosynthetic profiles from endogenous arachidonic acid were determined by capillary gas chromatography-mass spectrometry in matched fresh normal lung (NL) and lung cancer (LC) tissue fragments obtained from 42 individual LC patients at the time of diagnostic thoracotomy. The histological diagnoses represented were squamous cell carcinoma (N = 20), adenocarcinoma (N = 7), small cell carcinoma (N = 4), mixed cell carcinoma (N = 2), bronchioloalveolar cell carcinoma (N = 2), large cell undifferentiated carcinoma (N = 3), bronchial carcinoid (N = 1), and metastatic tumors (N = 3). When PG biosynthesis was determined in NL tissue separately, low mean levels of PGE2 and PGF2 alpha (less than 2 pmol/mg protein/15 min), intermediate levels of PGD2 and 6-keto-PGF1 alpha (6KPGF1 alpha) (2-7 pmol/mg protein/15 min), and high levels of thromboxane B2 (TXB2) (greater than 7 pmol/mg protein/15 min) were observed. There was no particular correlation with cigarette smoking history and PG biosynthesis in NL. When PG production in LC tissue was evaluated separately, high levels of PGE2, PGF2 alpha, and 6KPGF1 alpha as well as TXB2 and low levels of PGD2 were noted. In addition, LC tissue from cigarette smokers demonstrated elevated levels of PGE2, 6KPGF1 alpha, and TXB2 when compared to current nonsmokers with LC (P less than 0.05 in all instances). Simultaneous comparison of PG production in matched LC and NL tissue from individual patients indicated increased biosynthesis of PGE2 and PGF2 alpha and low levels of PGD2 in LC compared to NL tissue (P less than 0.05 in all instances; paired, two-tailed, Student's t test). Individual comparison of PG biosynthesis according to LC histological cell type revealed that PGE2 and PGF2 alpha were consistently elevated in all four common primary LC histological cell types, the only exception being large cell undifferentiated carcinoma. Interestingly, this latter LC histological cell type presented a unique profile with lower levels of PGE2 and PGD2 in LC than in NL tissue (P less than 0.05 in both instances). In addition, the biosynthesis of all 5 PGs studied was consistently higher in primary than metastatic adenocarcinomas of the lung (P less than 0.05 in all instances). No differences were observed in NL and LC tissue for the major LC histological cell types when PGD2, TXB2, or 6KPGF1 alpha biosyntheses were compared. These findings indicate that the profiles of PG biosynthesis in LC and NL tissue from individual patients may differ substantially. These differences may reflect, in part, contributions to the PG biosynthetic profile unique to malignant cells.
Outcome of ICSI cycles using frozen-thawed surgically obtained spermatozoa in poor responders to ovarian stimulation: cancellation or proceeding to ICSI? To investigate the ICSI outcome of the patients who produced four follicles or less after ovarian stimulation using frozen-thawed surgically obtained spermatozoa. The patient cohort of this study was composed of a carefully selected group of 20 men suffering from obstructive and non-obstructive azoospermia and in whom spermatozoa had been seen in their harvested epididymal aspirates and testicular tissues and the cryopreserved specimens had been used for subsequent ICSI cycles. This group of men represent those in whom the female partners produced only four follicles or less after ovarian stimulation. For the cases of obstructive azoospermia with MESA (n=6) a total of nine cycles was carried out. Four couples went through one cycle, one couple underwent two cycles, one couple accomplished three cycles. Out of the nine cycles, seven went to embryo transfer. No pregnancy occurred in the MESA-ICSI group of patients. The mean+/-S.D. number of oocytes per cycle was 2.556+/-1.236, the mean+/-S.D. number of embryos per transfer was 1.444+/-1.014. Two couples did not have an embryo replacement because of absence of fertilisation. The mean+/-S. D. number of gonadotropin ampoules was 53.88+/-37.30 and the mean+/-S.D. duration of ovarian stimulation was 13.38+/-4.534 days. For the cases of non-obstructive azoospermia with TESE (n=14) a total of 16 cycles was carried out. Thirteen couples went through one cycle, one couple accomplished three cycles. Out of the 16 cycles, 11 cycles went to embryo transfer. One pregnancy occurred in the TESE-ICSI group of patients, which produced live offspring. The mean+/-S.D. number of oocytes per cycle was 3.00+/-1.211, the mean+/-S.D. number of embryos per transfer was 1.313+/-1.195. Five couples did not have an embryo replacement, four of them because of absence of fertilisation and one because of abnormal fertilisation (3 PN). The mean+/-S.D. number of gonadotropin ampoules was 81. 77+/-53.40 and the mean+/-S.D. duration of ovarian stimulation was 16.71+/-3.667 days. In our opinion, these data show that it is possible to achieve satisfactory fertilisation rates using frozen-thawed epididymal and testicular spermatozoa obtained from men with obstructive or non-obstructive azoospermia, but the limiting factor in reaching the stage of embryo transfer is the poor ovarian response to stimulation induction. It therefore seems preferable to cancel these cycles, in the hope that a better response might be obtained in a subsequent cycle, avoiding in this way financial and emotional implications.
Boronated protoporphyrin (BOPP): localization in lysosomes of the human glioma cell line SF-767 with uptake modulated by lipoprotein levels. Boronated protoporphyrin (BOPP) is a candidate for use in both boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) of glioblastoma multiforme (GBM). Our objectives are to identify factors that influence the uptake and retention of BOPP in vitro and to determine BOPP distribution in a human glioma cell line in vitro. This information will aid the development of compounds and treatment strategies that increase the effectiveness of BNCT therapy for GBM. The amount, distribution pattern, and site of internalization of BOPP were assessed using fluorescence microscopy. Living human glioma (SF-767) cells were imaged after a 24-h exposure to BOPP (20-135.6 microg/ml, normal serum). Dose-dependent uptake of BOPP was determined using both fluorescence microscopy of individual living cells and inductively-coupled plasma-atomic emission spectroscopy (ICP-AES) analysis of cell pellets. Lysosome- or mitochondria-specific fluorescent probes were used to identify the cellular compartment containing BOPP. Two human fibroblast cell lines, AG-1522 (LDL receptor-positive) and GM019-15C (LDL receptor-deficient), were used to investigate LDL receptor-dependent BOPP uptake. The dependence of BOPP uptake on lipoproteins in the media was determined by exposing each of the three cell types to BOPP in medium containing either normal (NS) or lipoprotein deficient serum (LPDS). BOPP accumulated in the lysosomes of human glioma cells in vitro, and not in the mitochondria, as reported for C6 rat glioma cells in vitro. BOPP uptake was concentration-dependent and was also dependent on the amount of lipoproteins in the medium. Over the range of incubation concentrations studied and at the single exposure duration time point investigated (24 h), all cells retained a similar amount of BOPP. At the lowest incubation concentration (20 microg/ml, NS), the amount of boron retained was near 10(9) atoms per cell (15 microg B/g cells). Lysosomes containing high concentrations of BOPP were randomly distributed throughout the cytoplasm; however, larger lysosomes containing BOPP were concentrated around the cell nucleus. Little or no BOPP accumulated in the cell nucleus. At incubation concentrations of 20 and 40 microg/ml (24-h time point), BOPP uptake in SF-767 cells was reduced in LPDS compared with NS (66% reduction). A similar result was observed for normal human fibroblasts (AG-1522 cells, 40 microg/ml, 24 h). At 40 microg/ml, in both NS and LPDS at 24 h, BOPP accumulation in LDL receptor-deficient human fibroblasts (GM019-15C cells) was reduced relative to AG-1522 cells. BOPP accumulation in GM019-15C cells (40 microg/ml, 24 h) was not affected by serum lipoprotein levels. In cell culture, BOPP is taken up by human glioma cells via the LDL pathway and is compartmentalized into cellular lysosomes. Knowledge of this mechanism of BOPP uptake and retention will be important in attempts to modify toxicity and efficacy of this drug.
Topical review on the abuse and misuse potential of tramadol and tilidine in Germany. Tramadol and tilidine (in combination with naloxone) are used as weak opioid analgesics in Germany. Tramadol is not scheduled in the German Narcotic Drugs Act. Tilidine is scheduled, whereas Tilidine in fixed combinations with naloxone is exempt from some of the provisions of the Narcotic Drugs Act. Recent reports on misuse of both substances led to an evaluation of their potential for misuse, abuse, and dependency by the expert advisory committee established by the German Federal Government, resident at the Federal Institute for Drugs and Medical Devices. A subcommittee formulated key questions and identified available data sources for each of these questions. Additional information was solicited where necessary, including a survey among a panel of pharmacists, a survey in an addiction clinic, analysis of prescription patterns, and information from the boards of pharmacists of the federal states and the Federal Bureau of Criminal Investigation. Analgesic efficiency in the treatment of acute and chronic pain has been proven for both tramadol and tilidine/naloxone. For tramadol, high evidence has been confirmed in systematic reviews, and tramadol is listed in national and international guidelines on acute and chronic pain management. Animal and human studies found a low potential for misuse, abuse, and dependency for both substances. Information from 2 tramadol safety databases allowed calculation of the incidence of abuse or dependency as 0.21 and 0.12 cases per million defined daily dosages (DDDs), with lower incidences in recent years. For tilidine/naloxone, the incidence was calculated as 0.43 cases per million DDDs for oral solution and 0.18 for slow-release tablets. In an online survey among German pharmacies as well as in the reports from state pharmacy boards, fraud attempts were repeated more frequently with tilidine/naloxone than with tramadol in the last 2 years. The Federal Bureau of Criminal Investigations reported prescription fraud only with tilidine/naloxone and predominantly in the region of Berlin. Dependency on tramadol or tilidine/naloxone is reported only rarely from addiction counseling centers. One third of the patients surveyed in an addiction clinic reported experiences with tramadol or tilidine/naloxone, but mostly with duration of less than 4 weeks and with a medical prescription based on a reasonable indication. Also, occasional illegal use of opioid analgesics as a substitute of heroin was reported. An evaluation of pooled data from statutory health insurance companies found 2.5% of persons receiving at least 1 prescription of tramadol or the combination of tilidine and naloxone in 2009 (1.6% with tramadol and 1.0% with tilidine/naloxone). High usage with more than 180 DDDs per year was found in 8.6% of patients treated with tramadol and 17.2% of patients with tilidine/naloxone. In conclusion, the subcommittee of the expert advisory committee found a low potential for misuse, abuse, and dependency for tramadol, and a low prevalence in clinical practice. Considerable less information is available for the combination of tilidine and naloxone. However, the cumulation of evidence indicated a higher risk of misuse, abuse, and dependency for tilidine/naloxone solution, but not for slow-release tablets.
