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pubmed_285_391 | PURPOSE OF REVIEW
As the most popular psychostimulant in the world, methamphetamine use has reached epidemic proportions. Its enormous popularity has created subcultures of methamphetamine users all over the globe. The purpose of this review is to describe the geographic availability of different types of methamphetamine, the characteristics of each user population, and the psychosocial impact the two have on society.
RECENT FINDINGS
Methamphetamine has diversified immensely from the early days of its use. Different forms of methamphetamine - ICE, powder, and pills - have different pharmacokinetic characteristics that make them popular among certain types of users. New studies have shown that addiction to methamphetamine results in a very characteristic loss of inhibition that augments various risk-taking behaviors in its users. Also, recent seizure data suggest that its production and trafficking is spreading into new areas of the globe.
SUMMARY
From recreational use to addiction, methamphetamine use represents a serious risk to health and wellbeing of the community. Recognizing the pattern of abuse in specific populations is the key to assessing the risk, implementing prevention, and harm reduction measures, as well as making public policies. | 10.1097/YCO.0000000000000168 |
pubmed_952_7529 | Removal of glass wool-adherent cells resulted in an enhancing effect on DNA synthesis as measured by increased [3H]-thymidine uptake by normal swine spleen cells stimulated with phytohemagglutinin or concanavalin A (Con A). Depletion of nylon-adherent cells caused decreased DNA synthesis in response to Con A, except at high doses of Con A, whereas similar cultures stimulated with phytohemagglutinin showed enhanced DNA synthesis throughout the dose range employed. Titration experiments revealed that enhancing effects of adherent cell removal are most pronounced at higher cell and mitogen concentrations. Glass wool was more efficient than nylon in the enhancement of mitogen-induced DNA synthesis. | pubmed_952_7529 |
pubmed_210_23279 | The increasing need for safe, inexpensive, and sustainable construction, combined with novel technological enablers, has made large-scale construction by robot teams an active research area. Collective robotic construction (CRC) specifically concerns embodied, autonomous, multirobot systems that modify a shared environment according to high-level user-specified goals. CRC tightly integrates architectural design, the construction process, mechanisms, and control to achieve scalability and adaptability. This review gives a comprehensive overview of research trends, open questions, and performance metrics. | 10.1126/scirobotics.aau8479 |
pubmed_239_3981 | Recently, several studies have investigated the effectiveness of the ultrasound-guided lumbosacral transforaminal epidural injection. However, the ultrasound-guided S1 transforaminal epidural injection using an out-of-plane approach, which was previously reported, may cause an intestinal injury or intravascular injection because the needle tip tends to be invisible in the out-of-plane approach. In this study, therefore, we report a new method of ultrasound-guided S1 transforaminal epidural injection using the in-plane approach and color Doppler. In addition, we also report the usefulness of color Doppler imaging for finding the S1 foramen and confirming the accuracy of the injection. | 10.1097/PHM.0000000000000754 |
pubmed_635_9024 | BACKGROUND
We examined trends in adherence to highly active antiretroviral therapy (HAART) and HIV RNA suppression and estimated the minimum cutoff of adherence to newer HAART formulations needed for HIV RNA suppression by regimen type.
METHODS
We used Veterans Affairs pharmacy dispensing data from the Veterans Aging Cohort Study Virtual Cohort between October 2000 and September 2010 and defined adherence as the duration of time the patient had the medications available, relative to the total number of days between refills for all antiretrovirals in a year. Temporal trends in adherence and viral load suppression were examined by the patient's most frequently used HAART regimen in the year. The minimum needed adherence was defined as the level at which the odds of suppression was not significantly different than that observed with ≥ 95% adherence using repeated-measures logistic regression.
RESULTS
A total of 21,865 HAART users contributed 82,217 person-years of follow-up. There was a significant increase (P(trend) < 0.001) in the proportion virally suppressed even among those with <95% adherence (2001: 38% to 2010: 84%), and the trend was similar when restricting to their first HAART regimen. For nonnucleoside reverse transcriptase inhibitor multi-pill users, the odds of suppression did not differ for 85%-89% adherence compared to those with ≥ 95% adherence [odds ratios: 0.82 (0.64-1.04)], but for protease inhibitor users, the odds of suppression significantly differed if adherence levels were <95% compared to ≥ 95% adherence.
CONCLUSIONS
Although all HIV-infected persons should be instructed to achieve perfect adherence, concerns of slightly lower adherence should not hinder prescribing new HAART regimens early in HIV infection. | 10.1097/QAI.0000000000000643 |
pubmed_920_17770 | Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors. | 10.3390/biom11070936 |
pubmed_165_3190 | Proteolysis in Escherichia coli serves to rid the cell of abnormal and misfolded proteins and to limit the time and amounts of availability of critical regulatory proteins. Most intracellular proteolysis is initiated by energy-dependent proteases, including Lon, ClpXP, and HflB; HflB is the only essential E. coli protease. The ATPase domains of these proteases mediate substrate recognition. Recognition elements in target are not well defined, but are probably not specific amino acid sequences. Naturally unstable protein substrates include the regulatory sigma factors for heat shock and stationary phase gene expression, sigma 32 and RpoS. Other cellular proteins serve as environmental sensors that modulate the availability of the unstable proteins to the proteases, resulting in rapid changes in sigma factor levels and therefore in gene transcription. Many of the specific proteases found in E. coli are well-conserved in both prokaryotes and eukaryotes, and serve critical functions in developmental systems. | 10.1146/annurev.genet.30.1.465 |
pubmed_273_15453 | Bonamiosis due to the intrahaemocytic protistan parasite Bonamia ostreae is a European endemic disease affecting the flat oyster Ostrea edulis. The parasite has been described in various ecosystems from estuaries to open sea, but no clear correlation has yet been demonstrated between disease development and environmental parameters. In this study, the effect of temperature and salinity on the survival of purified parasites maintained in vitro in seawater was investigated by flow cytometry. Purified parasites were incubated in various seawater media (artificial seawater, natural seawater, seabed borewater) at various temperatures (4, 15 and 25 degrees C) and subjected to a range of salinities from 5 to 45 g l(-1). Parasites were collected after 12, 24 and 48 h of incubation for flow cytometry analyses including estimation of parasite mortality and parasite viability through detection of non-specific esterase activities. Artificial seawater appeared unsuitable for parasite survival, and results for all media showed a significantly lower survival at 25 degrees C compared to 4 degrees C and 15 degrees C. Moreover, high salinities (> or = 35 g l(-1)) favoured parasite survival and detection of esterase activities. Flow cytometry appears to be a suitable technique to investigate survival and activities of unicellular parasites like B. ostreae under varied conditions. Although these results contribute to a better understanding of existing interactions between the parasite B. ostreae and its environment, validation through epidemiological surveys in the field is also needed. | 10.3354/dao02047 |
pubmed_688_4508 | By means of biomicroscopic method the bulbar conjunctiva in 150 women (18-35 years of age) have been examined. Of them: 30 healthy women make the control group; the second group includes 60 healthy women at their first and second half of pregnancy; the third group includes 60 women with pregnancy developing against the background of noncomplicated insulin-dependent diabetus mellitus during their first and second half of pregnancy. In the healthy women there are not any significant changes in most of the parameters of the microcirculatory bed during the first half of their pregnancy, and in the second half of their pregnancy a great density of the blood vascular bed is determined. Diameters of all vessels in the hemomicrocirculatory bed are significantly increased, as compared to those in the control group. In the women suffering from diabetus mellitus, during the first half of pregnancy certain changes in the picture of the vascular network is observed, as well as an increased convolution. uneveness in distribution of blood vessels; in the second half of their pregnancy a pronounced deformity of the vacular network is observed, decreasing diameter of afferent vessels and an essential dilatation of postcapillaries and venules are registered. Certain signs of aggregation of blood formed elements is noted. | pubmed_688_4508 |
pubmed_528_18425 | We report an abnormal slowdown of the longitudinal diffusion of F-actin across the isotropic-to-nematic phase transition region. To probe the underlying physics of this counterintuitive discovery, we compared the diffusion of F-actin, microtubules and fd virus in F-actin solutions across the transition region and found the F-actin diffusion markedly different from the other two filament types. Also, the viscous drag probed by F-actin was found to increase sharply with [Mg(2+)] in the nematic but not in the isotropic state. Based on the experimental results, we propose that the abnormal slowdown is caused by the weak electrostatic attraction between actin filaments in the nematic phase, in which neighboring filaments in parallel associate with each other transiently as they collide due to thermal fluctuations. | 10.1103/PhysRevLett.99.068103 |
pubmed_177_3036 | Behçet's disease (BD) is a chronic, idiopathic, relapsing immune-mediated disease involving multiple organs, and is characterized by recurrent oral and genital ulcers, ocular disease, gastrointestinal ulcers, vascular diseases, and skin lesions. In particular, gastrointestinal involvement in BD is followed by severe complications, including massive bleeding, bowel perforation, and fistula, which can lead to significant morbidity and mortality. However, the management of intestinal BD has not yet been properly established. Intestinal BD patients with a severe clinical course experience frequent disease aggravations and often require recurrent corticosteroid and/or immunomodulatory therapies, or even surgery. However, a considerable number of patients with intestinal BD are often refractory to conventional therapies such as corticosteroids and immunomodulators. Recently, there has been a line of evidence suggesting that biologics such as infliximab and adalimumab are effective in treating intestinal BD. Moreover, new biologics targeting proteins other than tumor necrosis factor α are emerging and are under active investigation. Therefore, in this paper, we review the current therapeutic strategies and new clinical data for the treatment of intestinal BD. | 10.3904/kjim.2017.377 |
pubmed_311_25532 | The discovery of the epigenetic regulation of transcription has provided a new source of mechanistic understanding to long lasting effects of chemicals. However, this information is still seldom exploited in a toxicological context and studies of chemical effect after washout remain rare. Here we studied the effects of two nephrocarcinogens on the human proximal tubule cell line RPTEC/TERT1 using high-content mRNA microarrays coupled with miRNA, histone acetylation (HA) and DNA methylation (DM) arrays and metabolomics during a 5-day repeat-dose exposure and 3 days after washout. The mycotoxin ochratoxin A (OTA) was chosen as a model compound for its known impact on HA and DM. The foremost effect observed was the modulation of thousands of mRNAs and histones by OTA during and after exposure. In comparison, the oxidant potassium bromate (KBrO3) had a milder impact on gene expression and epigenetics. However, there was no strong correlation between epigenetic modifications and mRNA changes with OTA while with KBrO3 the gene expression data correlated better with HA for both up- and down-regulated genes. Even when focusing on the genes with persistent epigenetic modifications after washout, only half were coupled to matching changes in gene expression induced by OTA, suggesting that while OTA causes a major effect on the two epigenetic mechanisms studied, these alone cannot explain its impact on gene expression. Mechanistic analysis confirmed the known activation of Nrf2 and p53 by KBrO3, while OTA inhibited most of the same genes, and genes involved in the unfolded protein response. A few miRNAs could be linked to these effects of OTA, albeit without clear contribution of epigenetics to the modulation of the pathways at large. Metabolomics revealed disturbances in amino acid balance, energy catabolism, nucleotide metabolism and polyamine metabolism with both chemicals. In conclusion, the large impact of OTA on transcription was confirmed at the mRNA level but also with two high-content epigenomic methodologies. Transcriptomic data confirmed the previously reported activation (by KBrO3) and inhibition (by OTA) of protective pathways. However, the integration of omic datasets suggested that HA and DM were not driving forces in the gene expression changes induced by either chemical. | 10.3389/fgene.2018.00558 |
pubmed_202_21042 | The present study was undertaken to evaluate the mechanism of protective effect of semisoluble alpha-1,3-carboxymethylglucan during massive acute hemorrhage. CBA mice were injected i.v. with glucan (25 mg/kg) 24 h prior to hemorrhage (50% of blood circulating volume). Survival data indicated that glucan increased survival compared with the control. However alpha 1-proteinase inhibitor activity in serum has been even decreased 24 h after glucan administration. Moreover enhancement of active oxygen form production and leakage of cytosolic and lysosomal enzymes after alpha-1,3-carboxymethylglucan application was noted. | pubmed_202_21042 |
pubmed_955_6826 | We present a case of recurrent meconium peritonitis detected in the second trimester and treated by intrauterine intervention. Antenatal ultrasound findings included fetal ascites and intra-abdominal calcification. Aspiration of fetal ascites under ultrasound guidance and determination of the bilirubin concentration established the diagnosis of meconium peritonitis. Paracentesis was repeated to remove irritating intestinal contents and to decrease pressure on the fetal thorax. Although the exact cause of the meconium peritonitis remains unknown, the recurrence of the condition suggests a genetic basis. A possibility of cystic fibrosis was not considered because the clinical picture did not suggest it. Intrauterine intervention helped to establish the diagnosis of meconium peritonitis and may have contributed to the good outcome. | 10.1002/pd.1970141016 |
pubmed_149_8531 | BACKGROUND
Reported ischemia time of vascularized lymph nodes was 5 hours. This study investigated the effects of arterial ischemia and venous occlusion on vascularized lymph node function in rats.
METHODS
Bilateral pedicled groin lymph node flaps were raised in 27 Lewis rats. Femoral artery and vein were separated and clamped for 1, 3, 4, or 5 hour(s). Lymph node flap perfusion and drainage were assessed by laser Doppler flowmetry and indocyanine green lymphography. Histologic changes were assessed using hematoxylin and eosin stain, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), and glutathione assays.
RESULTS
Perfusion units of 2.84 ± 1.41, 2.46 ± 0.64, 2.42 ± 0.37, and 2.01 ± 0.90 were measured in arterial ischemia groups, and 1.71 ± 0.45, 2.20 ± 0.98, 1.49 ± 0.35, and 0.81 ± 0.20 in venous occlusion groups after 1, 3, 4, and 5 hours of clamping, respectively. Lymphatic drainage showed mean latency periods of 5.33 ± 0.88, 9.00 ± 3.21, 10.00 ± 2.08, and 24.50 ± 11.50 seconds in arterial clamping groups, and 25.00 ± 3.61, 26.00 ± 3.06, 23.33 ± 4.41, and 152.00 ± 0 seconds in venous clamping groups, respectively. Severe medullary and cortical congestion and hemorrhage on histology and cell damage by glutathione levels and TUNEL assay were found after 4 hours of venous clamping.