Chewing gum vs. ibuprofen in the management of orthodontic pain, a multi-centre randomised controlled trial - the effect of anxiety. Pain is a common side effect of orthodontic treatment. An objective of this study, part of a large previously reported RCT on pain and analgesic use, was to determine the effect of anxiety on perceived pain and use of analgesia. 1000 patients aged 11-17 years, undergoing upper and lower fixed appliance treatment in nine hospital departments were recruited into this two-arm parallel design randomised controlled trial. One arm was given sugar-free chewing gum and the other arm ibuprofen for pain relief. Neither the clinicians nor patients were blinded to assignment. In addition to recording pain experience and analgesic use for 3 days following appliance placement and first archwire change, each patient recorded their level of anxiety immediately following the fitting of the appliance and the first archwire change. 419 chewing gum group (84%) and 407 ibuprofen group (83%) questionnaires were returned following appliance placement, and 343 chewing gum group (70%) and 341 ibuprofen group (71%) questionnaires were returned following the first archwire change. The mean anxiety scores following fitting of the appliance and first archwire change were 2.7 (SD 2.1) and 1.6 (SD 1.8), respectively. There were weak but significant positive associations between anxiety scores and pain scores. Multi-level modelling produced a coefficient for anxiety of 0.23 (95% CI 0.17-0.28) for appliance placement, suggesting a small rise (0.23) on the 11-point pain scale for a one-point increase on the corresponding anxiety scale. Following archwire change, the corresponding coefficient was 0.32 (0.24-0.39). For ibuprofen use, again simple analyses suggested a relationship with anxiety. Multi-level logistic modelling produced an odds ratio for ibuprofen use of 1.11 (95% CI 1.07-1.15) at appliance placement and 1.21 (1.10-1.33) at the first archwire change. There was a 10-20% increase in the odds of using ibuprofen for each one-point increase on the anxiety scale. No such relationship was found between anxiety and chewing gum use. There were no adverse effects or harms reported during the trial. Approvals were granted by the Research Ethics Committee (08/H0106/139), R&D and MHRA (Eudract 2008-005522-36) and the trial was registered on the ISRCTN (79884739) and NIHR (6631) portfolios. Support was provided by the British Orthodontic Society Foundation. There was a weak positive correlation between anxiety reported and pain experienced following both the initial fitting of the fixed appliances and at the subsequent archwire change. Patients that were more anxious tended to take more ibuprofen for their pain relief.
Surgical treatment for urinary incontinence in women - Danish nationwide cohort studies . This PhD thesis is based on three original articles. The studies were performed at the Department of Obstetrics and Gynaecology, Herlev University Hospital and at the Center for Clinical Epidemiology, Odense University Hospital. Urinary incontinence (UI) is a frequent disorder among women, which for the individual can have physical, psychological and social consequences. The current standard of surgical treatment is the synthetic midurethral sling (MUS), which is a minimal invasive procedure. As the synthetic MUSs (TVT,TVT-O,TOT) were introduced in the late 1990s, there are only a few studies at the long-term follow-up based on nationwide populations; only a few have reported on the risk of reoperation and there is sparse evidence on which treatment should be used subsequently to failure of synthetic MUSs. Several surgical specialties have documented that department volume, surgeon volume and patient-related factors influence the quality of care. There is little knowledge regarding this in the surgical treatment for UI. The aims of the thesis were therefore: 1. To describe the five-year incidence of reoperation after different surgical procedures for UI based on a nationwide population over a ten-year period (1998-2007) and to evaluate the influence of department volume (Study I). 2. To describe the choice of repeat surgery after failed synthetic MUSs and the departmental volume for the surgical treatment at reoperation over a ten-year period (1998-2007) based on a nationwide background population (Study II). 3. To evaluate efficacy of urethral injection therapy (UIT) based on patient reported outcome measures (PROMs) and hospital contacts within 30 days for women registered in the Danish Urogynaecological Database (DugaBase) over a five-year period (2007-2011) and the influence of department volume, surgeon volume and patient-related factors (Study III). Study I: A total of 8671 women were recorded in the Danish National Patient Registry as having undergone surgical treatment for UI from 1998 through 2007. The lowest rate of reoperation within five years was observed among women who had pubovaginal slings (6%), TVT (6%) and Burch colposuspension (6%) followed TOT (9%), and miscellaneous operations (12%), while the highest observed risk was for UIT (44%). After adjustment for patient´s age, department volume and calendar effect TOT carried a 2-fold higher risk of reoperation (HR, 2.1; 95% CI, 1.5 -2.9) compared with TVT. Study II: A total of 5820 women had synthetic MUSs at baseline from 1998 through 2007 and were registered in the Danish National Patient Registry and 354 (6%) of these women had a reoperation. The first choice treatment for reoperation was a synthetic MUS and UIT was a frequent second choice. At reoperation, 289 (82%) of the women were treated at the department where they had undergone the primary synthetic MUS. Fewer treatment modalities were in usage and significantly more TOTs were implanted at low volume departments compared to high volume departments. Study III: A total of 731 women of age 18 or older with first time UITs were registered with first-time UIT in the DugaBase from 2007 through 2011. Logistic regression was used to predict the odds of success pertaining to department volume, surgeon volume and patient-related factors on the Incontinence Questionnaire-Short Form (ICIQ-SF) (frequency of UI, amount of leakage and impact of UI on daily life) and the rate of 30-day hospital contacts. We applied the definition of "cure" as set out by the steering committee of the DugaBase where a satisfactory result is leakage once a week or less, often or never based on the frequency score and similarly "no leakage at all" based on the frequency score as answering never to leakage. Among the 252 women who pre- and postoperatively had answered both questionnaires, 75 (29.8%) were cured and 23 (9.1%) achieved no leakage at all at three months follow-up. There was a statistically significant improvement on all three scores of the ICIQ-SF. The mean total ICIQ-SF score was 16.0 (SD 3.8) and after injection at three months follow-up 10.6 (SD 6.2) (p < 0.001). UIT was performed at 16 departments, of which four high volume departments performed 547 of 814 UITs (67.2%). The risk of hospital contacts was lower for women treated at a high volume department (adjusted OR 0.27; 95% CI 0.09-0.76). Women treated by a high volume surgeon (> 75 UITs during the career as a surgeon) had a higher chance of cure on the frequency score than the low volume surgeon (≤ 25 UITs) (adjusted OR 4.51; 95% CI, 1.21-16.82) and a lower risk of 30-day hospital contacts (adjusted OR 0.35; 95% CI, 0.16-0.79). Women with severe UI had less likelihood of cure in all ICIQ-SF scores. A preoperative use of antimuscarinic drugs lowered the chance of cure on the frequency (adjusted OR 0.14; 95%, CI 0.04-0.41) and the amount score (adjusted OR 0.33; 95%, CI 0.13-0.82). Conclusions: Study I: The study provided physicians with a representative evaluation of the rate of reoperations after different surgical procedures for UI. The observation that TOT was associated with a significantly higher risk of reoperation than TVT is novel in the literature and has important implications for both surgeons and patients when they consider surgical options for UI. Study II: The majority of women had reoperation at the same department as the primary synthetic MUS. Fewer treatment modalities were in use at low volume departments compared with high volume departments. It seems appropriate in the absence of evidence for the best treatment after failed synthetic MUSs, that women are referred to highly specialized departments for diagnosing and treatment. Study III: This national population-based cohort study represented cure among women who had UIT in an everyday life setting. Results seemed to be in the lower end of the spectrum compared to the literature. A learning curve for UIT indicated that the treatment should be restricted to fewer hands to improve the surgical education and consequently be a success for women with UIT. The severity of UI was a strong predictor for a lower degree of cure. Similarly, the use of antimuscarinic drug preoperatively decreased the likelihood of cure indicating that women with severe MUI or UUI also have less chance of cure.
Vitamin D status of children with moderate to severe chronic Kidney Disease at a Tertiary Pediatric Center in Cape Town. The prevalence of suboptimal Vitamin D levels is higher in patients with chronic kidney disease (CKD) than in the general population. Recent findings suggest that progression of CKD is linked to a suboptimal Vitamin D level. A high percentage of CKD patients have severe Vitamin D deficiency. These patients also have a low level of 25-hydroxy-vitamin D [25(OH)D] and consequently, a reduced ability to form active 1,25-dihydroxyvitamin D. Various factors underlie the low level of 25(OH)D, including a sedentary lifestyle, decreased intake of Vitamin D due to CKD-related dietary restrictions, and decreased synthesis of Vitamin D in skin due to uremia. All these factors may be particularly influential in patients with progressively worsening CKD, including those receiving chronic dialysis. The objective of our study is to determine the prevalence of Vitamin D deficiency in children with CKD stages three to five and those receiving chronic dialysis, to ascertain whether there is a relationship between Vitamin D deficiency and the stage of CKD, and to identify any clinical correlates associated with the Vitamin D status. A single-center, retrospective review was conducted of 46 children (younger than 18 years) with CKD stages 3-5D who attended the renal clinic of the Red Cross Children's Hospital between October 2013 and November 2014. In total, 73.9% of the study population had suboptimal Vitamin D levels (43.5% and 30.4% had Vitamin D deficiency and insufficiency, respectively). The prevalence of Vitamin D deficiency was significantly higher in older children (≥10 years of age) than in younger children (P = 0.000) but did not significantly differ between males and females (P = 0.693). In total, 12 of 15 black children (80%), 19 of 26 colored children (73.1%), two of four white children (50%), and one Asian child (100%) had suboptimal Vitamin D levels. Neither white nor Asian child had Vitamin D deficiency. In addition, 90% of patients undergoing chronic dialysis, 80% of whom were receiving peritoneal dialysis, had suboptimal Vitamin D levels. Age, weight, height, and the albumin concentration were significantly associated with the Vitamin D level. There was a positive linear relationship between the Vitamin D level and the serum albumin concentration (Spearman's rho correlation coefficient = 0.397, P = 0.007). In total, 87.5% of patients with nephrotic-range proteinuria had suboptimal Vitamin D levels, and 80% were Vitamin D deficient (P = 0.004). A higher percentage of Vitamin D deficiency/insufficiency cases was documented during the winter (24/34, 70.6%) than during the summer (10/34, 29.4%); however, this difference was not statistically significant (P = 0.685). Sub-optimal Vitamin D is high among children with moderate to severe CKD and significantly higher in those undergoing chronic dialysis. The emerging evidence of the role of Vitamin D in slowing progression of CKD highlights the need for monitoring and correction of Vitamin D levels in predialysis children.
Qualitative needs assessment: healthcare experiences of underserved populations in Montgomery County, Virginia, USA. Portions of Montgomery County, Virginia, are designated a Medically Underserved Area with a large portion of this population experiencing limited access to healthcare services. In September 2008, the Federal Bureau of Primary Care awarded the authors a planning grant to assess community need in Montgomery County and to develop a strategic plan to establish a Federally Qualified Health Center (FQHC) to best meet these needs. An FQHC is a federally funded clinic mandated to provide medical, dental and mental health services to underserved communities. As part of the planning process, the decision was made to include qualitative data to better understand the needs of underserved residents in the community. Descriptive studies of target populations can provide further insight into community priorities for effective health improvement and planning. The objective of the study was to investigate and describe the perceptions, beliefs and practices that impact healthcare utilization among underserved populations in Montgomery County, Virginia. This study was conducted as part of a comprehensive community assessment to determine the feasibility of developing a FQHC. Community focus groups were conducted with target populations which were representative of the community. A thematic analysis of the transcribed field notes and group interviews was conducted. Qualitative data analysis was performed using the Analysis Software for Word-Based Records (AnSWR) developed by the Centers for Disease Control. Three important categories of beliefs which may impact healthcare utilization emerged from the discussions: (1) cultural health perceptions; (2) perceived barriers to care; and (3) coping strategies. Participants expressed a right to access quality care, preferred to spend money on basic living expenses rather than healthcare services; frequently neglected seeking care for adults while rarely neglecting to seek care for their children; valued but infrequently utilized preventative care; and had a lack of confidence in the care that was provided. Perceived barriers to healthcare services reported by participants included a lack of access to affordable care; complexities of health insurance and payer status; limited hours of clinic operation; lack of transportation and geographic distance; and the complexity of navigating the healthcare system. Finally, participants reported using various coping strategies to overcome barriers to accessing healthcare services. These strategies included delaying treatment and self-care; seeking financial and transportation assistance; and using community resources to navigate the system. Establishing care that is culturally relevant, targets perceived barriers and incorporates and enhances coping strategies is needed to increase accessibility and utilization of preventative and comprehensive healthcare services. The findings from this study will assist in creating a strategic plan for a FQHC that capitalizes on community strengths while addressing the challenges and complex needs of the community.
Internalization and excretion of epidermal growth factor-dextran-associated radioactivity in cultured human squamous-carcinoma cells. Certain tumor cells, such as squamous carcinomas and gliomas, can have an increased number of epidermal-growth-factor (EGF) receptors. The EGF receptors can in these cases be targets for toxic conjugates with specific binding. EGF-based toxic conjugates are potential targeting agents. We have analyzed the internalization and excretion of 125I administered in the form of 125I-EGF-dextran in squamous-carcinoma A431 cells. 125I-EGF without dextran was used for comparison. A431 cells have large numbers of EGF receptors and are capable both of recycling and of degradation of internalized receptor-ligand complexes. The binding of 125I-EGF-dextran and 125I-EGF was receptor-specific, since both ligands competed with non-radioactive EGF for binding. The amount of internalized 125I as a function of time increased continuously within 24 hr following administration of radioactivity as 125I-EGF-dextran. The time pattern was quite different when 125I-EGF without dextran was applied. In the latter case, the amount of internalized radioactivity decreased already after a few hours, probably depending on degradation of EGF. Pre-incubation of the cells with 125I-EGF-dextran or 125I-EGF and analysis of retained and released 125I activity at different times after washing showed that the 125I activity was retained for longer periods of time when EGF-dextran was used instead of EGF. About 30% of the internalized 125I activity was retained after 24 hr when EGF-dextran was used, compared with excretion of nearly all the radioactivity within 5 hr when EGF was used. In some experiments a high concentration of non-radioactive EGF, 5 micrograms/ml, was given to the cells after pre-incubation with 125I-EGF-dextran. This changed the retention and excretion patterns, so that a larger amount of 125I was excreted in the macromolecular fraction and a smaller amount of 125I activity was retained in the cells. Gel chromatography of the 125I activity released into the culture medium showed that the variations in molecular weight were larger after administration of a high concentration of non-radioactive EGF, most likely due to partial degradation of EGF-dextran. The results regarding excretion are in conformity with a model of competition between recycling of EGF-dextran-EGF-receptor complexes and "trapping" of EGF-dextran in the lysosomes followed by slow degradation. For targeting purposes, it is worth noting that the radioactivity administered in the form of 125I-EGF-dextran had a longer retention time than when 125I-EGF without dextran was used, and that the retention and excretion rates could be modified by post-treatment with the receptor ligand itself.
Optimizing scaleup yield for protein production: Computationally Optimized DNA Assembly (CODA) and Translation Engineering. Translation Engineering combined with synthetic biology (gene synthesis) techniques makes it possible to deliberately alter the presumed translation kinetics of genes without altering the amino acid sequence. Here, we describe proprietary technologies that design and assemble synthetic genes for high expression and enhanced protein production, and offers new insights and methodologies for affecting protein structure and function. We have patented Translation Engineering technologies to manage the complexity of gene design to account for codon pair usage, translational pausing signals, RNA secondary structure and user-defined sequences such as restriction sites. Failure to optimize for codon pair-encoded translation pauses often results in the relatively common occurrence of a slowly translated codon pair that slows the rate of protein elongation and decreases total protein production. Translation Engineering technology improves heterologous expression by tuning the gene sequence for translation in any well-characterized host, including cell-free expression techniques characterized by "broken"Escherichia coli systems used in kits for today's molecular tools market. In addition, we have patented a novel gene assembly method (Computationally Optimized DNA Assembly; CODA) that uses the degeneracy of the genetic code to design oligonucleotides with thermodynamic properties for self-assembly into a single, linear DNA product. Fast translational kinetics and robust protein expression are optimized in synthetic "Hot Rod" genes that are guaranteed to express in E. coli at high levels. These genes are optimized for codon usage and other properties known to aid protein expression, and importantly, they are engineered to be devoid of mRNA secondary structures that might impede transcription, and over-represented codon pairs that might impede translation. Hot Rod genes allow translating ribosomes and E. coli RNA polymerases to maintain coupled translation and transcription at maximal rates. As a result, the nascent mRNA is produced at a high level and is sequestered in polysomes where it is protected from degradation, even further enhancing protein production. In this review we demonstrate that codon context can profoundly influence translation kinetics, and that over-represented codon pairs are often present at protein domain boundaries and appear to control independent protein folding in several popular expression systems. Finally, we consider that over-represented codon pairs (pause sites) may be essential to solving problems of protein expression, solubility, folding and activity encountered when genes are introduced into heterologous expression systems, where the specific set of codon pairs controlling ribosome pausing are different. Thus, Translation Engineering combined with synthetic biology (gene synthesis) techniques may allow us to manipulate the translation kinetics of genes to restore or enhance function in a variety of traditional and novel expression systems.
[Effect of preventive acupuncture and moxibustion at "Guanyuan" (CV 4) on the expression of HSP 70 and HSP 70 mRNA in spleen and the contents of serum IL-2, TNF-alpha in menopausal rats]. To observe the influence of preventive acupuncture (PA) and preventive moxibustion (PM) at "Guanyuan" (CV 4) on the immune function in natural climacteric rats. A total of 160 female SD rats were randomized into control, PA and PM groups, the former one group was further divided into 10 month (mon), 12 mon, 14 mon and 16 mon subgroups, and the later two groups were further divided into 12 mon, 14 mon and 16 mon subgroups, with 16 rats in each. In addition, other 16 female SD rats aged 3.5 mon were used as the young control (YC) group. "Guanyuan" (CV 4) was punctured with an acupuncture needle and the needle was retained for 20 min, or given with one ignited moxa-cone from the age of 10 mon on. The treatment was conducted twice every week, 8 weeks altogether. The expression of HSP 70 and HSP 70 mRNA of the spleen tissue was detected by using immunohistochemistry and in situ hybridization respectively, and serum IL-2 and TNF-alpha contents were assayed by using radio-immunoassay. In comparison with YC group, 1) the expression of spleen HSP 70 and HSP 70 mRNA increased significantly in 10 mon control (mon-C), 12 mon-PM and 12 mon-PA groups, and 14 mon-PA group (only HSP 70 mRNA) (P < 0.05, P < 0.01); 2) HSP 70 expression decreased remarkably in 14 mon-C, 16 mon-C and 16 mon-PA groups (P < 0.05, P < 0.01); 3) IL-2 contents decreased evidently in 12 mon-C and 14 mon-C groups, and TNF-alpha contents increased obviously in 12 mon-PM, 12 mon-PA and 16 mon-C groups (P < 0.05). In comparison with the corresponding same age control groups, HSP 70 and HSP 70 mRNA expression increased significantly in 12 mon-PM and 12 mon-PA groups, 14 mon-PM and 16 mon-PM (HSP 70 only), 14 mon-PA (HSP 70 mRNA only) groups (P < 0.05, P < 0.01); IL-2 level of 12 mon-PM group, and TNF-alpha contents of 12 mon-PM and 12 mon-PA groups increased markedly (P < 0.05, P < 0.01). No significant differences were found between PM and PA groups in most different age groups (P > 0.05). Both preventive acupuncture and preventive moxibustion can upregulate the expression of spleen HSP 70 and HSP 70 mRNA and serum IL-2 and TNF-alpha levels, which may contribute to their effects in enhancing the immune function in menopausal rats.
Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial. Intra-aortic balloon counterpulsation (IABC) is an adjunct to revascularization in patients with cardiogenic shock and reduces infarct size when placed prior to reperfusion in animal models. To determine if routine IABC placement prior to reperfusion in patients with anterior ST-segment elevation myocardial infarction (STEMI) without shock reduces myocardial infarct size. An open, multicenter, randomized controlled trial, the Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) included 337 patients with acute anterior STEMI but without cardiogenic shock at 30 sites in 9 countries from June 2009 through February 2011. Initiation of IABC before primary percutaneous coronary intervention (PCI) and continuation for at least 12 hours (IABC plus PCI) vs primary PCI alone. Infarct size expressed as a percentage of left ventricular (LV) mass and measured by cardiac magnetic resonance imaging performed 3 to 5 days after PCI. Secondary end points included all-cause death at 6 months and vascular complications and major bleeding at 30 days. Multiple imputations were performed for missing infarct size data. The median time from first contact to first coronary device was 77 minutes (interquartile range, 53 to 114 minutes) for the IABC plus PCI group vs 68 minutes (interquartile range, 40 to 100 minutes) for the PCI alone group (P = .04). The mean infarct size was not significantly different between the patients in the IABC plus PCI group and in the PCI alone group (42.1% [95% CI, 38.7% to 45.6%] vs 37.5% [95% CI, 34.3% to 40.8%], respectively; difference of 4.6% [95% CI, -0.2% to 9.4%], P = .06; imputed difference of 4.5% [95% CI, -0.3% to 9.3%], P = .07) and in patients with proximal left anterior descending Thrombolysis in Myocardial Infarction flow scores of 0 or 1 (46.7% [95% CI, 42.8% to 50.6%] vs 42.3% [95% CI, 38.6% to 45.9%], respectively; difference of 4.4% [95% CI, -1.0% to 9.7%], P = .11; imputed difference of 4.8% [95% CI, -0.6% to 10.1%], P = .08). At 30 days, there were no significant differences between the IABC plus PCI group and the PCI alone group for major vascular complications (n = 7 [4.3%; 95% CI, 1.8% to 8.8%] vs n = 2 [1.1%; 95% CI, 0.1% to 4.0%], respectively; P = .09) and major bleeding or transfusions (n = 5 [3.1%; 95% CI, 1.0% to 7.1%] vs n = 3 [1.7%; 95% CI, 0.4% to 4.9%]; P = .49). By 6 months, 3 patients (1.9%; 95% CI, 0.6% to 5.7%) in the IABC plus PCI group and 9 patients (5.2%; 95% CI, 2.7% to 9.7%) in the PCI alone group had died (P = .12). Among patients with acute anterior STEMI without shock, IABC plus primary PCI compared with PCI alone did not result in reduced infarct size. clinicaltrials.gov Identifier: NCT00833612.
Production of insulin-like growth factor-I by granulosa cells but not thecal cells is hormonally responsive in cattle. To determine whether the hormonal regulation of IGF-I production differs between granulosa and thecal cells in cattle, granulosa and thecal cells from bovine follicles were collected, cultured for 2 d in medium containing 10% fetal calf serum, washed, and then treated for an additional 24 h in serum-free medium with various hormones. In Exp. 1, granulosa cells were treated with 0 or 100 ng/mL of insulin and(or) 50 ng/mL of follicle-stimulating hormone (FSH), insulin plus 10 ng/mL of epidermal growth factor, or insulin plus 10 ng/mL of basic fibroblast growth factor. In Exp. 2, thecal cells were treated as described in Exp. 1 except that 100 ng/mL of luteinizing hormone (LH) was used instead of 50 ng/mL of FSH. In Exp. 3, granulosa and thecal cells were treated with 0 or 30 ng/mL of cortisol with or without 100 ng/mL of insulin, 300 pg/mL of glucagon, or glucagon plus insulin. In Exp. 4, granulosa and thecal cells were treated with 0 or 300 ng/mL of estradiol with or without 100 ng/mL of insulin and(or) 100 ng/mL of LH. At the end of treatment, medium was collected, concentrated with Centricon-3 concentrators, and assayed for IGF-I by radioimmunoassay. Cell numbers were determined by Coulter counting at the end of culture. Thecal cells produced low amounts of IGFI (0.48 +/- 0.04, 0.63 +/- 0.03, and 0.82 +/- 0.03 ng per 100,000 cells per 24 h in Exp. 2, 3, and 4, respectively), and this production was not influenced (P > 0.05) by the various treatments. In contrast, IGF-I production by granulosa cells (2.0 to 6.2 ng per 100,000 cells per 24 h) was influenced by treatment in Exp. 1, 3, and 4 and was greater than IGF-I production by thecal cells (Exp. 2, 3, and 4). Alone, insulin, FSH, LH, and cortisol (but not estradiol) each decreased (P < 0.05) granulosa-cell IGF-I production by 20 to 57%; combined treatments of insulin plus FSH or insulin plus cortisol decreased IGF-I production to levels seen with insulin alone. Glucagon had no effect (P > 0.10) on IGF-I production in the absence or presence of insulin. In the presence of insulin, epidermal growth factor, basic fibroblast growth factor, and estradiol decreased (P < 0.05) IGF-I production below that observed for insulin alone. These results indicate that, during follicular development in cattle, changes in intrafollicular levels of IGF-I may be due to hormonally-induced changes in granulosa-cell, but not thecal-cell, IGF-I production.
Prevalence of Sport Specialization in High School Athletics: A 1-Year Observational Study. The prevalence of sport specialization in high school athletes is unknown. This information is needed to determine the scope of this issue in an active population. To determine the prevalence of sport specialization in high school athletes and to determine if specialization is influenced by classification method, year in school, sex, and school size. A secondary purpose was to determine if highly specialized athletes would be more likely to report a history of lower extremity injuries. Cross-sectional study; Level of evidence, 3. High school athletes between the ages of 13 and 18 years from 2 local high schools completed both a sport specialization survey and an injury history survey. Athletes were classified into low, moderate, or high specialization groups using a recently developed 3-point system and were also classified using a self-classification method. A total of 302 athletes completed the surveys and were classified as low specialization (n = 105, 34.8%), moderate specialization (n = 87, 28.8%), or high specialization (n = 110, 36.4%). Athletes from the small school were more likely to be classified in the low specialization group (low, 43%; moderate, 32%; high, 25%) compared with those from the large school (low, 26%; moderate, 26%; high, 48%) (P < .001). Athletes in the high specialization group were more likely to report a history of overuse knee injuries (n = 18) compared with moderate (n = 8) or low specialization (n = 7) athletes (P = .048). Athletes who trained in one sport for more than 8 months out of the year were more likely to report a history of knee injuries (odds ratio [OR], 2.32; 95% CI, 1.22-4.44; P = .009), overuse knee injuries (OR, 2.93; 95% CI, 1.16-7.36; P = .018), and hip injuries (OR, 2.74; 95% CI, 1.09-6.86; P = .026). Using the self-classification method, more participants self-classified as multisport (n = 213, 70.5%) than single sport (n = 89, 29.5%). Athletes from the small school were more likely to classify themselves as multisport (n = 128, 86%) (P < .001) than those from the large school (n = 85, 56%). There were no differences in the history of hip, knee, or ankle injuries between athletes who self-classified as single sport (hip: n = 10, 3%; knee: n = 19, 6%; ankle: n = 35, 12%) versus those who self-classified as multisport (hip: n = 45, 8%; knee: n = 23, 15%; ankle: n = 98, 33%) (P > .370). Classification method and school size influenced the prevalence of specialization in high school athletes. Highly specialized athletes were more likely to report a history of overuse knee or hip injuries. Participating in a single sport for more than 8 months per year appeared to be an important factor in the increased injury risk observed in highly specialized athletes.
"Recovery" vena cava filter: experience in 96 patients. The purpose of the study was to assess the clinical safety and efficacy of the "Recovery(TM)" (Bard) inferior vena cava (IVC) filter. We retrospectively evaluated the clinical and imaging data of patients who had a "Recovery(TM)" IVC filter placed between January 2003 and December 2004 in our institution. The clinical presentation, indications, and procedure-related complications during placement and retrieval were evaluated. Follow-up computed tomography (CT) examinations of the abdomen and chest were evaluated for filter-related complications and pulmonary embolism (PE), respectively. "Recovery" filters were placed in 96 patients (72 males and 24 females; age range: 16-87 years; mean: 46 years). Twenty-four patients presented with PE, 13 with deep vein thrombosis (DVT) and 2 with both PE and DVT. The remaining 57 patients had no symptoms of thromboembolism. Indications for filter placement included contraindication to anticoagulation (n = 27), complication of anticoagulation (n = 3), failure of anticoagulation (n = 5), and prophylaxis (n = 61). The device was successfully deployed in the infrarenal (n = 95) or suprarenal (n = 1) IVC through a femoral vein approach. Retrieval was attempted in 11 patients after a mean period of 117 days (range: 24-426). The filter was successfully removed in nine patients (82%). Failure of retrieval was due to technical difficulty (n = 1) and the presence of thrombus in the filter (n = 1). One of the nine patients who had the filter removed developed IVC thrombus after retrieval and another had an intimal tear of the IVC. Follow-up abdominal CT (n = 40) at a mean of 80 days (range: 1-513) showed penetration of the IVC by the filter arms in 11, of which 3 had fracture of filter components. In one patient, a broken arm migrated into the pancreas. Asymmetric deployment of the filter legs was seen in 12 patients and thrombus within the filter in 2 patients. No filter migration or caval occlusion was encountered. Follow-up chest CT (n = 27) at a mean of 63 days (range: 1-386) showed PE in one patient (3%). During clinical follow-up, 12 of 96 patients developed symptoms of PE and only 1 of the 12 had PE on CT. There was no fatal pulmonary embolism in our group of patients following "Recovery" filter placement. However, the current version of the filter is associated with structure weakness, a high incidence of IVC wall penetration, and asymmetric deployment of the filter legs.
Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. The serum amyloid A (SAA) family of proteins is encoded by multiple genes that display allelic variation and a high degree of homology in mammals. Triggered by inflammation after stimulation of hepatocytes by lymphokine-mediated processes, the concentrations of SAA may increase during the acute-phase reaction to levels 1000-fold greater than those found in the noninflammatory state. In addition to its role as an acute-phase reactant, SAA (104 amino acids, 12 kDa) is considered to be the precursor protein of secondary reactive amyloidosis, in which the N-terminal portion is incorporated into the bulk of amyloid fibrils. However, the association with lipoproteins of the high-density range and subsequent modulation of the metabolic properties of its physiological carrier appear to be the principal role of SAA. Because SAA may displace apolipoprotein A-I, the major protein component of native high density lipoprotein (HDL), during the acute-phase reaction, the present study was aimed at (1) investigating binding properties of native and acute-phase (SAA-enriched) HDL by J774 macrophages, (2) elucidating whether the presence of SAA on HDL particles affects selective uptake of HDL-associated cholesteryl esters, and (3) comparing cellular cholesterol efflux mediated by native and acute-phase HDL. Both the total and the specific binding at 4 degrees C of rabbit acute-phase HDL were approximately 2-fold higher than for native HDL. Nonlinear regression analysis revealed K(d) values of 7.0 x 10(-7) mol/L (native HDL) and 3.1 x 10(-7) mol/L (acute-phase HDL), respectively. The corresponding B(max) values were 203 ng of total lipoprotein per milligram of cell protein (native HDL) and 250 ng of total lipoprotein per milligram of cell protein (acute-phase HDL). At 37 degrees C, holoparticle turnover was slightly enhanced for acute-phase HDL, a fact reflected by 2-fold higher degradation rates. In contrast, the presence of SAA on HDL specifically increased (1. 7-fold) the selective uptake of HDL cholesteryl esters from acute-phase HDL by J774 macrophages, a widely used in vitro model to study foam cell formation and cholesterol efflux properties. Although ligand blotting experiments with solubilized J774 membrane proteins failed to identify the scavenger receptor-BI as a binding protein for both native and acute-phase HDL, 2 binding proteins with molecular masses of 100 and 72 kDa, the latter comigrating with CD55 (also termed decay-accelerating factor), were identified. During cholesterol efflux studies, it became apparent that the ability of acute-phase HDL with regard to cellular cholesterol removal was considerably lower than that for native HDL. This was reflected by a 1.7-fold increase in tau/2 values (22 versus 36 hours; native versus acute-phase HDL). Our observations of increased HDL cholesteryl ester uptake and reduced cellular cholesterol efflux (acute-phase versus native HDL) suggest that displacement of apolipoprotein A-I by SAA results in considerable altered metabolic properties of its main physiological carrier. These changes in the apolipoprotein moieties appear (at least in the in vitro system tested) to transform an originally antiatherogenic into a proatherogenic lipoprotein particle.
Receptive properties of mouse sensory neurons innervating hairy skin. Using an in vitro nerve skin preparation and controlled mechanical or thermal stimuli, we analyzed the receptive properties of 277 mechanosensitive single primary afferents with myelinated (n = 251) or unmyelinated (n = 26) axons innervating the hairy skin in adult or 2-wk-old mice. Afferents were recorded from small filaments of either sural or saphenous nerves in an outbred mice strain or in the inbred Balb/c strain. On the basis of their receptive properties and conduction velocity, several receptor types could be distinguished. In adult animals (>6 wk old), 54% of the large myelinated fibers (Abeta, n = 83) showed rapidly adapting (RA) discharges to constant force stimuli and probably innervated hair follicles, whereas 46% displayed a slowly adapting (SA) response and probably innervated Merkel cells in touch domes. Among thin myelinated fibers (Adelta, n = 91), 34% were sensitive D hair receptors and 66% were high-threshold mechanoreceptors (AM fibers). Unmyelinated fibers had high mechanical thresholds and nociceptive functions. All receptor types had characteristic stimulus-response functions to suprathreshold force stimuli. Noxious heat stimuli (15-s ramp from 32 to 47 degrees C measured at the corium side of the skin) excited 26% (5 of 19) of AM fibers with a threshold of 42.5 +/- 1.4 degrees C (mean +/- SE) and an average discharge of 15.8 +/- 9.7 action potentials and 41% (7 of 17) C fibers with a mean threshold of 37.6 +/- 1.9 degrees C and an average discharge of 22.0 +/- 6.0 action potentials. Noxious cold stimuli activated 1 of 10 AM fibers and 3 of 10 C fibers. One of 10 C units responded to both heat and cold stimuli. All types of afferent fibers present in adult mice could readily be recognized in mice at postnatal day 14. However, fibers had reduced conduction velocities and the stimulus-response function to mechanical stimuli was more shallow in all fibers except for the D hairs. In juvenile mice, 22% of RA units also displayed an SA response at high stimulus intensities; these units were termed RA/SA units. We conclude that all types of cutaneous afferent fibers are already committed to their phenotype 2 wk after birth but undergo some maturation over the following weeks. This preparation has great potential for the study of transgenic mice with targeted mutations of genes that code factors that are involved in the specification of sensory neuron phenotypes.
Influence of aerobic exercise on maternal lipid levels and offspring morphometrics. Maternal BMI, lipid levels (cholesterol, triglyceride, LDL, HDL), and exercise amount are interrelated and each influence offspring body size. This study proposed to determine the influence of exercise on maternal lipid levels and infant body size. We had 36 participants complete these measures. Participants in the aerobic exercise intervention (n = 14) completed three 50-min sessions weekly from 16 weeks gestation to delivery and were compared with a non-exercise control group (n = 22). Maternal lipid profiles were assessed at 16 and at 36 weeks gestation. Fetal body size was measured at 36 weeks gestational age using ultrasound assessment. Neonatal body size measures were acquired from birth records. Statistical analysis included two-sample t-tests, correlations, and regression models. Participants were similar in age, pre-pregnancy BMI, gravida, parity, education, and gestational weight gain (GWG). There were no differences in gestational age, Apgar scores at 1 and 5 min for infants of exercisers relative to controls. Exercisers had higher pre-training triglycerides (p = 0.004) and pregnancy change in triglycerides (p = 0.049) compared to controls. Head circumference was significantly larger in exercise exposed infants relative to infants of controls. Pregnancy METs had a positive relationship with birth length (r = .445, p = .006) and birth weight (r = .391, p = .02). GWG had a moderate, positive relationship with fetal abdominal circumference (r = .570, p = .004). Regression analysis indicated 5 predictors explained 61.7% of the variance in birth weight (Adj.R2 = 0.469, F(5,13) = 5,13, p = 0.02); it was found that pregnancy METs (β = .724, p = .007), 36 week cholesterol (β = 1.066, p = .02), and 36 week LDL (β = -1.267, p = .006) significantly predict birth weight. Regression analysis indicated 4 predictors explained 43.8% of the variance in birth length (Adj.R2 = 0.306, F(4,17) = 3.32, p = 0.04); it was found that pregnancy METs (β = .530, p = .03), and 36 week LDL (β = -.891, p = .049) significantly predict birth length. The primary association and predictors of infant body size was related to pregnancy exercise and late pregnancy cholesterol and LDL levels. Considering these relationships, it is essential that women maintain aerobic exercise during pregnancy, but should also be cognizant of lipid levels during their pregnancy. Therefore intervention during pregnancy focused on infant body size should involve exercise and and quality nutritional intake foods during pregnancy.
Migration of neuroblasts by perikaryal translocation: role of cellular elongation and axonal outgrowth in the acoustic nuclei of the chick embryo medulla. The neuroblasts forming nucleus magnocellularis, the avian homologue of the mammalian ventral cochlear nucleus, migrate by growth and elongation of their leading processes and by perikaryal translocation through these processes from the matrix zone of the rhombic lip to the acoustico-vestibular anlage. Golgi methods were used on staged chick embryos to reconstruct the morphogenetic phases of migration and early differentiation in situ. Fluorescence labeling of the living cells in vitro elucidated the role of axonal growth in the migratory process. In situ, branching cochlear nerve fibers, tipped with growth cones, enter the acoustico-vestibular anlage at E4.5-5.5 before migration of the magnocellularis neuroblasts at E.5.5-6.5. The premigratory neuroblasts in the matrix zone of the rhombic lip resemble primitive epithelial cells, which extend branched, curving processes into a characteristic formation, the rhombic whorl. The leading process of the migrating magnocellularis neuroblasts gives rise to a bifurcating axon at the interface between the matrix and mantle zones. The lateral branch becomes the recurrent ipsilateral collateral; the medial branch crosses the midline, heading toward the contralateral target site in the region of the presumptive nucleus laminaris. The cell bodies of the migratory neuroblasts appear in intermediate locations along the migration route as they translocate radially through their leading processes past the axonal bifurcation and then tangentially and obliquely into the mantle zone. Neuroblasts destined for nucleus laminaris migrate coincidentally with magnocellularis neuroblasts. Nucleus angularis neuroblasts migrate later in development, after E6.5. In vitro, injections of a nontoxic fluorescent dye (diI) were made into explants of the medulla in the region of the contralateral target area at the time of neuroblast migration. DiI retrogradely labeled the cell bodies of premigratory magnocellularis neuroblasts in the matrix zone and of migratory neuroblasts in the mantle zone through their medial, crossing axonal branches. The morphology of the living neuroblasts in the explants resembled that in the Golgi impregnations at the corresponding stages of migration. Anterograde axonal transport also occurred. These results demonstrate migration by perikaryal translocation and early axon extension of a specific group of neuroblasts in the central nervous system. The morphology of the migrating neuroblasts is such that a simple radial arrangement of cellular guides, glial or otherwise, would not account for their configurations. The available evidence supports the proposition that cellular elongation and perikaryal translocation constitute the general mode of neuronal migration in the central nervous system. The early extension of axons into their target sites may play a critical role in migration and early development of specific types of neurons.