CONCLUSIONS
Arterial ischemia and venous occlusion impact the function and viability of vascularized lymph node flaps differently. The critical venous occlusion time was 4 hours. | 10.1002/jso.25518 |
pubmed_389_4790 | INTRODUCTION
Relationship perception focuses on social interactions, is reduced in schizophrenia and is related to daily functioning. It can be assessed with the Relationships Across Domains (RAD) test, built on Relational Models Theory which states that people use four relational models to interpret social interaction. RAD is time consuming, low on tolerability and only used in English-speaking countries. We evaluated the psychometric properties of a translated, abbreviated Norwegian version.
METHODS
Sixty-two schizophrenia participants and 56 healthy controls underwent assessments of social and non-social cognition. The schizophrenia group completed functional and clinical measures. RAD's internal consistency was investigated with Cronbach's alphas, group differences with logistic regressions and associations between study variables with Pearson's correlations.
RESULTS
RAD was reduced from 25 (Cronbach's alpha = .809) to 12 vignettes (Cronbach's alpha = .815). Schizophrenia participants had significant impairments, with larger effect sizes for the full version. Associations of RAD with study variables were similar for the two versions: smaller for clinical measures and larger for functional and cognitive measures. Results were comparable to results for the English version.
CONCLUSIONS
The length of the Norwegian RAD was reduced while retaining its psychometric properties, which were similar to the English version. This suggests the test's cross-cultural utility. | 10.1080/13546805.2017.1307174 |
others_290_11073 | Although red (R; 600–700 nm) and blue (B; 400–500 nm) radiation can be sufficient for plants grown indoors, other wavebands such as green (G; 500–600 nm) and far red (FR; 700–800 nm) can also regulate photosynthesis, plant morphology, and secondary metabolism. The objective of this study was to determine how substitutions of B radiation with G and/or FR radiation influence growth of leafy greens grown indoors under light-emitting diodes (LEDs). We postulated G and/or FR radiation (and low B radiation) would trigger shade-avoidance responses and thus promote biomass accumulation through increased radiation interception. We grew lettuce (Lactuca sativa ‘Rex’ and ‘Rouxai’) and kale (Brassica oleracea var. sabellica ‘Siberian’) under warm-white (WW) LEDs at 180 μmol·m –2 ·s –1 (400–800 nm) for 9–11 days and then transplanted seedlings into a hydroponic system with ten different lighting treatments. The air temperature (20 °C), photoperiod (20 h), total photon flux density (180 μmol·m –2 ·s –1 ; 400–800 nm), and fertility were maintained the same across treatments. In addition to WW and equalized-white (EQW) controls, combinations of B (peak =449 nm), G (peak =526 nm), and FR (peak =733 nm) LEDs, each at 0, 20, 40, or 60 μmol·m –2 ·s –1 , were delivered in a R background (peak =664 nm) of 120 μmol·m –2 ·s –1 . One month after seed sow, we collected data on shoot mass, leaf morphology, and pigmentation. Substituting G or FR radiation for B radiation promoted leaf expansion and increased shoot mass but decreased chlorophyll concentrations in all crops. For example, lettuce ‘Rex’ grown under 60 μmol·m –2 ·s –1 of G +120 μmol·m –2 ·s –1 of R radiation was 38% greater in plant diameter and 54% greater in shoot dry mass compared to those under 60 μmol·m –2 ·s –1 of B +120 μmol·m –2 ·s –1 of R radiation. Substituting B radiation with G radiation at 60 μmol·m –2 ·s –1 also reduced red coloration of lettuce ‘Rouxai’. At the same photon flux density, FR radiation increased leaf expansion and decreased red foliage coloration more than G radiation. We conclude that substituting G and/or FR radiation for B radiation triggers shade-avoidance responses, accelerating plant growth while decreasing pigment concentrations. © 2019 Elsevier B.V | 10.1016/j.envexpbot.2019.03.016 |
pubmed_625_5018 | BACKGROUND
Anatomical variation may represent a challenge in achieving a close fit between a prosthesis and a patient's osseous geometry in total knee arthroplasty (TKA). The purposes of this study were to determine whether the shape of the distal part of the femur differs among ethnicities, whether these differences affect the fit of the femoral component of a standard prosthesis, and whether the additional availability of a femoral component with a reduced mediolateral dimension for the same anteroposterior dimension improves femoral component fit across ethnicities.
METHODS
Femoral dimensions were measured intraoperatively during 967 TKAs performed using the same type of prosthesis in patients of 5 different ethnicities. Aspect ratios were calculated to determine whether the shapes of the femora differed among ethnicities. The component fit ("perfect," overhang, or underhang) when only standard prostheses were available was compared with the fit when both standard and narrow prostheses were available in all ethnic groups. This enabled us to determine whether the femoral component fit was improved by the additional availability of the narrow version.
RESULTS
Wide variations in shape were found among ethnicities as were variations among individuals of the same ethnicity. Differences in shape among ethnicities influenced the rate of overhang. However, overhang was more frequent at the trochlear than at the condylar level across all ethnicities. The availability of both the standard and the narrow femoral components improved the rate of a perfect fit in women in 3 of the 5 ethnic groups and reduced the overhang rate in women in all 5 of the ethnic groups. In contrast, only modest improvements in femoral component fit, which were not statistically significant, were seen in men.
CONCLUSIONS
The shape of the distal part of the femur varies not only among ethnicities but also within ethnic groups, leading to a high prevalence of overhang when only standard prostheses are available. The additional availability of a femoral component with a reduced mediolateral dimension for the same anteroposterior size can reduce overhang and improve component fit across ethnicities. | 10.2106/JBJS.OA.16.00014 |
pubmed_200_9574 | This paper investigates the impact of trade openness on CO2 emissions using time series data over the period of 1970QI-2011QIV for Malaysia. We disintegrate the trade effect into scale, technique, composition, and comparative advantage effects to check the environmental consequence of trade at four different transition points. To achieve the purpose, we have employed augmented Dickey-Fuller (ADF) and Phillips-Perron (PP) unit root tests in order to examine the stationary properties of the variables. Later, the long-run association among the variables is examined by applying autoregressive distributed lag (ARDL) bounds testing approach to cointegration. Our results confirm the presence of cointegration. Further, we find that scale effect has positive and technique effect has negative impact on CO2 emissions after threshold income level and form inverted U-shaped relationship-hence validates the environmental Kuznets curve hypothesis. Energy consumption adds in CO2 emissions. Trade openness and composite effect improve environmental quality by lowering CO2 emissions. The comparative advantage effect increases CO2 emissions and impairs environmental quality. The results provide the innovative approach to see the impact of trade openness in four sub-dimensions of trade liberalization. Hence, this study attributes more comprehensive policy tool for trade economists to better design environmentally sustainable trade rules and agreements. | 10.1007/s11356-015-5217-9 |
pubmed_15_14715 | OBJECTIVES
Component-wise boosting algorithms have evolved into a popular estimation scheme in biomedical regression settings. The iteration number of these algorithms is the most important tuning parameter to optimize their performance. To date, no fully automated strategy for determining the optimal stopping iteration of boosting algorithms has been proposed.
METHODS
We propose a fully data-driven sequential stopping rule for boosting algorithms. It combines resampling methods with a modified version of an earlier stopping approach that depends on AIC-based information criteria. The new "subsampling after AIC" stopping rule is applied to component-wise gradient boosting algorithms.
RESULTS
The newly developed sequential stopping rule outperformed earlier approaches if applied to both simulated and real data. Specifically, it improved purely AIC-based methods when used for the microarray-based prediction of the recurrence of metastases for stage II colon cancer patients.
CONCLUSIONS
The proposed sequential stopping rule for boosting algorithms can help to identify the optimal stopping iteration already during the fitting process of the algorithm, at least for the most common loss functions. | 10.3414/ME11-02-0030 |
others_53_15890 | Physalis peruviana L. contains polyphenols and carotenoids with antiinflammatory and antioxidant activities used against diabetes. To establish an efficient regeneration system using nodal segments excised from 4-week-old germinated seedlings, direct plant regeneration, without additional rooting stage, was achieved on LS medium containing 0.5 mg/L 6-benzylaminopurine (BAP), kinetin (KIN), thidiazuron (TDZ), or gibberellic acid (GA3), alone or in combination with 0.25 mg/L indole-3-acetic acid (IAA) or indole-3- butyric acid (IBA), after 2 weeks of incubation. The highest mean numbers of shoots and well-developed roots were obtained on LS medium containing solely 0.5 mg/L TDZ, producing 5.3 shoots and 3.3 roots per explant after 2 weeks of incubation. Direct shoot and root formation were also recorded on LS medium containing no plant growth regulators. Due to the high regeneration capacity of nodal segments, synthetic seed production was also investigated using the sodium alginate (NaAlg) encapsulation technique. Four different matrix compositions, including NaAlg with or without LS medium containing 3% (w/v) sucrose alone or in combination with 0.5 mg/L abscisic acid (ABA) as a growth retardant were tested for the regrowth performance of synthetic seeds after storage at 4 °C up to 70 days. The highest regrowth (100%) was observed at 28 days of storage for all matrix compositions. All plantlets were acclimatized to the soil and then progressively transferred to the field. The fruits were harvested after 5 months. This study might provide a new insight through protocol development for micropropagation and synthetic seed production of many solanaceous species with economical relevance. © 2015, TÜBITAK | 10.3906/tar-1412-86 |
pubmed_969_17688 | The effect of suramin on the ATP-induced response in vas deferens DDT1 MF-2 smooth muscle cells was studied. Stimulation of P2-purinoceptors by ATP caused a change in membrane currents, measured by using the whole-cell patch-clamp configuration, and enhanced the formation of inositol phosphates, as analysed by high performance liquid chromatography. The ATP-induced membrane current consisted of a triphasic response, carried by a fast inward current, followed by a transient outward current and a sustained inward current. Inositol tetrakisphosphate (InsP4) formation increased in the presence of ATP. The formation of the isomers Ins(1,3,4,5)P4, Ins(1,3,4,6)P4 and Ins(3,4,5,6)P4 increased significantly after 5 min stimulation with ATP. Suramin inhibited the ATP-evoked membrane currents and the ATP-induced formation of inositol tetrakisphosphate isomers concentration dependently, but did not affect the basal inositol phosphate levels in the absence of ATP. These results indicate that suramin inhibits ATP-activated cellular processes in DDT1 MF-2 vas deferens cells, most likely by acting on P2-purinoceptors. | 10.1016/0014-2999(90)90253-3 |
pubmed_530_95 | Despite a general acknowledgment that research in children is necessary and ethical, the evidence base for child-specific treatments is still sparse. We investigated children's biomedical and health services research in the UK in relation to training, infrastructure and activity, research evidence, and visibility. We show that excellent opportunities for career researchers exist through a competitive, national integrated academic training programme, but that the number of academic paediatricians has decreased by 18% between 2000 and 2011, falling from 11·3% to 5·9% of the consultant workforce. The potential for rapid delivery of studies in children through the National Health Service (NHS) is not being realised: clinical trainees are poorly equipped with core research skills; most newly appointed consultant paediatricians have little or no research experience; less than 5% of contracted consultant time supports research; less than 2·5% of the 2 million children seen in the NHS every year are recruited to studies; and ten of the 20 UK children's hospitals do not have a clinical research facility. Support through National Institute for Health Research networks is good for studies into drugs, but inconsistent for non-drug research; less than 5% of registered studies involve children and only one children's biomedical research centre has been allocated funding from 2012. Of the UK annual public and charitable biomedical research expenditure of roughly £2·2 billion, about 5% is directed at child health research. The scant evidence base is impeding the development of clinical guidance and policy-less than 20% of the outputs of the National Institute for Health and Clinical Excellence are applicable to children. Paediatric representation on major research boards is weak. Parent and young people's advocacy is fragmented, and their views are insufficiently heeded by regulatory bodies. The strong UK Government commitment to biomedical research has not been translated fully to research for children. The power of research in children to turn the tide of the growing burden of non-communicable, chronic, adult diseases that have their origins in early life, to benefit the health of an ageing population and future generations, and to reduce health-care costs is inadequately recognised. On the basis of our findings, we make several recommendations to improve early-years research, including the formation of multidisciplinary, cross-institutional groups of clinical and non-clinical child health researchers and their access to diagnostic and laboratory facilities suitable for children; a unified Children's Research Network for drug studies and non-drug studies; regulatory assessment of research that is proportionate and based on consistent national criteria; an expansion of research posts; support for parents' and young people's advocacy; collaboration between children's research charities; improved research training for paediatric trainees; and closer integration of child health research with core NHS activities. | pubmed_530_95 |
pubmed_580_201 | BACKGROUND
The aim of the present study was to examine whether different treatment schedules could be associated with tolerance development to the ataxic and sedative effects of flunitrazepam in mice.
METHODS
Effects of repeated flunitrazepam administration were studied in the rotarod and the chimney test for motor coordination and in a photocell apparatus for locomotor activity in mice. Flunitrazepam doses varied in particular types of injections or in different experiment duration periods.
RESULTS
Repeated flunitrazepam administration (1 mg/kg, sc and 2 mg/kg, ip) for 8 consecutive days induced tolerance to the motor impairing effects of flunitrazepam in mice, both in the rotarod and the chimney test. In turn, no tolerance developed to sedative flunitrazepam effects, regarding either dose level, injection type or treatment duration.