Assessment of inflammatory response and sequestration of blood iron transferrin complexes in a rat model of lung injury resulting from exposure to low-frequency shock waves. Impact of air blast overpressure waves (OPW), or shock wave, with the body wall or body armor produces two types of energy waves: high-frequency low-amplitude stress waves and long-duration low-frequency share waves. These types of energy waves are characterized by different mechanisms of primary tissue injury that mostly affect lung. Systemic inflammation and resultant acute respiratory distress syndrome are known major secondary causative agents of delayed multiple organ failure and subsequent death after OPW exposure. However, association of each pattern of the blast OPW-produced energy waves with postexposure inflammatory events has not yet been delineated. The objectives of the present research were a) establishment of a rat model for assessment of the inflammatory response following lung injury produced by exposure to medium-amplitude (approximately 120 kPa) low-frequency (260+/-5 Hz) OPWs; and b) assessment of the dynamics of alteration in polymorphonuclear leukocyte counts and expression of CD11b adhesion molecules on the surface of polymorphonuclear leukocytes and status of iron-transferrin complexes in peripheral blood after OPW exposure. This study focused on the OPW effects at different time periods, using a sequential approach to postexposure events. Lung injury in rat was induced by OPW generated in a laboratory shock tube. Animals were exposed to OPW (at peak overpressure of 118+/-7 kPa) that produced "moderate" lung injury. Military research institute. Twenty-seven CVF Sprague-Dawley rats were subjected to OPW exposures, and 17 sham-treated animals were used as control. Lung tissue and blood samples were collected at 1, 3, 6, 12, and 24 hrs following OPW exposures and compared with samples collected from nonexposed animals. OPW-induced lung injury caused a 2.7-fold increase in the number of circulatory polymorphonuclear leukocytes as early as 1 hr postexposure, which is indicative of mobilization of the pool of marginated polymorphonuclear leukocytes into the free circulation. Polymorphonuclear leukocyte counts increased through the following 3- and 6-hr periods, when they were, respectively, 5-fold and 3.5-fold higher than in controls. These effects were accompanied by a pronounced expression of CD11b in polymorphonuclear leukocytes and tissue sequestration of blood iron-transferrin complexes during the entire 24-hr period of observations. The increase in circulatory polymorphonuclear leukocytes was accompanied by a decrease in iron-transferrin complex concentrations that apparently reflected implication of blood plasma iron in the inflammatory cell response to OPW-induced injury. The observed dynamics in polymorphonuclear leukocyte alterations in peripheral blood after OPW exposure were similar to those found recently in clinical observations of nonpenetrating injury and in animal models of infectious insults. Therefore, our data suggest that the main pattern of proinflammatory alterations in the rat model of lung injury induced by exposure to long-duration shock wave is similar to patterns that are characteristic of major trauma. The data further suggest that the expression of polymorphonuclear leukocyte CD11b and the response of iron-transferrin complex can be considered as potential surrogate markers in blood for systemic alterations following OPW-induced injury and, therefore, warrant further investigation in a human pilot study.
[Factors associated with malnutrition among infants and young children aged 6-23 months in poor rural areas in Hunan Province, China]. Objective: To describe the situation and identify factors associated with malnutrition among infants and young children aged 6-23 months in poor rural areas in Hunan Province in 2015. Methods: 8 735 rural infants and young children aged 6-23 months in 30 poor counties of Wuling Mountains and Luoxiao Mountains in Hu'nan province were selected by township-level probability proportional to size sampling (PPS) in August 2015, infants' body length and weight were measured, and questionnaires were used to collect infants' information on personal and family, and feeding status in the past 24 h. The prevalence of stunting, underweight and wasting were calculated according to the Growth Standards of Child Aged Under 7 in China which was established in 2009 by Community Health Department of National Health and Family Planning Commission, China (formerly Chinese MOH), and the prevalence of malnutrition was calculated according to the classification of children with anthropometric failure. Multi non-conditional logistic regression model were used to analyze factors associated with malnutrition among infants and young children aged 6-23 months. Results: The prevalence of malnutrition among infants and young children aged 6-23 months was 13.7% (1 198/8 735), the prevalence of stunting, underweight and wasting among infants and young children aged 6-23 months were 4.8% (419/8 735), 9.7% (849/8 735) and 6.1% (531/8 735) respectively. Compared with male group, the OR value of malnutrition for the female group was 1.16; Compared with Han ethnic group, the OR value of malnutrition for the Miao and Tujia ethnic group were 0.83 and 0.66, respectively; Compared with mother with an education level of primary school or below, the OR value of malnutrition for the mother with junior high school, senior high school and university or above education were 0.65, 0.61 and 0.56, respectively; Compared with father with an education level of primary school or below, the OR value of malnutrition for the father with senior high school and university or above education were 0.71 and 0.61 respectively; Compared with normal birth weight group, the OR value of malnutrition for the low birth weight group and high birth weight group were 2.85 and 0.27 respectively; Compared with normal delivery group, the OR value of malnutrition for the premature delivery group was 1.37; all P values<0.05. Conclusion: The prevalence of malnutrition among infants and young children aged 6-23 months in poor rural areas in Hunan province in 2015 was high; Infants and young children who were female, Han ethnic, parents with low education, low birth weight and premature delivery had higher risk of malnutrition.
Inflammatory cells, motor weakness, and straight leg raising in transligamentous disc herniations. Possible statistically significant relationships between inflammatory cells and either motor weakness or straight leg raising were determined. To look for any clinically relevant links between inflammatory cells in disc herniations and signs of radiculopathy. Many studies have during recent years shown a presence of various types of inflammatory cells in disc herniations, but their clinical relevance has been questioned. To be clinically relevant, a presence of inflammatory cells should show a clear relationship to clinical evidence of nerve root involvement. Macrophages repeatedly demonstrated in a high proportion of disc herniations studied are of particular interest. Their major role may be in disc herniations tissue resorption and not in sciatica. A total of 96 disc herniations, all transligamentous, were analyzed by immunohistochemistry for presence of macrophages, T or B lymphocytes, and activated T lymphocytes separately. From recorded patient data, motor weakness and straight leg raising data were compared with a presence or absence of abundant (+ = at least 20 cells in a group) inflammatory cells. When not abundant, inflammatory cells were classified as "only few cells" (+) and grouped together with "no cells" (-). Patients with or without motor weakness were compared. Straight leg raising was compared for a positive (at <70 degrees ) or a negative test, and separately using the median as cut-off value. Groups were compared by chi-square analysis with the level of statistical significance set at P<0.05. None of the four inflammatory cell types showed any significant association with motor weakness. Nor was any association observed when comparing positive and negative straight leg raising. With the median (straight leg raising = 47.5 degrees ) as cut-off, only activated T cells showed a weak (chi2 = 4.40, P<0.05) relationship with tighter straight leg raising, but none of the other cell types did. Even when straight leg raising was < 47.5 degrees, three times more disc herniations lacked (n = 34) inflammatory cells than showed (n = 13) inflammation. In a subgroup of only sequestrated discs, the findings were similar. However, in the patients with a bilaterally positive straight leg raising (n = 25), the prevalence of at least one inflammatory cell type was much higher in sequestrated discs (80%) than in extrusions (33%). This may suggest more subtle interrelationships between type of disc herniation, straight leg raising, and inflammatory cells. The results of this study do not support a clinically relevant role for disc herniation inflammatory cells in sciatica. For the cells to be clinically relevant, a strong relationship between a presence of inflammatory cells and either or both of motor weakness and a tight straight leg raising should have been observed. The authors conclude that macrophages, which have been demonstrated in a high proportion of disc herniations in previous studies, are probably more important for disc tissue resorption processes than for producing sciatica. Other types of inflammatory cells are more rarely observed and may have no clinical meaning at all. However, more subtle interrelationships, considering the various types of disc herniations, should be further explored.
NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.
General oncologic effects of the laparoscopic surgical approach. 1997 Frankfurt international meeting of animal laparoscopic researchers. The results from the majority of the reviewed studies support the hypothesis that abdominal surgery, performed via either a large incision or CO2 pneumoperitoneum, systemically encourages tumor growth in the postoperative period. A full laparotomy incision appears to have a significantly greater effect than CO2 pneumoperitoneum on postoperative tumor growth. Whether the large tumor observed in the surgical groups are the result of increased tumor cell proliferation or diminished tumor cell death remains unclear. There is some evidence pointing to both mechanisms. The loss of the postoperative tumor growth differences between the open and pneumo animals in the athymic mouse experiment suggests that cell-mediated immune function plays a role in tumor containment. The proliferation study results, however, suggest that other stimulatory influence(s) are also at work. Clearly, much research needs to be done regarding the etiology of these tumor growth differences. Other tumor cell lines need to be studied, and investigations regarding tumor growth in an intra-abdominal location need be performed as well. This body of research suggests that the manner in which the surgeon gains access to the abdominal cavity may have an impact on the propensity of tumor cells to implant, survive, and grow in the period immediately after surgery. If true, this may be the most compelling justification for the use of minimally invasive techniques for the curative resection of malignancies. However, it remains to be proven that human tumors will demonstrate differences in tumor growth similar to those noted in some of these animals models. Furthermore, it is not all clear that slight differences in tumor growth postoperatively will translate into significant differences in long-term survival or recurrence rates. At first glance, the existence of port-site tumors would appear to contradict totally the conclusions of many studies discussed in this synopsis. If laparoscopic methods are associated with decreased rates of tumor growth and establishment, then why do port-site tumors form? This is a complex issue calling for discussion that goes far beyond the scope of this article. However, several brief comment on this topic follow. The etiology of port tumors is unknown, although traumatization of the tumor during mobilization, resection, or removal is likely to play a significant role in the liberation of tumor cells from the primary. A relatively small protective benefit, in terms of slower tumor growth rates in laparoscopic patients, will likely not be sufficient to prevent a large inoculum of viable tumor cells in an abdominal wound from establishing a metastasis. Furthermore, as suggested earlier, the systemic effects on tumor growth may be different from the local (i.e., intra-abdominal or abdominal wound) effects. Finally, the true incidence of port tumors remains unknown. It has not been definitively established that the laparoscopic wound tumor incidence is significantly higher than the open rate, although this is the assumption of most surgeons. Several relatively large recently published laparoscopic series have reported port tumor incidences of 0 to 1.2%, which is in the same "ballpark" as the 0.6 1.0% abdominal wound tumor incidences mentioned in several open colectomy series. Clearly, much more research in this area is needed to understand port tumors better and to reconcile the port tumor results with the systemic tumor growth benefits that may be associated with minimally invasive methods.
A pilot trial of TAC (paclitaxel, doxorubicin, and carboplatin) chemotherapy with filgastrim (r-metHuG-CSF) support followed by radiotherapy in patients with "high-risk" endometrial cancer. To determine the toxicity, tolerability, and feasibility of delivering combination chemotherapy with subsequent radiation therapy to women with high-risk endometrial cancer and to evaluate the long-term bowel toxicity of this regimen. The trial was approved by the Dana Farber/Partners Cancer Care (DFPCC) Institutional Review Board (IRB). Patients with stage 3 or stage 4 endometrial cancer or patients with high-risk histology and any stage disease were prospectively entered. Complete surgical staging and a normal gated blood pool scan were required prior to entry. Patients were treated with three cycles of paclitaxel (160 mg/m(2) ), doxorubicin (45 mg/m(2)) and carboplatin (AUC 5) (TAC) all on day 1 of a 21-day schedule as an outpatient with G-CSF support. At the conclusion of chemotherapy, patients received radiation therapy (4500 cGy to the whole pelvis) commencing within 35 days of the last cycle of chemotherapy. Paraaortic radiation and/or vaginal brachytherapy were allowed at the discretion of the treating radiation oncologist. Twenty patients were entered onto the trial from November 2000 through February 2003. Eighteen patients successfully completed the trial, and two patients came off trial during chemotherapy (both later completed planned radiation therapy). Patients were initially stage 1 (n = 3), stage 3 (n = 14), and stage 4 (n = 3). Papillary serous was the dominant histology with 13 patients. Chemotherapy was given on average within 32 days of surgery (range 11-63 days) and radiation was initiated on average within 14 weeks of surgery (range 10-18 weeks). Chemotherapy was well tolerated, with 57 total cycles delivered of a planned 60 cycles. Two patients required dose modification in two cycles (two patients in cycle 3 secondary to hematologic toxicity). No grade 3 or grade 4 neurotoxicity was reported. There were six episodes of grade 3 short-term toxicity with radiation therapy reported in a single patient. Late radiotherapy toxicity included bowel obstruction requiring laparotomy in two patients and grade 3 constipation in one patient. Late radiation toxicity data are still being collected as follow-up continues. The TAC chemotherapy regimen is well tolerated and three cycles were delivered successfully with G-CSF support without evidence of the neurotoxicity or cardiac toxicity reported with the cisplatin containing TAP regimen. Standard radiation was deliverable following TAC therapy without excessive toxicity. Further study of this regimen with subsequent radiation therapy is warranted in patients at risk for systemic and regional recurrence of their malignancy.
Neonatal whisker removal reduces the discrimination of tactile stimuli by thalamic ensembles in adult rats. Simultaneous recordings of up to 48 single neurons per animal were used to characterize the long-term functional effects of sensory plastic modifications in the ventral posterior medial nucleus (VPM) of the thalamus following unilateral removal of facial whiskers in newborn rats. One year after this neonatal whisker deprivation, neurons in the contralateral VPM responded to cutaneous stimulation of the face at much longer minimal latencies (15.2 +/- 8.2 ms, mean +/- SD) than did normal cells (8.8 +/- 5.3 ms) in the same subregion of the VPM. In 69% of these neurons, the initial sensory responses to stimulus offset were followed for up to 700 ms by reverberant trains of bursting discharge, alternating in 100-ms cycles with inhibition. Receptive fields in the deafferented VPM were also atypical in that they extended over the entire face, shoulder, forepaw, hindpaw, and even ipsilateral whiskers. Discriminant analysis (DA) was then used to statistically evaluate how this abnormal receptive field organization might affect the ability of thalamocortical neuronal populations to "discriminate" somatosensory stimulus location. To standardize this analysis, three stimulus targets ("groups") were chosen in all animals such that they triangulated the central region of the "receptive field" of the recorded multineuronal ensemble. In the normal animals these stimulus targets were whiskers or perioral hairs; in the deprived animals the targets typically included hairy skin of the body as well as face. The measured variables consisted of each neuron's spiking response to each stimulus differentiated into three poststimulus response epochs (0-15, 15-30, and 30-45 ms). DA quantified the statistical contribution of each of these variables to its overall discrimination between the three stimulus sites. In the normal animals, the stimulus locations were correctly classified in 88.2 +/- 3.7% of trials on the basis of the spatiotemporal patterns of ensemble activity derived from up to 18 single neurons. In the deprived animals, the stimulus locations were much less consistently discriminated (reduced to 73.5 +/- 12.6%; difference from controls significant at P < 0.01) despite the fact that much more widely spaced stimulus targets were used and even when up to 20 neurons were included in the ensemble. Overall, these results suggest that neonatal damage to peripheral sense organs may produce marked changes in the physiology of individual neurons in the somatosensory thalamus. Moreover, the present demonstration that these changes can profoundly alter sensory discrimination at the level of neural populations in the thalamus provides important evidence that the well-known perceptual effects of chronic peripheral deprivation may be partially attributable to plastic reorganization at subcortical levels.
Symposium on health economics in oncology. Freiburg, Germany, June 1995. Dr. E. Enghofer (Wien, Austria) summarized the content of the presentations and discussions of the symposium in his concluding remarks. 1. The organizers should be congradulated on their initiative in bringing together at the symposium experts from different disciplines, i.e., medicine, ethics, health economics, jurisprudence, the pharmaceutical industry and, last but not least, cost providers. 2. Health economics as an issue in health care has been around for quite some while. One example can be found in the German Drug Guidelines dating back to 1990, where the following terms have already been defined: therapeutic benefit, medical needs, and achieving therapeutic goals. 3. Health economics serves as a "support function" in the medical decision-making process. It has as yet no decisive role in the application to license a drug nor in questions concerning a physician's liability. Health economics as a discipline, however, was a reminder of, and served as a catalytic function for: a) The differentiation between the benefit of a medical intervention and its pure effectiveness. b) The definition of medical standards as a means to compare the quality of health care between different institutions, to uncover quality deficits and to develop strategies for the optimization of medical quality (quality management). Routine deviation from these standards is unethical. The German Cancer Society has taken on the task of defining such standards in cancer care. c) The difference between rationalising and rationing health care. The spending of the current health-care budget needs to be screened for unnecessary and/or inappropriate diagnostic procedures and treatment modalities as well as for "below-standard" care. The money that can be saved here can then be shifted towards financing "state of the art" medicine or can be used in the decision to substitute certain procedures. 4. The a priori definition of the desired outcome of a medical intervention is of paramount importance for the evaluation of the actual treatment result. Economical evaluations are easier when cure rather than palliation is the aim of a particular treatment and when alternative therapies do exist such that cost comparisons are possible. In any case, therapeutic interventions need to be adapted to the desired treatment goal; only then can the question be answered whether or not the means (cost) are (is) justified. 5. Outcome studies need to take into account every relevant medical aspect (i.e. disease management studies), and they should be accompanied by evaluation studies. The latter must also include unselected patients in daily practice.(ABSTRACT TRUNCATED AT 400 WORDS)
Is posttraumatic cerebrospinal fluid fistula a predictor of posttraumatic meningitis? A US Nationwide Inpatient Sample database study. Various factors have been reported in literature to be associated with the development of posttraumatic meningitis. There is a paucity of data regarding skull fractures and facial fractures leading to CSF leaks and their association with the development of meningitis. The primary objective of this study was to analyze the US Nationwide Inpatient Sample (NIS) database to elucidate the factors associated with the development of posttraumatic meningitis. A secondary goal was to analyze the overall hospitalization cost related to posttraumatic meningitis and factors associated with that cost. The NIS database was analyzed to identify patients admitted to hospitals with a diagnosis of head injury from 2005 through 2009. This data set was analyzed to assess the relationship of various clinical parameters that may affect the development of posttraumatic meningitis using binary logistic regression models. Additionally, the overall hospitalization cost for the head injury patients who did not undergo any neurosurgical intervention was further categorized into quartile groups, and a regression model was created to analyze various factors responsible for escalating the overall cost of the hospital stay. A total of 382,267 inpatient admissions for head injury were analyzed for the 2005-2009 period. Meningitis was reported in 0.2% of these cases (708 cases). Closed skull base fractures, open skull base fractures, cranial vault fractures, and maxillofacial fractures were reported in 20,524 (5.4%), 1089 (0.3%), 5064 (1.3%), and 88,649 (23.2%) patients, respectively. Among these patients with fractures, meningitis was noted in 0.17%, 0.18%, 0.05%, and 0.10% admissions, respectively. Cerebrospinal fluid rhinorrhea was reported in 453 head injury patients (0.1%) and CSF otorrhea in 582 (0.2%). Of the patients reported to have CSF rhinorrhea, 35 (7.7%) developed meningitis, whereas in the cohort with CSF otorrhea, 15 patients (2.6%) developed meningitis. Cerebrospinal fluid rhinorrhea (p < 0.001, OR 22.8, 95% CI 15.6-33.3), CSF otorrhea (p < 0.001, OR 9.2, 95% CI 5.2-16.09), and major neurosurgical procedures (p < 0.001, OR 5.6, 95% CI 4.8-6.5) were independent predictors of meningitis. Further, CSF rhinorrhea (p < 0.001, OR 2.0, 95% CI 1.6-2.7), CSF otorrhea (p < 0.001, OR 2.3, 95% CI 1.9-2.7), and posttraumatic meningitis (p < 0.001, OR 3.1, 95% CI 2.5-3.8) were independent factors responsible for escalating the cost of head injury in cases not requiring any major neurosurgical intervention. Cerebrospinal fluid rhinorrhea and CSF otorrhea are independent predictors of posttraumatic meningitis. Furthermore, meningitis and CSF fistulas may independently lead to significantly increased cost of hospitalization in head injury patients not undergoing any major neurosurgical intervention.
Kenya. The Kenya coast is bathed by the northward-flowing warm waters of the East Africa Coastal Current, located between latitudes 1 and 5 degrees S. With a narrow continental shelf, the coastal marine environments are dominated by coral reefs, seagrass beds and mangroves, with large expanses of sandy substrates where river inputs from Kenya's two largest rivers, the Tana and Athi rivers, prevent the growth of coral reefs. The northern part of the coast is seasonally influenced by upwelling waters of the Somali Current, resulting in lower water temperatures for part of the year. The coast is made up of raised Pleistocene reefs on coastal plains and hills of sedimentary origin, which support native habitats dominated by scrub bush and remnant pockets of the forests that used to cover East Africa and the Congo basin. The marine environment is characterized by warm tropical conditions varying at the surface between 25 degrees C and 31 degrees C during the year, stable salinity regimes, and moderately high nutrient levels from terrestrial runoff and groundwater. The semi-diurnal tidal regime varies from 1.5 to 4 m amplitude from neap to spring tides, creating extensive intertidal platform and rocky-shore communities exposed twice-daily during low tides. Fringing reef crests dominate the whole southern coast and parts of the northern coast towards Somalia, forming a natural barrier to the wave energy from the ocean. Coral reefs form the dominant ecosystem along the majority of the Kenya coast, creating habitats for seagrasses and mangroves in the lagoons and creeks protected by the reef crests. Kenya's marine environment faces a number of threats from the growing coastal human population estimated at just under three million in 2000. Extraction of fish and other resources from the narrow continental shelf, coral reef and mangrove ecosystems increases each year with inadequate monitoring and management structures to protect the resource bases. Coastal development in urban and tourist centers proceeds with little regard for environmental and social impacts. With a faltering economy, industrial development in Mombasa proceeds with few checks on pollution and other impacts. In 1998 Kenya's coral reefs suffered 50-80% mortality from the El Niño-related coral bleaching event that affected the entire Indian Ocean. The institutional, human resource and legal infrastructure for managing the coastal environment has in the past been low, however these are rapidly improving with the revitalization of national institutions and the passing in 1999 of an Environment Act. Marine Protected Areas are the key tool currently used in management of marine ecosystems, and focus principally on coral reefs and biodiversity protection. New initiatives are underway to improve application of fisheries regulations, and to use Integrated Coastal Area Management (ICAM) as a framework for protecting marine and coastal environments.