CONCLUSIONS
Those findings confirmed the previous observations that tolerance to benzodiazepines was not simultaneous for each pharmacological property of the drugs. Interestingly enough, an acute dose of flunitrazepam (1 mg/kg, sc) in our study enhanced locomotor activity of mice. | 10.1016/s1734-1140(13)70963-0 |
pubmed_229_18708 | BACKGROUND
Helicobacter pylori infection has been described as a risk factor for hepatic encephalopathy in patients with chronic liver disease although the topic remains controversial.
AIMS
To determine whether Helicobacter pylori infection is an independent predictive factor for encephalopathy in patients with liver cirrhosis.
METHODS
Clinical, epidemiological, analytical and nutritional parameters of 205 patients were collected. Helicobacter pylori infection was determined by serology. Encephalopathy (grade II or higher) was clinically assessed during follow-up. The relationship between each parameter and encephalopathy was analysed by Kaplan-Meier curves and the Log rank test. The most significant parameters underwent multivariate analysis by Cox regression.
RESULTS
Twenty-five variables were related to encephalopathy in the bivariate analysis. Multivariate analysis selected five independent factors: previous bouts of encephalopathy (Odds ratio 3.79; 95% confidence interval 1.94-7.38), albumin (Odds ratio 0.86; 95% confidence interval 0.80-0.92), tricipital skin fold (Odds ratio 0.79; 95% confidence interval 0.66-0.95) chronic pulmonary disease (Odds ratio 2.78, 95% confidence interval; 1.31-5.92), and on-going alcoholism (Odds ratio 2.62; 95% confidence interval 1.16-5. BB).
CONCLUSIONS
Helicobacter pylori is not an independent risk factor for hepatic encephalopathy. | 10.1016/s1590-8658(01)80013-x |
others_314_74245 | Riboswitch, a part of mRNA (50-250nt in length), has two main classes: aptamer and expression platform. One of the main challenges raised during the classification of riboswitch is imbalanced data. That is a circumstance in which the records of a dataset of one group are very small compared to the others. Such circumstances lead classifier to ignore minority group and emphasize on majority class, that resulting with a skewed classification. We considered sixteen riboswitch families, to be in accord with recent riboswitch classification work, that contain imbalanced dataset ranging from 4,826 instances (RF00174) to 39 (RF01051) instances. The dataset was divided into training and test set using new developed pipeline. From 5460 k-mers, 156 features were produced calculated based on CfsSubsetEval and BestFirst. Statistically tested result was significantly difference between balanced and imbalanced dataset (p < 0.05). Besides, each algorithm also showed a significant difference in sensitivity, specificity, accuracy, and macro F-score when used in both groups (p < 0.05). Several k-mers clustered from heat map were discovered to have biological functions and motifs at the different positions like interior loops, terminal loops and helices. They were validated to have a biological function and some are riboswitch motifs. The analysis has discovered the importance of solving the challenges of majority bias analysis and overfitting. Presented results were generalized evaluation of both balanced and imbalanced models, which implies their ability of classifying novel riboswitches. The scientific community can use python source code at https://github.com/Seasonsling/riboswitch, which can contribute to the process of developing software packages.
Author SummaryMachine learning application has been used in many ways in bioinformatics and computational biology. Its use in riboswitch classification is still limited and existing attempt showed challenges due to imbalanced dataset. Algorithms classify dataset with majority and minority group, but they tend to ignore minority group and emphasize on majority class, consequential return a skewed classification We used new pipeline including SMOTE for balancing datasets that showed better classified riboswitch as well as improved performance of algorithms selected. Statistically significant difference observed between balanced and imbalanced in sensitivity, specificity, accuracy and F-score, this proved balanced dataset better for classification of riboswitch. Biological functions and motif search of k-mers in riboswitch families revealed their presence in interior loops, terminal loops and helices, some of the k-mers were reported to be riboswitch motifs of aptamer domains and critical for metabolite binding. The pipeline can be used in machine learning and deep learning study in other domains of bioinformatics and computational biology suffering from imbalanced dataset. Finally, scientific community can use python source code, the work done and flow to develop packages | 10.1101/2020.03.02.972778 |
pubmed_167_14883 | Oxidation of tryptophan not only generates heterogeneity of a therapeutic monoclonal antibody (mAb) but also can be a potential critical quality attribute (CQA) of the product. In this study, mAbs A-C of IgG1 and IgG4 (immunoglobulin G, IgG) isotypes with oxidized tryptophan (Trp) residues were selectively generated by incubating the mAbs with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) in formulations containing l-methionine. The site-specific oxidation of tryptophan residues were confirmed by liquid chromatography coupled with mass spectrometry (LC-MS) studies. The site of oxidation was identified to be a conserved tryptophan residue in the heavy chain complementarity determining region 3 (CDR3) of mAbs A and B with no significant oxidation found on other tryptophan residues including those in close proximity to CDR3. For mAb C, all tryptophan residues including one in the heavy chain CDR1 and a tryptophan in close proximity to heavy chain CDR3 were not susceptible to oxidation. For all three mAbs, the structure and tryptophan oxidation relationship was further studied by computational modeling of the variable domain of the antibodies (variable fragment, Fv). The computational modeling provided a structural understanding at the molecular level to the tryptophan oxidation, where high solvent accessibility is a prerequisite for heavy chain CDR3 tryptophan oxidation. However, higher oxidation susceptibility of tryptophan in heavy chain CDR3 did not linearly correlate to higher solvent accessibility, suggesting that other factors including side-chain orientation and/or surrounding structure elements around the heavy chain CDR3 may also be involved. Through this study, we demonstrate that a selective oxidation system, together with computational modeling, can be an important tool to identify potential CQAs of a therapeutic mAb such as tryptophan oxidation liabilities during the mAb's development. | 10.1021/acs.analchem.8b04768 |
pubmed_41_6241 | For the first time, co-polymer of dimethyl diallyl ammonium chloride and diallylamin (PDDACD) was used to modify the films derived from the waste of palm date fruits, which were then investigated by the purification of colored aqueous solutions. The physico-chemical characteristics were identified using data color, FT-IR spectroscopy, and SEM features. The modified films were evaluated as adsorbents of Methylene Blue (MB), Direct Yellow 50 (DY50), Reactive Blue 198 (RB198) and Naphtol Blue Black (NBB). High retention capacities were achieved in the following order: The equilibrium da DY50 (14 mg g-1) < RB198 (16 mg g-1) < NBB (63.9 mg g-1) < MB (150 mg g-1). The kinetic modeling of the data revealed that the adsorption data follows the pseudo second order model. It was fitted to the Langmuir, Freundlich, Temkin, and Dubinin-Redushkevich equations, and the data best fit the Freundlich model indicating that the adsorption might occur in the heterogeneous adsorption sites. These results reveal that PDDACD modified films are valuable materials for the treatment of industrial wastewater. Moreover, the as-prepared adsorbent is economically viable and easily controllable for pollutant adsorption. | 10.1038/s41598-017-14327-7 |
pubmed_492_1151 | This study was designed to measure hyperreactivity of bronchi in patients aged from 7-8 to 13-14 years presenting with allergic rhinitis. The efficiency of the bronchoprovocative test with physical exercises was shown to be higher than the study of external respiratory function at rest. | pubmed_492_1151 |
pubmed_986_14147 | The Bushmen of southern Africa use the expressed contents of beetle larvae (Diamphidia, Lebistina and Polyclada species) as arrow poison. an aqueous extract of Diamphidia nigroornata larvae was fractionated by gel filtration on Sephadex G-50. Two fractions were obtained: one (I) of high molecular weight which contains a protein of 60 000 daltons, and a low molecular weight fraction (II) of non-protein nature. Both fractions proved to be lethal to mice: an LD50 of 0.5 - 0.95 (I) and 3.2 - 3.5 (II) mg/kg (intraperitoneal injection), respectively, was determined. The toxic principle of fraction I could be partly separated from the protein by ammonium sulfate precipitation followed by gel filtration. That of fraction II was further resolved into several subfractions by gel filtration of Sephadex G-10; however, the lethal activity was completely lost during purification. In thin-layer chromatography the low molecular weight toxin(s) did not react with reagents for steroids, alkaloids, sugars or terpenes, but showed a positive ninhydrin reaction. It is concluded that the toxic principle of the Bushman arrow poison is a highly labile, low molecular weight compound which is closely attached or bound to a protein protecting it from inactivation. | 10.1016/0378-8741(82)90068-x |
pubmed_564_10821 | Hypotensive haemorrhage increased the production of Fos, a marker of cell activation, in cells of the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as well as in the supraoptic (SON) and paraventricular (PVN) nuclei in conscious rats. Pretreatment with captopril (100 mg/kg i.p.) inhibited the production of Fos in cells of the SFO and OVLT but did not reduce the concentration of Fos-positive cell nuclei in the PVN and SON. The results suggest that the production of Fos in the SFO and OVLT induced by the haemorrhage is probably due to elevated levels of circulating angiotensin II. | 10.1016/0304-3940(93)90821-2 |
pubmed_920_7667 | BACKGROUND AND OBJECTIVES
Ketogenic diet (KD), a well-known nonpharmacologic treatment of intractable epilepsy, could adversely affect growth and nutritional status; however, such data are limited in Thailand. This study aimed to assess growth and nutritional status of Thai children treated with KD together with dietary adherence and its related factors.
METHODS AND STUDY DESIGN
The records of children treated with KD for more than 1 month between January 2009 to September 2020 were reviewed. Weight, height, and biochemical indices were retrieved at baseline, 1, 3, 6, 12, 18, and 24 months. Type of KDs, compliance and adverse effects were extracted.
RESULTS
Forty-eight patients (21 male) were enrolled. Median age was 3.5 years (IQR 0.9, 10.1). There was no significant decrease in weight-for-age z-score (WAZ) despite a trend toward minimal reduction in WAZ at 3 months. Median follow-up time was 13 months (IQR 7, 29.5). Height-for-age z-score (HAZ) significantly decreased at 12 months [median -1.55 (IQR -3.35, -0.43) vs baseline median -0.6 (IQR -2.07, 0.29)]. Adherence of KD in tube feeding patients was better than oral feeding. Thirty seven percent (18/48) of the patients continued the diet beyond 2 years. Early discontinuation before 6 months was mostly due to poor compliance from patients and families (6/11, 55%). Common adverse effects were GI problems (77%), dyslipidemia (64%) and hypercalciuria (29%).
CONCLUSIONS
Under close monitoring, KD can be administered in Thai children with minimal adverse effects on growth and nutritional status. Adherence depends on route of feeding, clinical response, and cooperation of the families. | 10.6133/apjcn.202106_30(2).0007 |
pubmed_704_5723 | Nuclear proteins, like histone H2A, are promising non-viral carriers for gene delivery since they are biocompatible, biodegradable, bear intrinsic nuclear localization signal, and are easy to modify. The addition of surface-protein-binding ligand to histone H2A may increase its DNA delivery efficiency. Tumor microenvironment (TME) is a promising target for gene therapy since its surface protein repertoire is more stable than that of cancer cells. Cancer-associated fibroblasts (CAFs) are important components of TME, and one of their surface markers is beta-type platelet-derived growth factor receptor (PDGFRβ). In this study, we fused histone H2A with PDGFRβ-binding peptide, YG2, to create a novel non-viral fibroblast-targeting DNA carrier, H2A-YG2. The transfection efficiency of histone complexes with pDNA encoding a bicistronic reporter (enhanced green fluorescent protein, EGFP, and firefly luciferase) in PDGFRβ-positive and PDGFRβ-negative cells was estimated by luciferase assay and flow cytometry. The luciferase activity, percentage of transfected cells, and overall EGFP fluorescence were increased due to histone modification with YG2 only in PDGFRβ-positive cells. We also estimated the internalization efficiency of DNA-carrier complexes using tetramethyl-rhodamine-labeled pDNA. The ligand fusion increased DNA internalization only in the PDGFRβ-positive cells. In conclusion, we demonstrated that the H2A-YG2 carrier targeted gene delivery to PDGFRβ-positive tumor stromal cells. | 10.3390/polym12081695 |
pubmed_581_11912 | End stage chronic kidney disease (CKD) requiring renal replacement therapy is related to poor quality of life and high mortality. Thus, slowing the progression of CKD is an important purpose of therapy. Some general therapeutic approaches aim to slow the decline of renal function and they can be applied in all patients with CKD - irrespective of the underlying cause of CKD. A key intervention is lowering blood pressure (target: ≤ 140/90 mmHg, and in patients with albuminuria ≤ 130/80 mmHg). Inhibitors of the renin angiotensin system preferentially should be used in case of albuminuria, depending on the diabetic status and the level of albuminuria: in diabetics with albuminuria ≥ 30 mg/d, in non-diabetics with albuminuria > 300 mg/d. Mineralocorticoid receptor blockers and endothelin receptors blockers promise novel anti-proteinuric strategies - but still validation of their positive effects on retarding CKD progression is necessary. In patients with diabetic kidney disease, glycemic control aiming for an HbA1c of ≈ 7.0 % has been established to slow CKD progression. Furthermore, SGLT-2 inhibition with empagliflozin may be considered as a new therapeutic approach that provides additional cardiovascular and renal protection. Finally, recent studies suggest: correction of metabolic acidosis and avoidance of episodes of acute renal failure may provide protection against the progression of CKD. | 10.1055/s-0042-115782 |
pubmed_652_14630 | PURPOSE
Adnexal masses in pregnancy are often incidentally detected during sonography and most resolve spontaneously by early second trimester. This study aimed to look at the prevalence and management of adnexal masses in pregnancy at a tertiary care referral perinatal hospital.
METHODS
This is a retrospective study of all women with adnexal masses (excluding ectopic gestations and non-gynaecological lesions) identified pre-pregnancy or during pregnancy (antepartum/intrapartum) from January 2006 to August 2013 at the study institute.
RESULTS
The study identified 252 women (0.6, 95 %, CI: 0.5, 0.7) with adnexal masses and mean (SD range) age of 27.1 (4.21, 18-39) years. Majority (80 %) of the masses were diagnosed incidentally. 170 (67.5 %) women were offered conservative management and cysts resolved in half of them. 87 (34.5 %) women had adnexal surgery and 15.1 % were operated during the antepartum period because of persistent abdominal pain or suspicious sonographic findings. Three (1.2 %) malignancies and five (2.0 %) borderline ovarian tumours were diagnosed on histopathological examination. 16 (6.3 %) women were lost to follow-up antenatally. Pregnancy carried to term in 175 (69.4 %) women. Perinatal mortality rate was 31.1/1,000 total births (caused by prematurity). Complications encountered were torsion (7.1 %), malignancy (1.2 %), rupture (0.4 %) and infection (0.4 %).
CONCLUSION
Although conservative management was appropriate in the majority of cases, the study identifies the need to standardize diagnosis, investigations and management for a better evaluation of outcomes. | 10.1007/s00404-014-3395-1 |
pubmed_804_8785 | OBJECTIVES
Stereotactic body radiotherapy (SBRT) is potentially curative treatment for small hepatocellular carcinomas (HCC), but data are limited on its efficacy and toxicity. We hypothesized that SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis.
MATERIALS AND METHODS
Thirty-seven nonmetastatic HCC patients received SBRT to 43 lesions between October 2012 and April 2016. Median dose was 50 Gy/5 fractions. All Child-Pugh (CP) ≥B patients underwent a planned 1-month break after the first 3 fractions to assess hepatic toxicity. Patients were treated without separately placed fiducial markers using Linac-based SBRT with breath-hold (67%) or 4D-computed tomography with compression belt (33%) to reduce motion. Patients underwent magnetic resonance imaging q3 months post-SBRT.
RESULTS
Median age was 65 (range, 44 to 88). Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP≥B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP≥B8 patients had no grade ≥3 hepatic toxicity.
CONCLUSIONS
SBRT for HCC is well-tolerated even in patients with advanced cirrhosis and prior liver-directed treatment and provides excellent LC even for larger lesions that cannot be controlled with radiofrequency ablation. LC with SBRT compares favorably to other liver-directed therapies. Prospective studies comparing SBRT with other liver-directed therapies are warranted. | 10.1097/COC.0000000000000435 |
pubmed_471_7849 | Autoimmune hepatitis (AIH) is a rare cause of chronic liver disease. The backbone of treatment is immunosuppressive medication, typically prednisolone as induction therapy and azathioprine as a maintenance therapy. Side effects of the long-term use of systemic corticosteroids are well known and have led to the use of alternative induction regimens. An attractive alternative is budesonide, a nonhalogenated glucocorticosteroid characterized by a high first-pass effect in the liver (90%), resulting in a high topical anti-inflammatory activity and a low systemic activity. It should be stressed that budesonide is contraindicated in patients with established cirrhosis with portal hypertension and portocaval shunting. In this case report, we present the first case of adrenal insufficiency following treatment with budesonide for AIH. | 10.1159/000492204 |
pubmed_24_840 | INTRODUCTION
The conventional view that admission lactate levels predict outcome in trauma patients stems from simple comparisons of mean blood levels between groups and small sample sizes. To better address this question, we performed more rigorous statistical analyses of lactate in a larger patient sample.
METHODS
We prospectively collected data on admission lactate and outcomes in 5,995 patients admitted to an urban, university-based trauma center. The ability of admission lactate to predict mortality was assessed by logistic regression, calculation of positive predictive values (PPV), and measurement of areas under receiver operating characteristic (ROC) curves.
RESULTS
Differences between survivors and nonsurvivors in means of most proposed prognosticators was again demonstrated. However, the large overlap in these variables between survivors and nonsurvivors prevented clinically useful predictions. The overall PPV of elevated lactate was only 5.4%. Even in severely injured patients (Injury Severity Score >20; mortality 23%), elevated admission lactate level was a poor predictor of outcome. ROC analyses found no useful sensitivity threshold overall or after stratification by age, sex, Glasgow Coma Scale score, revised trauma score, or mechanism of injury.
CONCLUSIONS
This large retrospective examination of admission lactate levels failed to show useful predictive accuracy for hospital death. Serum lactate levels need not be obtained routinely but can be reserved for patients who will be admitted to the intensive care unit and/or require an emergency operation. | 10.1097/01.ta.0000205858.82575.55 |
pubmed_633_6208 | BACKGROUND, AIM AND SCOPE
This paper presents a preliminary study of the water profile with reference to microbiological parameters, required by Directive 2006/07/EC (European Community 2006) concerning the management of bathing water quality, in the coastal belt of the Province of Venice (Italy, Northern Adriatic Sea). A historical database has been implemented with monitoring data for the period 2000-2006 (data on rivers, bathing and marine coastal waters and on the characterization of Wastewater Treatment Plant (WWTP) discharges) from the institutional activity of Veneto Regional Environmental Prevention and Protection Agency (ARPAV). An integrated areal analysis for the microbiological investigation of homogeneous stretches along the coast of the Province of Venice was performed for a preliminary characterization of the bathing water profile considering water quality status and existing pressure sources.
MATERIALS AND METHODS
ARPAV is the institutional body responsible for environmental monitoring and control activities. Data were produced from monitoring and controls made available by the Regional Environmental Informative System and extracted and elaborated for the period of interest (2000-2006). Sampling and analysis of microbiological parameters were executed following the official Italian methods in accordance with international procedures (APHA et al. 1998). For the purpose of this study, the coast was divided into eight stretches, which were considered to be homogeneous according to their physical and geographical characteristics. An ANOVA statistical assessment has been performed on stretches I, V and VIII.
RESULTS AND DISCUSSION
From the integrated areal analysis of microbiological parameters in the homogeneous stretches along the coast of all the investigated matrices, high mean levels of faecal contamination were found in some cases. The most critical situation amongst the stretches evaluated is to be found in stretch VIII-Ca' Roman, Sottomarina and Isola Verde shores (Southern part of the Province). These results can be widely attributed to pressure sources from the Brenta and Adige rivers, rather than to local contributions. Stretches VI and VII, which correspond to the area from Punta Sabbioni (Cavallino shore N-E) to the Pellestrina shore (S-W), present the best conditions for faecal contamination parameters (low pollution levels). These situations can probably be explained given that WWTPs 7 and 8 have two submarine outfalls at a distance of about 4 km from the coastline and therefore a discharge point which is distant from the bathing and marine coastal monitoring stations; there are also no river mouths in these two stretches. Due to lack of data, it was not possible to implement seasonal assessments.
CONCLUSIONS
This study aimed to develop an integrated areal analysis for biological parameters along the coast over the period 2000-2006 for the identified homogeneous stretches in order to develop a preliminary approach for the characterization of the water profile, as requested by directive 2006/7/EC. From the integrated analysis of the stretches, it is evident that in some cases there are high levels of faecal contamination along the coast which can be caused by river flows which heavily condition the quality of coastal waters as verified with the statistical assessment.
RECOMMENDATIONS AND PERSPECTIVES
From the preliminary analysis, the submarine outfalls seem to be the best solution to guarantee good bathing water quality on the coast. Nevertheless, it must be observed that this solution cannot overlook the possible impact of the discharges on seawaters intended for a specific use, such as mussel farms with reference to coastal hydrodynamics. Therefore, a sound wastewater dispersion analysis on the discharges of the WWTPs for the identification of the interested area and the level of contamination must be performed; a modelling study on pollution dispersion is complementary to this study (Scroccaro et al. 2009). This analysis highlights the critical stretches as being numbers II and, above all, VIII with particular correlation with the main river mouths. Thus, it is evident that the issue of microbiological impact must be studied following a river basin approach according to the influence of river loads on coastal areas. | 10.1007/s11356-010-0368-1 |
pubmed_1118_16672 | Objectives
Breast cancer (BC) is the most common cause of cancer death in Iranian women. Sometimes death from other causes precludes the event of interest and makes the analysis complicated. The purpose of this study was to identify important prognostic factors associated with survival duration among patients with BC using random survival forests (RSF) model in presence of competing risks. Also, its performance was compared with cause-specific hazard model.
Methods
This retrospective cohort study assessed 222 patients with BC who were admitted to Ayatollah Khansari hospital in Arak, a major industrial city and the capital of Markazi province in Iran. The cause-specific Cox proportional hazards and RSF models were employed to determine the important risk factors for survival of the patients.
Results
The mean and median survival duration of the patients were 90.71 (95%CI: 83.8-97.6) and 100.73 (95%CI: 89.2-121.5) months, respectively. The cause-specific model indicated that type of surgery and HER2 had statistically significant effects on the risk of death of BC. Moreover, the RSF model identified that HER2 was the most important variable for the event of interest.
Conclusion
According to the results of this study, the performance of the RSF model was better than the cause-specific hazard model. Moreover, HER2 was the most important variable for death of BC in both of the models. | 10.15167/2421-4248/jpmh2022.63.2.2405 |
pubmed_918_10136 | Transgenic animals have become a widely used model to identify and study specific cell types in whole organs. Promotor-driven reporter gene labeling of the cells under investigation has promoted experimental efficacy to a large degree. However, rigorous assessment of transgene expression specificity in these animal models is highly recommended to validate cellular identity and to isolate potentially mislabeled cell populations. Here, we report on one such mislabeled neuron population in a widely used transgenic mouse line in which GABAergic somatostatin-expressing interneurons (SOMpos INs) are labeled by eGFP (so-called GIN mouse, FVB-Tg(GadGFP)45704Swn/J). These neurons represent a subpopulation of all SOMpos INs. However, we report here on GFP labeling of non-GABAergic neurons in the nucleus endopiriformis of this mouse line. | 10.1002/cne.24673 |
pubmed_118_6367 | PEP-19 is a small protein that increases the rates of Ca2+ binding to the C-domain of calmodulin (CaM) by an unknown mechanism. Although an IQ motif promotes binding to CaM, an acidic sequence in PEP-19 is required to modulate Ca2+ binding and to sensitize HeLa cells to ATP-induced Ca2+ release. Here, we report the NMR solution structure of a complex between PEP-19 and the C-domain of apo CaM. The acidic sequence of PEP-19 associates between helices E and F of CaM via hydrophobic interactions. This allows the acidic side chains in PEP-19 to extend toward the solvent and form a negatively charged surface that resembles a catcher's mitt near Ca2+ binding loop III of CaM. The topology and gradients of negative electrostatic surface potential support a mechanism by which PEP-19 increases the rate of Ca2+ binding to the C-domain of CaM by 'catching' and electrostatically steering Ca2+ to site III. | 10.1038/ncomms13583 |
pubmed_632_6544 | We introduce a new class of substrates (compounds I-III) for leukocyte esterase (LE) that react with LE yielding anodic current in direct proportion to LE activity. The kinetic constants Km and kcat for the enzymatic reactions were determined by amperometry at a glassy carbon electrode. The binding affinity of I-III for LE was two orders of magnitude better than that of existing optical LE substrates. The specificity constant kcat /Km was equal to 2.7, 3.8, and 5.8×105 m-1 s-1 for compounds containing the pyridine (I), methoxypyridine (II), and (methoxycarbonyl)pyridine (III), respectively, thus showing an increase in catalytic efficiency in this order. Compound III had the lowest octanol/water partition coefficient (log p=0.33) along with the highest topological surface area (tPSA=222 Å2 ) and the best aqueous solubility (4.0 mg mL-1 ). The average enzymatic activity of LE released from a single leukocyte was equal to 4.5 nU when measured with compound III. | 10.1002/cbic.201800164 |
pubmed_1015_1307 | Under investigation were 207 female patients with carcinoma of the rectum aged 17 to 68 subjected to bilateral ovariectomy in addition to radical operation. A control group (95 women) subjected only to radical operations for carcinoma of the rectum was also analyzed. It was found that the metastatic spreading of the rectum carcinoma into the ovaries took place in 8.2% of cases. The ovaries were established to be involved in patients with a considerable spread of the primary tumor (T3-T4) growing through all the layers of the intestine wall (P4) disposed superior to the pelvic peritoneum. The metastatic spreading into the ovaries was most frequently observed in women in the postmenopausal period. The data obtained suggest the implantation to be the most probable way of the involvement of the ovaries. | pubmed_1015_1307 |
pubmed_1086_10556 | Despite absence of clear proof of efficacy, the use of inhaled corticosteroids (ICS) is widespread in cystic fibrosis (CF) patients. Therefore, the effect of ICS on lung function and other clinical variables was studied in 27 prepubertal CF children with mild to moderate lung disease. In a prospective double-blind case-controlled study, fluticasone propionate 500 microg or placebo were administered twice daily during 12 months. The mean (standard error of the mean, SEM) patient age was 8.2 (0.6) years in the placebo group and 9.0 (0.5) years in the fluticasone group. The mean (SEM) forced expiratory volume in 1 s (FEV(1)) was 91% (4%) in the placebo group and 86% (4%) in the fluticasone group. There was no statistically significant difference in the evolution of lung function and the number of respiratory exacerbations between groups. However, longitudinal growth in fluticasone patients was significantly slower than in placebo patients: 3.96 (0.29) cm versus 5.49 (0.38) cm [p<0.005, analysis of variance (ANOVA)] over the 12-month study duration. This resulted in a significant change in height standard deviation score (SDS) of -0.38 (0.09) in the fluticasone group versus -0.01 (0.07) in the placebo group (p<0.003, ANOVA). No catch-up growth was noted 1-2 years after discontinuation of inhaled steroids. The use of high-dose ICS in CF patients with mild lung disease may lead to persistent growth impairment. | 10.1007/s00431-006-0198-9 |
pubmed_425_3258 | Studies over the years have described a filamentous structure to mature elastin that suggests a complicated packing arrangement of tropoelastin subunits. The currently accepted mechanism for tropoelastin assembly requires microfibrils to serve as a physical extracellular scaffold for alignment of tropoelastin monomers during and before crosslinking. However, recent evidence suggests that the initial stages of tropoelastin assembly occur within the cell or at unique assembly sites on the plasma membrane where tropoelastin self assembles to form elastin aggregates. Outside the cell, elastin aggregates transfer to growing elastic fibers in the extracellular matrix where tensional forces on microfibrils generated through cell movement help shape the growing fiber. Overall, these observations challenge the widely held idea that interaction between monomeric tropoelastin and microfibrils is a requirement for elastin assembly, and point to self-assembly of tropoelastin as a driving force in elastin maturation. | 10.1016/j.matbio.2019.10.002 |
pubmed_921_17166 | DESIGN
Qualitative case study and mathematical model.