Monitoring the subcellular localization of doxorubicin in CHO-K1 using MEKC-LIF: liposomal carrier for enhanced drug delivery. Doxorubicin (DOX) is an extensively used anthracycline that has proven to be effective against a variety of human malignant tumors, such as ovarian or breast cancer. While DOX was administered into cultured cancer cell targets (such as CHO-K1) in either free drug form or in drug carrier-associated form (i.e., DOX encapsulated in the drug delivery carrier), various action of mechanisms for DOX were initiated, among which, it has been long believed that DOX enters the nucleus, interacts with DNA in numerous ways, and finally halts cell proliferation. Aside from its therapeutic effect, regrettably DOX treatment may be accompanied by the occurrence of cardiac and liver toxicity and drug resistance that are attributed from cellular processes involving the parent drug or its metabolites. Liposomal formulation of DOX, known to be capable of attenuating direct uptake of reticuloendothelial system (RES) and prolonging the circulation time in blood, demonstrated reduced toxic side-effects. We herein report the development of a modified MEKC-LIF (Micellar electrokinetic chromatography-Laser-induced fluorescence) method suitable for analyzing DOX in biological samples. The MEKC migration buffer, consisting of 10 mM borate, 100 mM sodium dodecyl sulfate (SDS) (pH 9.3), was found to provide an efficient and stable electrophoretic separation and analysis for DOX. Responses were linear in the range of 11.3-725 ng/mL; the limit of quantitation (LOQ) was found to be 43.1 ng/mL (S/N=10) (equivalent to 74.3 nM) and limit of detection (LOD) was calculated as 6.36 ng/mL (S/N=3) (equivalent to 11.0 nM). This approach was subsequently employed to compare the intracellular accumulation in three subcellular fractions of DOX-treated CHO-K1 cells. These fractions form a pellet at <1400 g, 1400-14000 g, and >14000 g and are enriched in nuclei, organelles (mitochondria and lysosomes), and cytosole components, respectively, resulting from treatment of CHO-K1 cells with 25 μM (equivalent to 14.5 μg/mL) of two DOX formats (in free drug form or liposomal form synthesized in current study) for different periods of time. Our results indicated that the most abundant DOX was found in the nuclear-enriched fraction of cells treated for 12 h and 6 h with free and liposomal DOX, respectively, providing direct evidence to confirm the enhanced efficiency of liposomal carriers in delivering DOX into the nucleus. The observations presented herein suggest that subcellular fractionation followed by liquid-liquid extraction and MEKC-LIF could be a powerful diagnostic tool for monitoring intracellular DOX distribution, which is highly relevant to cytotoxicity studies of anthracycline-type anticancer drugs.
The semen of fertile men: statistical analysis of 1300 men. The prevasectomy semen analyses of 1300 men who had fathered at least two children were studied. The ages of the men ranged from 23 to 64 years, with a mean age of 39.6 years; 84% of the men were Caucasian, 5% were black, and 5% were of other ethnic groups; 32% of the men were Roman Catholic, 26% Jewish, 22% Protestant, and 11% professed no religion; in 9% religion was not recorded. The number of children ranged from 2 (48%) and 3 (30.6%) to 10 (0.1%). The volume of the ejaculate ranged from 0.1 to 11.0 ml, with a mean of 3.2 ml plus or minus 1.4 SD. Sperm density ranged from 1.5 to 375 million/ml, with an arithmetic mean of 79 million/ml plus or minus 57 SD; however, the logarithmic or geometric mean was chosen as being more representative of the asymmetric distribution under study. The geometric mean was 65 million/ml, with standard deviation limits of 30 to 142 million/ml, figures that correspond to the 16th and 84th percentiles. The percentage of motile sperm ranged from 5 to 95%, with a mean of 65% plus or minus 22 SD. The grade of sperm motility, according to MacLeod and Gold's classification (Fertil Steril 2:187, 1951) of 0 to 4, ranged from 1 to 4, with a mean grade of 3. There were 25 men (2%) with a sperm count below 10 million/ml and 26 (2%) in whom the percentage of motile sperm was less than 20%. Polyzoospermy (count greater than 250 million/ml) was found in 15 men (1.2%); one or more spontaneous abortions had occurred in six of the spouses of these men (40%), whereas the over-all spontaneous abortion rate was 7% and the spontaneous abortion rate for wives of men with sperm counts below 10 million/ml was 4%. A positive relationship was found between sperm density and percentage of motile sperm; the relationship between motility and the logarithm of sperm density was represented by a straight line (a 10-fold increase in sperm count was accompanied by an increase of 20.4% in sperm motility); the slope of the line was highly significant, although the correlation coefficient was weak (0.27). A similarly positive relationship was found between sperm density and grade of motility; however, the correlation coefficient was also weak (0.22). The relationship between the grade of motility and the proportion of motile sperm also positive, was reasonably large (0.70), although its significance is questionable because of the crudeness of the scale utilized to assess the grade of sperm motility. A comparison of the findings with those of similar studies was made.
Dicopper(II) metallacyclophanes as multifunctional magnetic devices: a joint experimental and computational study. Metallosupramolecular complexes constitute an important advance in the emerging fields of molecular spintronics and quantum computation and a useful platform in the development of active components of spintronic circuits and quantum computers for applications in information processing and storage. The external control of chemical reactivity (electro- and photochemical) and physical properties (electronic and magnetic) in metallosupramolecular complexes is a current challenge in supramolecular coordination chemistry, which lies at the interface of several other supramolecular disciplines, including electro-, photo-, and magnetochemistry. The specific control of current flow or spin delocalization through a molecular assembly in response to one or many input signals leads to the concept of developing a molecule-based spintronics that can be viewed as a potential alternative to the classical molecule-based electronics. A great variety of factors can influence over these electronically or magnetically coupled, metallosupramolecular complexes in a reversible manner, electronic or photonic external stimuli being the most promising ones. The response ability of the metal centers and/or the organic bridging ligands to the application of an electric field or light irradiation, together with the geometrical features that allow the precise positioning in space of substituent groups, make these metal-organic systems particularly suitable to build highly integrated molecular spintronic circuits. In this Account, we describe the chemistry and physics of dinuclear copper(II) metallacyclophanes with oxamato-containing dinucleating ligands featuring redox- and photoactive aromatic spacers. Our recent works on dicopper(II) metallacyclophanes and earlier ones on related organic cyclophanes are now compared in a critical manner. Special focus is placed on the ligand design as well as in the combination of experimental and computational methods to demonstrate the multifunctionality nature of these metallosupramolecular complexes. This new class of oxamato-based dicopper(II) metallacyclophanes affords an excellent synthetic and theoretical set of models for both chemical and physical fundamental studies on redox- and photo-triggered, long-distance electron exchange phenomena, which are two major topics in molecular magnetism and molecular electronics. Apart from their use as ground tests for the fundamental research on the relative importance of the spin delocalization and spin polarization mechanisms of the electron exchange interaction through extended π-conjugated aromatic ligands in polymetallic complexes, oxamato-based dicopper(II) metallacyclophanes possessing spin-containing electro- and chromophores at the metal and/or the ligand counterparts emerge as potentially active (magnetic and electronic) molecular components to build a metal-based spintronic circuit. They are thus unique examples of multifunctional magnetic complexes to get single-molecule spintronic devices by controlling and allowing the spin communication, when serving as molecular magnetic couplers and wires, or by exhibiting bistable spin behavior, when acting as molecular magnetic rectifiers and switches. Oxamato-based dicopper(II) metallacyclophanes also emerge as potential candidates for the study of coherent electron transport through single molecules, both experimentally and theoretically. The results presented herein, which are a first step in the metallosupramolecular approach to molecular spintronics, intend to attract the attention of physicists and materials scientists with a large expertice in the manipulation and measurement of single-molecule electron transport properties, as well as in the processing and addressing of molecules on different supports.
Initial treatment of Parkinson's disease. Initial treatment of early idiopathic Parkinson's disease (PD) begins with diagnosis based on clinical evaluation supplemented by laboratory studies and brain imaging to exclude causes of secondary parkinsonism. In most cases, testing is normal and the diagnosis of PD rests on clinical criteria. In patients with mild symptoms and signs, the diagnosis of PD may not initially be apparent, and follow-up evaluation is needed to arrive at a diagnosis. Once the diagnosis is made, pharmacologic treatment may not be the first step. First, patient education is essential, especially because PD is a high-profile disease for which information and misinformation are readily available to patients and families. Counseling concerning prognosis, future symptoms, future disability, and treatment must be provided. Questions from patients concerning diet, lifestyle, and exercise are especially common at this point. The decision of when to initiate treatment is the next major consideration. Much controversy but relatively little light has been brought to bear on this issue. L-dopa was the first major antiparkinson medication to be introduced and remains the "gold standard" of treatment. Next in efficacy are the dopamine agonists (DAs). A debate has raged concerning whether initial dopaminergic treatment should be with L-dopa or DAs. Physicians have been concerned about forestalling the appearance of dyskinesias and motor fluctuations, whereas patients have incorrectly understood that L-dopa and possibly other antiparkinson drugs have a finite duration of usefulness, making it important to defer treatment for as long as possible. This has created "L-dopa phobia," which may stand in the way of useful treatment. In spite of this controversy, there is uniform agreement that the appropriate time to treat is when the patient is beginning to be disabled. This varies from patient to patient and depends on age, employment status, nature of job, level of physical activity, concern about appearance, and other factors. The choice of a specific drug is sometimes dictated by the patient's symptoms. For example, L-dopa is preferable for severe akinesia, an anticholinergic may be useful when tremor is the most prominent symptom (especially in those aged younger than 70 years), and DAs may be indicated for younger patients, more prone to dyskinesias and fluctuations, with relatively mild symptoms. It is also important to manage non-motor symptoms in patients with early PD. Anxiety and depression are particularly common at this stage and may be presenting symptoms of PD. Where appropriate, counseling and/or treatment with anxiolytics and antidepressants should be considered.

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