SETTING
Belgium.
OBJECTIVES
To evaluate the correlation between the polyamine mean concentration of the milk drunk during the first postnatal month and the appearance of allergy in children who drank this milk.
RESULTS
A model that describes the dependence of the allergy appearance with the spermine mean concentration of milk drunk during the first postnatal month was established.
CONCLUSIONS
This model shows that 5.02 nmol ml(-1) of spermine is a critical value to prevent the appearance of allergy. | 10.1079/phn19980028 |
pubmed_839_11383 | New strategies that modify the coagulation/inflammatory cascades may be applicable to solid organ transplant (SOT) recipients in the treatment of complications. However, data on kinetics of post-SOT cascades are needed before considering these strategies. Prospectively collected pre-transplant serum measurements of inflammatory (high-sensitive C-reactive protein, HS-CRP) and coagulation (d-Dimer, DD; protein C, PC) markers were compared to post-operative (day 1-90) values in deceased-donor liver (DDLT) and renal (DDRT) transplant recipients, living-related renal recipients (LRT) and donors (LRD). A total of 85 SOT were enrolled: 25 DDLT, 32 DDRT/LRT, 28 LRD. HS-CRP increased in all groups, mainly immediate post-SOT and in LRDs. DD had a similar pattern mainly in LRT and LRD. PC increased significantly over time in the DDLT group ( p < 0.01). Compared to those with no complications (infection, rejection or thrombosis), day 30 HS-CRP (p = 0.04) and DD (p = 0.06) were elevated in the DDRT/LRT group with complications; PC was decreased at day 7 (p = 0.04) and day 30 (p = 0.009) in DDLT and DDRT/LRT groups with complications, respectively. In conclusion, activation of the inflammatory/coagulation cascades occurs after SOT and is least pronounced in DDLT. This activation diminishes over time unless transplant complications occur. Our results support further research in approaches to altering these cascades in SOT recipients. | 10.1111/j.1399-0012.2009.01038.x |
pubmed_890_3353 | BACKGROUND
Observations on Tuberculosis/HIV co-infection in addition to epidemiologic molecular studies have recently provided strong evidence for the state of immune system as the major determinant of the TB imaging spectrum. However, the presence of any correlation between radiographic findings and the degree of immunosuppression in HIV+ patients still remains controversial. The present study aimed to investigate the TB radiographic manifestation in HIV+ patients and its relationship to the CD4 cell count.
METHOD AND MATERIAL
Chest radiography of 15 HIV+ patients with a definite diagnosis of pulmonary Tuberculosis in Masih Daneshvari Hospital, between 2013 and 2014, were retrospectively reviewed. Radiographic findings and severity were categorized as typical (upper lobe infiltration/cavity) and atypical (middle/lower lobe opacity, adenopathy, pleural effusion and normal X-ray). Demographics and CD4+ cell count were also recorded. Data analysis was performed using SPSS version 23 (frequency and mean for descriptive quantitative variables and Logistic regression analysis for correlation, p<0.05).
RESULTS
Of a total 15 patients (86.7% men and 13.3% women), 78.6% had CD4+ counts <350 (mean±SD; 229.15±199.45). The most common radiographic findings in descending order of frequency were adenopathy (53.3%), pleural effusion (26.7%) and cavitation (6.7%) with an overall atypical presentation of 93.3%. This study failed to reveal any statistically significant correlation between CD4+ cell count and radiographic manifestation as well as severity.
CONCLUSION
In CD4+ cell count <500, the dominant radiographic pattern of Tuberculosis is atypical presentation. At this level of immunity, CD4+ T cell dysfunction may play a deterministic role in TB radiographic manifestation. | 10.1016/j.ijmyco.2016.11.027 |
others_320_13319 | Aeromonas hydrophila(Ah) strains isolated from diseased fish in India were studied for protein profiling using the SDS-PAGE protein fingerprinting profile pattern of whole cells of 12 local strains of A. hydrophilaand one reference strain (MTCC 646). Variability among the strains was observed. The average similarity between the 12 strains of A. hydrophila ranged from 0.272 to 0.916. Proteins with molecular mass of 55.6 and 14.67 kDa in Ah1, Ah2 and Ah3, 28.5 and 27.9 kDa in Ah4, Ah5 and Ah6, 21.4 and 19.5 kDa in Ah7, Ah8, Ah9 and 72.9, 91.5 and 71.3 kDa in Ah10, Ah11 and Ah12 were common. The protein polypeptide bands from 19.5 to 86.2 kDa were common in both local strains and reference strain of A. hydrophila. The protein fingerprinting study showed that there is genetic similarity between strains of A. hydrophila and reference strain (MTCC 646). These protein markers may be useful for further strain differentiation in epidemiological study. © Springer 2005 | 10.1007/s11274-004-3909-2 |
pubmed_222_5872 | The aims of the following study were to compare the efficacy of Dorzolamide 1% eye drops with systemic Acetazolamide on the ocular pressure diurnal curve in patients with maximal medical therapy. Three ocular pressure curve were performed in glaucomatous patients, already receiving maximal medical therapy. After a baseline curve, patients were pretreated either with Dorzolamide 1% eye drops or 250 mg Acetazolamide tablets in a double-blind cross-over study. Dorzolamide 1% eye drops and 250 mg Acetazolamide tablets significantly reduced intraocular pressure (IOP) at 2 and 4 h after pretreatment. Both treatments caused a significantly additional decrease of IOP despite maximal medical therapy. Dorzolamide 1% eye drops is as effective as Acetazolamide tablets in reducing the IOP curve. Topical carbonic anhydrase inhibitors may represent an additional and safer treatment for those patients with uncontrolled medical glaucoma. | 10.1006/phrs.1997.0167 |
pubmed_1043_1234 | The "return" of influenza A (HINI) virus after 20 years of absence raised the question of the sources and mechanisms of emergence of epidemic influenza viruses and, particularly, of a new HINI virus (A/USSR/90/77). Two alternative hypotheses answer this question differently: the new HINI virus is the progeny of old HINI viruses retained in the human population or is a newly arising recombinant between numerous human and animal influenza viruses circulation in the biosphere. For the acceptance of one or the other hypothesis further accumulation of facts is required and, first of all, comparative investigations of RNAs and proteins of various influenza viruses. This paper presents the results of comparative studies of RNAs and proteins of old and new influenza A (HINI) viruses. | pubmed_1043_1234 |
pubmed_100_5172 | The plasma membrane calcium ATPases (PMCA) are a family of genes which extrude Ca(2+) from the cell and are involved in the maintenance of intracellular free calcium levels and/or with Ca(2+) signalling, depending on the cell type. In the cardiovascular system, Ca(2+) is not only essential for contraction and relaxation but also has a vital role as a second messenger in signal transduction pathways. A complex array of mechanisms regulate intracellular free calcium levels in the heart and vasculature and a failure in these systems to maintain normal Ca(2+) homeostasis has been linked to both heart failure and hypertension. This article focuses on the functions of PMCA, in particular isoform 4 (PMCA4), in the heart and vasculature and the reported links between PMCAs and contractile function, cardiac hypertrophy, cardiac rhythm and sudden cardiac death, and blood pressure control and hypertension. It is becoming clear that this family of calcium extrusion pumps have essential roles in both cardiovascular health and disease. | 10.1007/s11427-011-4199-1 |
pubmed_730_8619 | The testis is divided into two compartments: the seminiferous tubules and the interstitial tissue. The latter essentially consists of the blood and lymphatic vessels, testosterone-producing Leydig cells, and testicular macrophages. In the exploration of the testicular antiviral defense system, we initially searched for interferon (IFN) production by the seminiferous tubule cells. The site of virus entry into the testis is probably the interstitial compartment; thus, it is important to know whether and how the cells in this compartment are protected against viral infection. In addition, as germ cell precursors (spermatogonia) are only partially protected by the blood-testis barrier, it was important to explore the antiviral capability of these cells. In this study we searched for IFN production by Leydig cells, testicular macrophages, and spermatogonia after exposure to Sendai virus. We also investigated the effect of viral exposure on testosterone production by Leydig cells. Our results show that spermatogonia do not constitutively express IFNs and give a very poor response to the virus. In contrast, testicular macrophages constitutively produced type I IFNs, and this production was markedly stimulated by Sendai virus. Leydig cells produced twice as much type I IFNs as testicular macrophages after viral exposure, and they were the only cells producing both IFNalpha and -gamma, with these IFNs being dramatically induced/ increased in response to exposure to the virus. Furthermore, incubation of Leydig cells with the Sendai virus stimulated testosterone production. In conclusion, this study further establishes the topography of IFN expression within the testis. This allows us to hypothesize that the potential antiviral system represented by Leydig cells and, to a lesser extent, by macrophages plays a key role in protecting both androgen production and spermatogenesis. | 10.1210/endo.139.7.6083 |
pubmed_166_1023 | BACKGROUND
Traumatic brain injury (TBI) survivors often report difficulties with understanding and producing paralinguistic cues, as well as understanding and producing basic communication tasks. However, a large range of communicative deficits in this population cannot be adequately explained by linguistic impairment. The review examines prosodic processing performance post-TBI, its relationship with injury severity, brain injury localization, recovery and co-occurring psychiatric or mental health issues post-TBI METHODS: A systematic review using several databases including MEDLINE, EMBASE, Cochrane, LLBA (Linguistics and Language Behaviour Abstract) and Web of Science (January 1980 to May 2015), as well as a manual search of the cited references of the selected articles and the search cited features of PubMed was performed. The search was limited to comparative analyses between individuals who had a TBI and non-injured individuals (control). The review included studies assessing prosodic processing outcomes after TBI has been formally diagnosed. Articles that measured communication disorders, prosodic impairments, aphasia, and recognition of various aspects of prosody were included. Methods of summary included study characteristics, sample characteristics, demographics, auditory processing task, age at injury, brain localization of the injury, time elapsed since TBI, reports between TBI and mental health, socialization and employment difficulties. There were no limitations to the population size, age or gender. Results were reported according to the PRISMA guidelines. Two raters evaluated the quality of the articles in the search, extracted data using data abstraction forms and assessed the external and internal validity of the studies included using STROBE criteria. Agreement between the two raters was very high (Cohen's kappa = .89, P < 0.001). Results are reported according to the PRISMA guidelines.
RESULTS
A systematic review of 5212 records between 1980 and 2015 revealed 206 potentially eligible studies and 8 case-control studies (3 perspective and 5 retrospective) met inclusion and exclusion criteria for content and quality. Performance on prosodic processing tasks was found to be impaired among all participants with a history of TBI (ages ranged from 8 to 70 years old), compared to those with no history of TBI, in all eight studies examined. Compared with controls, individuals with a history of TBI had statistically significantly slower reaction time in identifying emotions from prosody and impaired processing of prosodic information that is muffled, non-sense, competing, or in conflict (prosody versus semantics). Heterogeneous findings on correlations between specific brain locations and prosodic processing impairment were reported. Psychiatric issues, employment status or social integration post-TBI were scarcely reported but, when reported, they co-occurred with a history of TBI and prosodic impairments.
CONCLUSIONS
The current review confirms the relationship between impaired prosodic processing and history of TBI. Future studies should collect and report comprehensive details about severity of TBI, location of brain injury and time elapsed since injury, as they could key influence factors to the extent of prosodic processing impairments and recovery from auditory processing impairments post-TBI. The exploration of prosodic processing tasks as a possible neuropsychological marker of TBI diagnosis and recovery is warranted. | 10.1186/s13643-016-0385-3 |
pubmed_586_4535 | Reduction of the chromophores of mitochondrial NADH-ubiquinone reductase by NADPH reaches only 50% of the extent of reduction by NADH, monitored at 450 nm. This effect is due to autoxidation of an enzyme component at a higher rate than its reduction by NADPH. | 10.1042/bj1580149 |
pubmed_874_5954 | Oral health care in patients undergoing chemotherapy and/or radiation therapy can be complex. Care delivered by a multidisciplinary approach is timely and streamlines the allocation of resources to provide prompt care and to attain favorable outcomes. A hospital dentist, oral and maxillofacial surgeon, and a maxillofacial prosthodontist must be involved early to prevent avoidable oral complications. Prevention and thorough preparation are vital before the start of chemotherapy and radiation therapy. Oral complications must be addressed immediately and, even with the best management, can cause delays and interruption in treatment, with serious consequences for the outcome and prognosis. | pubmed_874_5954 |
pubmed_22_18956 | INTRODUCTION
There is concern that surgical quality initially declines during the learning phase of robotic surgery. At our institution, we used a multi-surgeon programmatic approach to the introduction of robotic surgery. The purpose of this study was to evaluate outcomes of patients treated during the first year of our program.
METHODS
This is a historical cohort of all radical prostatectomy patients during a one-year period. Baseline, perioperative, and long-term followup data were prospectively and retrospectively collected. Treatment failure was a composite of any postoperative radiation, androgen-deprivation, or prostate-specific antigen (PSA) ≥0.2.
RESULTS
During the study period, 225 radical prostatectomy procedures were performed (104 robotic and 121 open). Baseline characteristics were similar between groups (p>0.05). All patients were continent and 74% were potent prior to surgery. Mean estimated blood loss (280 cc vs. 760 cc; p<0.001) and blood transfusion (0% vs. 8.3%; p=0.002) was lower in the robotic cohort. Non-transfusion complications were similar between groups (13% vs. 12%; p=0.7). Mean hospital stay was shorter in the robotic cohort (1.4 vs. 2.5 days). There was no difference in overall positive margin rate (38% vs. 43%; p=0.4) or treatment failure at a median followup of 3.5 years (p=0.4). Robotically treated patients were more often continent (89% vs. 77%; p=0.02) and potent (48% vs. 32%; p=0.02).
CONCLUSIONS
Using an inclusive multi-surgeon approach, robotic pros-tatectomy was introduced safely at a Canadian academic institution. | 10.5489/cuaj.4528 |
pubmed_835_21483 | Objective
Long noncoding RNA neuroblastoma-associated transcript 1 (NBAT1) is implicated in the progression of various cancers. Nevertheless, its biological function in endometrial cancer (EC) remains unknown.
Methods
The levels of NBAT1, miR-21-5p, and PTEN in EC cells and EC tissues were examined by RT-qPCR. Western blot was carried out to assess the protein expression of PTEN. The dual-luciferase reporter assay was conducted to explore the interactions among NBAT1, miR-21-5p, and PTEN. The effect of NBAT1 on EC proliferation, metastasis, and apoptosis was evaluated by CCK-8, transwell assays, wound healing, and flow cytometry. miR-21-5p mimics or NBAT1+miR-21-5p were transfected into HEC-1A and Ishikawa cells to investigate whether NBAT1 regulated EC tumorigenesis via sponging miR-21-5p.
Results
NBAT1 is downregulated, and miR-21-5p is upregulated in EC cells and tumor tissues. Overexpression of NBAT1 inhibits the proliferation, migration, and invasion abilities of EC cells and facilitated apoptosis. NBAT1 directly binds and negatively regulates miR-21-5p in EC. miR-21-5p mimics reverses the effect of lncRNA NBAT1 overexpression on the proliferation and migration of EC cells. PTEN is a downstream gene of miR-21-5p. lncRNA NBTA1 elevates PTEN expression via sponging miR-21-5p.
Conclusions
lncRNA NBAT1 acts as a tumor suppressor in EC via regulating PTEN through sponging miR-21-5p. | 10.1155/2022/9304392 |
pubmed_721_13444 | 1. Digesta samples were collected from five West Indian manatees, Trichechus manatus, for volatile fatty acid (VFA) analysis. 2. Mean total VFA concentrations were low in the stomach and duodenum (18.6 and 12.3 mM/l, respectively). Mean VFA concentrations were considerably higher in the cecum and colon (220.6 and 307.3 mM/l, respectively). 3. The relative proportions of the individual VFA's shifted from predominantly acetic acid in the foregut to a mixture of acetic, butyric and propionic acids in the hindgut. 4. The VFA concentrations in the manatee are similar to those in the dugong, Dugong dugon, and the green sea turtle, Chelonia mydas. 5. The mean total VFA concentrations indicate that the cecum and colon of the manatee are sites of microbial cellulose fermentation. The contribution of VFAs to the manatees' total energy requirements could not be calculated, but it is probably considerable. | 10.1016/0305-0491(87)90077-0 |
pubmed_480_688 | C-H activation plays a central role in organometallic catalysis. Concerted metallation-deprotonation (CMD) has been dominant as the pathway for C-H bond cleavage. In the course of studying the mechanism of C-H activation of arylamides and arylureas with Pd complexes as part of catalytic oxidative Heck reactions, DFT calculations were carried out. The turnover-limiting C-H activation is acid-catalysed and can occur readily in the absence of acetate or other coordinating bases. The calculations simulated experiment, so that ligated sulfonate and water, both previously observed by X-ray characterization, were incorporated in the model. A Wheland-type complex between acetanilide and Pd was readily located, but the reactive C-H and the coordinated sulfonate were poorly placed for intramolecular proton transfer. Involvement of a water molecule coordinated to sulfonate provides a low-energy pathway to the palladacycle. The relative reactivity of substituted acetanilides and arylureas according to this model fits well with existing literature. General-base catalysis as described here has broader potential. | 10.1039/c6ob00897f |
pubmed_369_24734 | BACKGROUND
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition.
MATERIALS AND METHODS
We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual γH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well.
RESULTS
Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of γH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor.
CONCLUSIONS
The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy. | 10.1186/1748-717X-7-48 |
pubmed_568_15001 | Health care needs to continuously evolve and innovate to maintain the health of populations. Technology has the potential to enable better patient engagement and ownership, as well as optimise therapeutic interventions and data-science approaches to facilitate improved health care decisions. Yet, to date, technological innovation has not resulted in the rate of change that could have been predicted from other sectors. This article discusses multiple reasons for this and proposes a newly tested and deployed solution: the technology clinical trial. The technology clinical trial methodology has been developed through working directly with patients, clinical and medical devicetrial experts. This approach enables researchers to use the complex environment of health care as an opportunity to transform the pace of innovation and create new care pathways. Instead of testing a single innovation, researchers can 'step back' and systematically review all areas of the patient's journey for potential optimization. Then integrate novel data science, technological advances, process updates, behavioural science, and patient engagement to co-create a streamlined multidisciplinary solution. As a result, this research has the potential for larger advances due to the emergent benefits that can arise when the individual elements work together as a whole. These potential benefits are then robustly tested, characterised and measured in the trial environment to ensure that future application of the innovative pathway is supported by the robust empirical data health care requires. | 10.1177/20552076211012131 |
pubmed_131_5986 | A quantitative study on outer membrane components was performed in a number of envelope mutants of Escherichia coli K-12 exhibition different permeability properties for antimicrobial agents. The envA1 allele causing an increased influx for both hydrophobic and hydrophilic drugs was found to be associated with a deficiency in the amount of lipopolysaccharides. The sefA1 envA1 double mutant was found to have a higher outer membrane buoyant density, apparently due to an increase in protein content. This double mutant was still low in lipopolysaccharide content. | 10.1128/jb.144.3.884-890.1980 |
pubmed_52_16292 | Results of development of an experimental external electric defibrillator with programmable pulse shape are described. The defibrillator can be used for experimental determination of the optimal shape of defibrillation pulse. | pubmed_52_16292 |
pubmed_1072_15450 | The purpose of this study was to determine the muscular contributions to the acceleration of the whole body centre of mass (COM) of older compared to younger adults that were able to recover from forward loss of balance with a single step. Forward loss of balance was achieved by releasing participants (14 older adults and 6 younger adults) from a static whole-body forward lean angle of approximately 18 degrees. 10 older adults and 6 younger adults were able to recover with a single step and included in subsequent analysis. A scalable anatomical model consisting of 36 degrees-of-freedom was used to compute kinematics and joint moments from motion capture and force plate data. Forces for 92 muscle actuators were computed using Static Optimisation and Induced Acceleration Analysis was used to compute individual muscle contributions to the three-dimensional acceleration of the whole body COM. There were no significant differences between older and younger adults in step length, step time, 3D COM accelerations or muscle contributions to 3D COM accelerations. The stance and stepping leg Gastrocnemius and Soleus muscles were primarily responsible for the vertical acceleration experienced by the COM. The Gastrocnemius and Soleus from the stance side leg together with bilateral Hamstrings accelerated the COM forwards throughout balance recovery while the Vasti and Soleus of the stepping side leg provided the majority of braking accelerations following foot contact. The Hip Abductor muscles provided the greatest contribution to medial-lateral accelerations of the COM. Deficits in the neuromuscular control of the Gastrocnemius, Soleus, Vasti and Hip Abductors in particular could adversely influence balance recovery and may be important targets in interventions to improve balance recovery performance. | 10.1371/journal.pone.0185564 |
pubmed_836_14395 | Over the past several decades, great progress has been made in developing national nutrition policies and research agendas that address numerous problems faced by various segments of our population. Despite the success of these initiatives and our understanding of the importance of nutrition throughout the life cycle, ongoing nutrition-related problems have been identified and still need to be adequately addressed through research and policy. The recognition of these various issues inspired the development of an agenda for the National Nutrition Summit held in May 2000, jointly sponsored by the U.S. Departments of Agriculture and of Health and Human Services. The major goal of the Summit was to forge partnerships among policy makers and program planners at the federal, state, and community levels to examine what accomplishments were made since 1969 and to identify existing gaps in the areas of food, nutrition and health. This review provides an overview of the purpose and overarching themes that emerged from the Summit, along with a review of additional resources from the Summit available on a website sponsored by the U.S. Departments of Health and Human Services and Agriculture. | 10.1093/jn/133.6.1949 |
pubmed_504_6066 | OBJECTIVE
To evaluate the diagnostic value of serum Brain-derived neurotrophic factor (BDNF) levels for discriminating PD with depression from without depression, and to investigate whether serum BDNF levels were associated with motor severity and gender in depressed PD patients.
METHODS
Demographic and clinical data were collected from 122 PD patients with depression, 137 without depression and 110 healthy controls. All participants' serum BDNF concentrations were measured. Their motor abilities and activity were assessed by the Unified PD Rating Scale Part III (UPDRS III) score and the Hoehn and Yahr (H-Y) stage. Depression was scored using the 17-item Hamilton Rating Scale for Depression (HAMD-17). Associations were analyzed with multivariate regression.
RESULTS
The serum BDNF levels were lower in depressed PD patients compared to non-depressed PD patients and controls (p < 0.001). The BDNF levels were negatively correlated with UPDRS III score (r = - 0.54, p < 0.001) and H-Y stage (r = - 0.45, p < 0.001). Decreased BDNF levels were associated with women only among depressed PD patients (r = 0.45, p < 0.001). The HAMD-17 score was negatively correlated with BDNF levels (r = - 0.59, p < 0.001), and positively associated with UPDRS III score (r = 0.51, p < 0.001). Multiple regression analysis demonstrated that in the depressed PD patients, female, H-Y stage and UPDRS III score were independent contributors to the BDNF levels (p < 0.001; p = 0.006; p = 0.03, respectively), BDNF and UPDRS III score were independent contributors to HAMD-17 score (p < 0.001, p = 0.01, respectively).
CONCLUSIONS
Decreased serum BDNF levels may be a useful clinical biomarker of depression in PD patients. Serum BDNF may serve as a potential biomarker for motor severity of PD patients with depression, especially in female. | 10.1007/s00415-020-10299-3 |
pubmed_819_16974 | Unlike most other mucins described to date, two intestinal mucins, rat MLP (rat Muc 2) and human MUC2 have a C-terminal tail that is enriched in cationic amino acids. The distribution of charge in each case resembles that of several well known heparin binding proteins. Peptides designated E20-14 and F13-15, corresponding to the C-terminal 14 amino acids of the two mucins, were synthesized and shown to bind 3 H-labelled heparin by a process that was saturable and mediated by strong electrostatic interactions, giving Kd values of 10 (-7) to 10 (-8) M. Using turbidometric analyses and native gel electrophoresis, we observed that peptide-heparin mixtures formed polydisperse aggregates that dissociated with a progressive increase in the concentration of heparin. Under certain conditions heparin protected the peptide from proteolysis by trypsin. Both heparin and dextran sulfate, the latter a highly sulfated synthetic polysaccharide, were potent inhibitors of 3 H-heparin binding to peptide E20-14, while less sulfated glycosaminoglycans were poorly- or non-inhibitory. Mucin in tissue dispersions and homogenates, or purified from rat intestine, did not bind to heparin, and failed to interact with an antibody specific for the peptide E20-14. Both mucin samples however, reacted with antibodies that recognize regions upstream of the C-terminal 14 amino acids. Immunofluorescent localization of E20-14 was confined to the basal perinuclear regions of goblet cells, whereas localization of an antibody to a flanking sequence on the N-terminal side of the C-tail, localized to mature mucin storage granules. These findings suggest that the heparin -binding C-tail of the mucin may be removed at an early stage of biosynthesis. Heparin-mucin complexes, if they form in vivo, are thus likely to be confined to the ER and/or Golgi compartments. | 10.1007/BF01049683 |
pubmed_211_22367 | INTRODUCTION
Therapeutic endoscopic retrograde cholangiopancreatography (ERCP) was initially utilized at Binh Dan Hospital, Viet Nam, in August 1993. From August 1993 through March 1997, 318 ERCP procedures were performed on 271 patients. It was not possible to obtain cholangiography in 32 cases of the 318 procedures of ERCP, for a success rate of diagnostic ERCP approaching 89%.
MATERIALS AND METHODS
Cases treated by ERCP included: 14 cases of Ascaris lumbricoides in the common bile duct (CBD). 69 cases of bile duct stones. 12 cases managed by nasobiliary catheter drainage. 3 cases treated by bile duct stent. Sphincterotomy was attempted on 108 cases. Complications included: 5 cases of acute pancreatitis. 7 cases of purulent cholangitis, which resulted in 1 death. 2 cases of retroperitoneal duodenal perforation. 9 cases of postsphincterotomy bleeding.
CONCLUSIONS
We conclude that ERCP is a useful therapeutic modality for bile duct stones and parasitic worms in the bile ducts. | pubmed_211_22367 |
pubmed_341_7148 | Honeyberry (Lonicera caerulea) has been used for medicinal purposes for thousands of years. Its predominant anthocyanin, cyanidin-3-O-glucoside (C3G), possesses antioxidant and many other potent biological activities. We aimed to investigate the effects of honeyberry extract (HBE) supplementation on HepG2 cellular steatosis induced by free fatty acids (FFA) and in diet-induced obese mice. HepG2 cells were incubated with 1 mM FFA to induce lipid accumulation with or without HBE. Obesity in mice was induced by a 45% high fat diet (HFD) for 6 weeks and subsequent supplementation of 0.5% HBE (LH) and 1% HBE (MH) for 6 weeks. HBE suppressed fatty acid synthesis and ameliorated lipid accumulation in HepG2 cells induced by FFA. Moreover, HBE also decreased lipid accumulation in the liver in the supplemented HBE group (LH, 0.5% or MH, 1%) compared with the control group. The expressions of adipogenic genes involved in hepatic lipid metabolism of sterol regulatory element-binding protein-1 (SREBP-1c), CCAAT/enhancer-binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid synthase (FAS) were decreased both in the HepG2 cells and in the livers of HBE-supplemented mice. In addition, HBE increased mRNA and protein levels of carnitine palmitoyltransferase (CPT-1) and peroxisome proliferator-activated receptor α (PPARα), which are involved in fatty acid oxidation. Furthermore, HBE treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and Acetyl CoA Carboxylase (ACC). Honeyberry effectively reduced triglyceride accumulation through down-regulation of hepatic lipid metabolic gene expression and up-regulation of the activation of AMPK and ACC signaling in both the HepG2 cells as well as in livers of diet-induced obese mice. These results suggest that HBE may actively ameliorate non-alcoholic fatty liver disease. | 10.3390/nu11030494 |
pubmed_702_2806 | Pituitary tumor-transforming gene-1 (PTTG1) is an oncogene highly expressed in a variety of endocrine, as well as nonendocrine-related cancers. Several tumorigenic mechanisms for PTTG1 have been proposed, one of the best characterized being its capacity to act as a transcriptional activator. To identify novel downstream target genes, we have established cell lines with inducible expression of PTTG1 and a differential display approach to analyze gene expression changes after PTTG1 induction. We identified dlk1 (also known as pref-1) as one of the most abundantly expressed PTTG1 targets. Dlk1 is known to participate in several differentiation processes, including adipogenesis, adrenal gland development, and wound healing. Dlk1 is also highly expressed in neuroendocrine tumors. Here, we show that PTTG1 overexpression inhibits adipogenesis in 3T3-L1 cells and that this effect is accomplished by promoting the stability and accumulation of Dlk1 mRNA, supporting a role for PTTG1 in posttranscriptional regulation. Moreover, both pttg1 and dlk1 genes show concomitant expression in fetal liver and placenta, as well as in pituitary adenomas, breast adenocarcinomas, and neuroblastomas, suggesting that PTTG1 and DLK1 are involved in cell differentiation and transformation. | 10.1091/mbc.E08-09-0965 |
pubmed_849_17777 | Gene therapy is suggested to be one of the most specific and efficient modulations for gene deficient diseases and extended to other diseases like cancer and inflammation, even though there are still challenges to be faced, such as specific and selective delivery, minimal to no toxicity, efficient metabolism, simplicity, and measurable efficiency. It is important to identify and validate drug-able disease-specific targets for molecular and cellular therapies, while it is equally important to have disease biomarkers to trace and define the biological effects of molecular and cellular therapies. The importance and significance of allostery in molecular and cellular therapies and "allosteric disease", "allosteric effect", and "allosteric drug" should be more carefully examined and validated. Cell therapy has been attracting an increasing amount of consideration in the development of new treatments for diseases. Molecular and Cellular Therapies (MCT) is a new, open-access journal, devoted to molecular mechanisms, preclinical and clinical research and development of gene-, peptide-, protein-, and cell-based therapies. | 10.1186/2052-8426-1-1 |
pubmed_70_22451 | BACKGROUND
Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model.
METHODS
Seventy-five male SCID mice were fed a NCKD (84% fat-0% carbohydrate-16% protein kcal), low-fat (12% fat-72% carbohydrate-16% protein kcal), or Western diet (40% fat-44% carbohydrate-16% protein kcal). Low-fat mice were fed ad libitum and the other arms fed via a modified-paired feeding protocol. After 24 days, all mice were injected with LAPC-4 cells and sacrificed when tumors approached 1,000 mm(3).
RESULTS
Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice (rank-sum, P = 0.009). There were no differences in tumor volume between low-fat and NCKD mice. Dietary treatment was significantly associated with survival (log-rank, P = 0.006), with the longest survival among the NCKD mice, followed by the low-fat mice. Serum IGFBP-3 was highest and IGF-1:IGFBP-3 ratio was lowest among NCKD mice while serum insulin and IGF-1 levels were highest in Western mice. NCKD mice had significantly decreased hepatic fatty infiltration relative to the other arms.
CONCLUSIONS
In this xenograft model, despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet. | 10.1002/pros.20683 |
pubmed_777_13446 | OBJECTIVE
To investigate the acceptability of the HPV vaccine among a multiethnic sample of young women in Malaysia.
METHODS
A qualitative study of 40 young women aged between 13 and 27 years recruited into 7 focus groups to discuss their knowledge of HPV infection, and their attitudes toward and acceptance of the HPV vaccine. The women were divided into Malay, Chinese, and Indian groups to allow for comparison among ethnicities.
RESULTS
Poor knowledge about HPV did not influence the HPV vaccine's acceptability. Although participants were in favor of the vaccine, the majority preferred to delay vaccination because it is newly introduced, they did not perceive themselves to be at risk of HPV infection, or because of cost factors. Concerns were raised regarding the vaccine's safety, the potential to be perceived as promiscuous and sexually active, and whether the vaccine was halal.
CONCLUSION
Promotion of the HPV vaccine should take account of social and cultural acceptability. The findings will help develop strategies for effective vaccination initiatives in a multiethnic and multireligious Asian society. | 10.1016/j.ijgo.2008.07.005 |
pubmed_732_21025 | BACKGROUND
The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile.
METHODS
Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed.
RESULTS
Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34%, (16/47). Disease recurrence occurred in 19 patients (19/47, 40%). Median overall survival was 22 months, with 4-year survival of 47%. Chemotoxicities were consistent with those previously reported for this regimen.
CONCLUSION
This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF. | 10.1007/s11845-014-1135-y |
others_185_7382 | Limited data are available in rural Honduran settings describing the etiology of respiratory infections, partially due to limited specimen transport. A new molecular transport media (MTM) preserves released nucleic acid at ambient temperature for later detection. Prospective surveillance was conducted in a Honduran clinic to identify 233 children less than 5 years of age presenting with respiratory symptoms. We obtained 2 nasopharyngeal samples and stored 1 in PrimeStore® MTM at room temperature and 1 in universal transport media (UTM) at -80 °C. The specimens were then transported to Cincinnati Children's Hospital and tested for 16 respiratory viruses using a multiplex PCR panel. The 2 specimen collection systems were similar for detecting the 4 most common viruses: influenza (Kappa = 0.7676, P < 0.0001), human metapneumovirus (Kappa = 0.8770, P < 0.0001), respiratory syncytial virus (Kappa = 0.6849, P < 0.0001), and parainfluenza (Kappa = 0.8796, P < 0.0001). These results suggest that clinical specimens transported via PrimeStore® MTM and UTM yield similar viral multiplex PCR results. © 2014 Elsevier I | 10.1016/j.diagmicrobio.2014.05.018 |
pubmed_344_16108 | Two experiments on discrete-trial choice examined the conditions under which pigeons would exhibit exclusive preference for the better of two alternatives as opposed to distributed preference (making some choices for each alternative). In Experiment 1, pigeons chose between red and green response keys that delivered food after delays of different durations, and in Experiment 2 they chose between red and green keys that delivered food with different probabilities. Some conditions of Experiment 1 had fixed delays to food and other conditions had variable delays. In both experiments, exclusive or nearly exclusive preference for the better alternative was found in some conditions, but distributed preference was found in other conditions, especially in Experiment 2 when key location varied randomly over trials. The results were used to evaluate several different theories about discrete-trial choice. The results suggest that exclusive preference for one alternative is a frequent outcome in discrete-trial choice. When distributed preference does occur, it is not the result of inherent tendencies to sample alternatives or to match response percentages to the values of the alternatives. Rather, distributed preference may occur when two factors (such as reinforcer delay and position bias) compete for the control of choice, or when the consequences for the two alternatives are similar and difficult to discriminate. | 10.1037/a0017588 |
others_281_5025 | Most ethnic populations worldwide consume poultry products. Whereas poultry litter (PL) is a traditionally inexpensive and effective fertilizer to improve soil quality and agricultural productivity, overapplication to soils has raised concerns because excess nutrients in runoff could accelerate the eutrophication of fresh bodies of water. A long-term field experiment of land application of PL to soils used for pasture growth has been maintained for nearly two decades in the Sand Mountain region of north Alabama, USA. In this work, several soil parameters impacted by the long-term applied litter were characterized. The findings clearly support previous general observations that long-term applied litter on pasture soils altered soil properties and macrocation levels. Unlike other studies, however, the effects of applied litter at multiple rates and years were examined, thus revealing the dynamic impacts on soil properties. Hay yields increased with the increase of years of PL application, regardless of the applied rate. This observation was consistent with previous observations that the labile phosphorus (P) portion in these soils increases with application years whereas total P increases with the cumulative applied PL amounts. Poultry litter application did not markedly affect soil electric conductivity, bulk density, or sodium (Na) or potassium (K) levels, especially at the soil surface (0-20 cm). Soil pH, carbon (C), C/nitrogen (N) ratio, calcium (Ca), and magnesium (Mg) were profoundly affected at all three soil depths (0-20, 20-40, and 40-60 cm). Most soil parameters analyzed in this study reached peak values with 10-15 years of applied litter. This observation suggests that there was a turning point of impact for applied litter around 10 years: prior to that the soil macrocations were altered positively as a result of accumulative functions. Continuous litter application may negatively alter a soil's capacity to retain macrocations, leading to less impact observed in this study. In other words, pasture soils with more than 10 years of applied litter would have higher potential for leaching and runoff. Our observation suggested that best management practices for land application of PL should take into consideration the different effects of PL application history. Copyright © Taylor & Francis Group, LLC | 10.1080/00103620701880925 |
pubmed_172_8158 | We have identified a factor in nuclear extracts that binds to the c-fos enhancer. Treatment of A431 cells with epidermal growth factor results in a rapid increase in the level of transcription and a concomitant increase in binding of the factor to the enhancer. Surprisingly, as transcription decreases rapidly, the enhancer-binding activity remains elevated. In addition, although HeLa cells exhibit no detectable transcription of the c-fos gene, they contain significant amounts of binding activity, comparable to those in induced A431 cells. These results suggest that regulation of c-fos transcription involves more than simply an increased level of a factor capable of binding the enhancer. Finally, transcription of c-fos in A431 cells is markedly induced by the tumor promoter TPA and the calcium ionophore A23187, yet neither induced an increased level of the enhancer-binding activity. These agents thus appear to activate c-fos transcription via a mechanism distinct from that used by epidermal growth factors. | 10.1016/0092-8674(86)90520-9 |
pubmed_275_9066 | A software package and its design idealogy for the self-constructed CCD-ICP-OES are described. The MS Windows 95TR was used as the operating platform. The Software package written in MS Visual C + + TR V 4.2 included the control of grating and CCD, the dynamic monitoring, the treatment of spectral signal, the fixing of wavelength position, the automatic fixing of spectral line, the quantitative analysis, the stripping method, the Kalman filter and the artificial neural network. | pubmed_275_9066 |
pubmed_277_14343 | The effect of methylmercury on muscarinic receptors and the regeneration of functionally active muscarinic receptor in vitro by antagonists were investigated. The result showed that methylmercury chloride (MMC) inhibited the binding of [3H] QNB to muscarinic receptor of rat brain-lysed synaptosomes, with IC50 values of 4.18 mmol/L. Regeneration of functionally active rat brain muscarinic receptors after inhibition with methylmercury was achieved by 2,3-dimercapto-1-propanesulfonc acid, Na salt (DMPS) dithiothreitol (DTT), glutathione (GSH) and Cysteine. Blocking the sulfhydryl groups is suggested to be the molecular mechanism of inhibition of brain muscarinic receptors by methylmercury. Our results provide evidence that thiols chelate out mercuric cations that tightly bound to sulfhydryl groups in muscarinic receptor binding sites and regenerate [3H] QNB binding activity. | pubmed_277_14343 |
pubmed_439_18889 | Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT1 and MT2). The melatonergic system is an emerging therapeutic target for new pharmacological interventions in the treatment of sleep and mood disorders; thus, imaging tools to further investigate its role in the brain are highly sought-after. We aimed to develop selective radiotracers for in vivo imaging of both MT1 and MT2 by positron emission tomography (PET). We identified four previously reported MT ligands with picomolar affinities to the target based on different scaffolds which were also amenable for radiolabeling with either carbon-11 or fluorine-18. [11C]UCM765, [11C]UCM1014, [18F]3-fluoroagomelatine ([18F]3FAGM), and [18F]fluoroacetamidoagomelatine ([18F]FAAGM) have been synthesized in high radiochemical purity and evaluated in wild-type rats. All four tracers showed moderate to high brain permeability in rats with maximum standardized uptake values (SUVmax of 2.53, 1.75, 3.25, and 4.47, respectively) achieved 1-2 min after tracer administration, followed by a rapid washout from the brain. Several melatonin ligands failed to block the binding of any of the PET tracer candidates, while in some cases, homologous blocking surprisingly resulted in increased brain retention. Two 18F-labeled agomelatine derivatives were brought forward to PET scans in non-human primates and autoradiography on human brain tissues. No specific binding has been detected in blocking studies. To further investigate pharmacokinetic properties of the putative tracers, microsomal stability, plasma protein binding, log D, and membrane bidirectional permeability assays have been conducted. Based on the results, we conclude that the fast first pass metabolism by the enzymes in liver microsomes is the likely reason of the failure of our PET tracer candidates. Nevertheless, we showed that PET imaging can serve as a valuable tool to investigate the brain permeability of new therapeutic compounds targeting the melatonergic system. | 10.1021/acschemneuro.1c00678 |
pubmed_586_4954 | Patients who are victims of near drowning in fresh water or salt water very frequently have acute edema of the lung which occurs either immediately, or after a free interval of variable duration. The mechanism of this edema is explained, in near drowning in salt water, by the hyperosmolarity of the alveolar fluid leading to a seeping of plasma from the capillaries in the alveoli. In the case of near drowning in fresh water, it is on the contrary the inhaled liquid which passes into the circulation, therby leading to immediate hypervolemia, but this overload is only transitory and is not responsible for the pulmonary edema which occurs later is not accompanied by a rise in pulmonary capillary pressure. It is therefore a lesional edema as is certified by the anatomopathological modifications found in the lungs of drowned patients. Therapeutic management must therefore take into consideration this physiopathology of acute edema of the lung in the drowned. | pubmed_586_4954 |
pubmed_914_13108 | A growing evidence base on the management of social anxiety disorder has yielded many meta-analyses and guidelines on the pharmacotherapy of this clinically important condition. We aimed to update a pharmacotherapy algorithm for the treatment of social anxiety disorder that was developed to be concise and user friendly and that was addressed to the primary care practitioner in particular. The updated algorithm attempts to summarize succinctly the recent literature in this area, as well as to include the views of an international panel of experts with diverse experience. The algorithm comprises eight sequential steps, beginning with those focused on diagnosis and initiating treatment and ending with the management of the treatment-refractory patient. | 10.1007/s11920-010-0140-8 |
pubmed_336_2185 | BACKGROUND
Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D.
METHODS
Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean ± SD = 57 ± 13 years, % males = 46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors.
RESULTS
During the mean follow-up period of 8.5 ± 3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.) = 1.34 (1.08-1.65); P = 6.7 ×10(-3) under dominant model) and TCF7L2 rs290481 (HR (95% C.I.) = 1.16 (1.01-1.33); P = 0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.) = 0.80 (0.65-1.00); P = 0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.) = 1.25 (1.12-1.39); P = 4.8 × 10(-5)). The adjusted cancer risk was 2.41 (95% C.I. 1.23-4.69) for patients with four risk alleles comparing to patients without risk allele.
CONCLUSIONS
T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes.
IMPACT
Our findings provide novel insights into the pathogenesis of cancer in diabetes. | pubmed_336_2185 |
pubmed_30_14197 | The purpose of the present experiments was to investigate the role of the forebrain commissures in interhemispheric visual transfer when both eyes are open and the optic chiasm is intact. Cynomolgus monkeys (Macaca fascicularis) learned a series of two-choice simultaneous visual discriminations. The visual stimuli were bipartite, with independently determined left and right halves. If such a stimulus is fixated centrally, the two halves fall into opposite visual hemifields. After 10 trials of acquisition of each discrimination, the same discriminanda were presented for a further 10 trials in which, within each stimulus, the positions of the halves were exchanged: the left half became the right and vice versa. The unoperated animals transferred well to the altered stimuli, making many fewer errors than they made in learning the originally presented discrimination. In contrast, monkeys with section of the posterior corpus callosum and the anterior commissure transferred poorly. These effects show that the forebrain commissures are important for the interhemispheric transfer and integration of visual information in animals with a normal, intact peripheral visual system. | 10.1007/BF00248868 |
pubmed_725_14942 | Binding of biologically active 3H-PGE2 to particulate fractions of porcine gastrointestinal mucosa and muscle was investigated. Specific binding activity was detected in the 2500 xg and 30,000 xg sedimentation fractions of mucosa from esophagus, fundus, antrum, duodenum, ileum and colon, as well as in serosal muscle taken from the antrum, ileum, and colon. Optimal binding (greater than 40 fmol/mg protein) was observed in the 30,000 xg fraction of fundic mucosa incubated at pH 5.0. The characteristics of 3H-PGE2 binding were variable in the remainder of the gastrointestinal tract although binding in these tissues was significantly less (0.2 to 15 fmol/mg protein) than that observed in the fundic mucosa. These data suggest that the cellular and/or subcellular site of PG binding is not uniform throughout the gastrointestinal tract. In fundic mucosa removal of the surface epithelial layer by scraping did not significantly alter the total binding activity for PGE. This result suggests that in gastric secretory mucosa optimal binding activity for PGE2 occurs within the gastric pits deep to the surface epithelium. | 10.1016/0090-6980(81)90035-6 |
pubmed_28_14125 | Immobilization of single antioxidant enzyme systems was frequently studied in the past, however, there is a lack of reliable reports on the co-immobilization of such enzymes. Here, an antioxidant enzyme cascade involving superoxide dismutase (SOD) and horseradish peroxidase (HRP) was successfully immobilized on titania nanosheets (TNS) by the sequential adsorption method using poly(diallyldimethylammonium chloride) (PDADMAC) and poly(styrene sulfonate) (PSS) polyelectrolyte building blocks. The development of the cascade system was based on a colloid approach, in which the charging and aggregation processes were optimized in each synthetic step. The polyelectrolyte and enzyme multilayers were built up in two different sequences at the particle interface, namely, TNS-PDADMAC-SOD-PSS-HRP and TNS-HRP-PDADMAC-SOD-PSS. The formation of the polyelectrolyte layers led to charge reversal of the carrier and the saturated PDADMAC and PSS layers stabilized the dispersions, in particular, their resistance against salt-induced aggregation was especially excellent. The results of enzymatic assays revealed that the SOD and HRP-like activities of the composites depended on the location of the enzymes in the hybrid material. The obtained compounds showed remarkable antioxidant effect and were able to simultaneously decompose superoxide radical anions and hydrogen peroxide. The cascade systems are of great promise in industrial manufacturing processes during the preparation of high-quality products without any damages by reactive oxygen species. | 10.1016/j.jcis.2021.01.012 |
pubmed_875_6157 | Tri-n-butyl phosphate (TBP), a representative of neutral organophosphorous ligands, is an important extractant used in the solvent extraction process for the recovery of uranium and plutonium from spent nuclear fuel. Microscopic pictures of TBP isomerism and its behavior in n-dodecane diluent were investigated utilizing MD simulations with previously optimized force field parameters for TBP and n-dodecane. Potential mean force (PMF) calculations on a single TBP molecule show seven probable TBP isomers. Radial distribution functions (RDFs) of TBP suggest the existence of TBP trimers at high TBP concentrations in addition to dimers. 2D PMF calculations were performed to determine the angle and distance criteria for TBP trimers. The dimerization and trimerization constants of TBP in n-dodecane were obtained and match our own experimental values using the FTIR technique. The new insights into the conformational behaviors of the TBP molecule as a monomer and as part of an aggregate could greatly aid in the understanding of the complexation between TBP and metal ions in a solvent extraction system. | 10.1021/acs.jpcb.6b02924 |
pubmed_128_20446 | The article presents the results of a complex study on ultrasonography which included high-resolution grey scale B-scan, color Doppler imaging, and ultrasonic density measurement of eyelids and periorbital tissues. A total of 48 patients were enrolled. Echographic anatomy of eyelid layers, i.e. skin, orbicularis oculi muscle, tarsus, and orbital fat, is described in detail. Depth and ultrasonic density values for all layers are provided. The authors suggest performing an ultrasound examination of eyelids prior to reconstructive and plastic surgery in order to facilitate the choice of surgical tactics. | pubmed_128_20446 |
pubmed_210_17786 | During muscle regeneration, extracellular signal-regulated kinase (ERK) promotes both proliferation and migration. However, the relationship between proliferation and migration is poorly understood in this context. To elucidate this complex relationship on a physiological level, we established an intravital imaging system for measuring ERK activity, migration speed, and cell-cycle phases in mouse muscle satellite cell-derived myogenic cells. We found that in vivo, ERK is maximally activated in myogenic cells two days after injury, and this is then followed by increases in cell number and motility. With limited effects of ERK activity on migration on an acute timescale, we hypothesized that ERK increases migration speed in the later phase by promoting cell-cycle progression. Our cell-cycle analysis further revealed that in myogenic cells, ERK activity is critical for G1/S transition, and cells migrate more rapidly in S/G2 phase 3 days after injury. Finally, migration speed of myogenic cells was suppressed after CDK1/2-but not CDK1-inhibitor treatment, demonstrating a critical role of CDK2 in myogenic cell migration. Overall, our study demonstrates that in myogenic cells, the ERK-CDK2 axis promotes not only G1/S transition but also migration, thus providing a novel mechanism for efficient muscle regeneration. | 10.1080/15384101.2020.1838779 |
pubmed_784_716 | Researchers often feel tangled in a web of bureaucracy when attempting to conduct their research. However, it is vital that researchers get involved and develop review processes such as those described above, which facilitate animal research yet address the important ethical, legal, and other related issues raised by hospital administrators and the public. As we do so, it is vital that we communicate directly with the public. Without this participation, we will find more and more hospital radiology departments closing their doors to animal-based research. | 10.1097/00004424-199211000-00021 |
pubmed_777_7111 | A mixed-culture of bacteria collected from a wastewater treatment plant in Brits, North-West Province (South Africa) biocatalytically reduced Cr(VI) at much higher concentrations than previously observed in cultures isolated in North America. Cr(VI) reduction rate up to 8 times higher than the rate in previous cultures was achieved by the Brits culture under aerobic conditions. Near complete Cr(VI) reduction was observed in batches under initial concentrations up to 200mg Cr(VI)/L after incubation for 65h in aerobic cultures. Under anaerobic conditions up to 150mg Cr(VI)/L was completely removed after incubating for 130-155h. In the previous cultures, complete removal was only achieved in cultures at an initial Cr(VI) concentration lower than 30mg/L after incubation for 96-110h. Consortium cultures were characterised using 16S rRNA partial sequence analysis. Results showed that the Gram-positive Bacillus genera predominated under aerobic conditions with a small composition of the Gram-negative Microbacterium sp. More biodiversity was observed in anaerobic cultures with the marked appearance of Enterococcus, Arthrobacter, Paenibacillus and Oceanobacillus species. Experiments run on purified individual species did not achieve the same level of Cr(VI) reduction as observed in the original consortium from sludge indicating possible existence of interspecies interactions necessary for optimum Cr(VI) reduction. All Cr(VI) reduced was accounted for as Cr(III) with a small error range (2-6%). | 10.1016/j.watres.2008.07.040 |
pubmed_180_11249 | Hexagonal crown-capped ZnO micro rods were successfully prepared by a facile low-temperature hydrothermal method. The as-prepared ZnO micro rods are 4.4-5.2 μm in length and 2.4-3.6 μm in diameter, possessing a single-crystal hexagonal structure. The morphology evolution and structure changes were tracked during hydrothermal growth by field-emission scanning electron microscopy and X-ray diffraction, respectively. A three-stage growth mechanism of the hexagonal crown-capped ZnO micro rods was proposed and further verified by a growth solution renewal experiment. The room-temperature photoluminescence (PL) spectrum of the hexagonal crowns exhibits a strong UV emission at about 382 nm. The temperature dependent PL results indicate that the UV emission originates from the radiative free-exciton recombination. | 10.1021/ic401646t |
pubmed_140_25674 | Much data shows that biological metals other than Fe3+ can interfere with Fe3+ acquisition by siderophores in bacteria. Siderophores are small Fe3+ chelators produced by the microorganisms to obtain access to Fe3+. Here, we show that Co2+ is imported into Pseudomonas aeruginosa cells in a complex with the siderophore pyochelin (PCH) by the ferri-PCH outer membrane transporter FptA. Moreover, the presence of Co2+ in the bacterial environment strongly affects the production of PCH. Proteomic and transcriptomic approaches showed that a decrease of PCH production is associated with repression of the expression of the genes involved in PCH biosynthesis. We used various molecular biology approaches to show that this repression is not Fur-(ferric uptake transcriptional regulator) dependent but due to competition of PCH-Co with PCH-Fe for PchR (transcriptional activator), thus inhibiting the formation of PchR-PCH-Fe and consequently the expression of the PCH genes. We observed a similar mechanism of repression of PCH production, but to a lesser extent, by Ni2+, but not for Zn2+, Cu2+, or Mn2+. Here, we show, for the first time at a molecular level, how the presence of a contaminant metal can interfere with Fe3+ acquisition by the siderophores PCH and PVD. | 10.1039/c9mt00195f |
pubmed_955_14944 | Two Glu-166 mutants of beta-lactamase I from Bacillus cereus 569/H were constructed: one with a lengthened side chain (E166Cmc, the S-carboxymethylcysteine mutant) and the other with the side chain shortened and made non-polar (E166A). Their kinetic properties were studied and compared with those of the wild-type and the E166D mutant (with a shortened side chain) previously made by Gibson, Christensen and Waley (1990) (Biochem. J. 272, 613-619). Surprisingly, with good penicillin substrates, Km, kcat. and kcat./Km of the two conservative mutants (E166Cmc and E166D) are similar to those of the non-conservative mutant E166A. Their kcat. values are 3000-fold lower than that of the wild-type enzyme, showing that Glu-166 is a very important residue. The acylenzyme intermediate of E166A and a good substrate, penicillin V, was trapped by acid-quench and observed by electrospray ionization mass spectrometry, suggesting that Glu-166 is more important in catalysing the deacylation step than the acylation step. The beta-lactamase I E166A mutant is about 200-fold more active than the Bacillus licheniformis E166A mutant with nitrocefin or 6 beta-furylacryloyl-amidopenicillanic acid as substrate. This suggested that other groups in the active site of the beta-lactamase I mutant may activate the catalytic water molecule for deacylation. | 10.1042/bj2990671 |
pubmed_1076_14091 | Mutations in the KCNQ2 gene cause myokymia and neonatal epilepsy, indicating that this K(+) channel regulates the excitability of lower motoneurons and CNS neurons. Little is known about the parameters that direct the assembly of this multimeric molecule and other KCNQ subunits. Here, we show that the carboxy-terminal subunit interaction domain of KCNQ2 autonomously folds and assembles into tetramers. This domain contains a bipartite coiled-coil motif. Whereas structural integrity of the second coiled-coil motif is crucial for tetramer formation, that of the first motif is less important. These data suggest a crucial role of coiled-coil motifs in tetrameric KCNQ channel assembly. | 10.1016/j.febslet.2007.03.024 |
pubmed_588_5770 | PURPOSE
Repetitive transcranial electrical stimulation (rTES) was used to activate descending output to the external urethral sphincter muscle.
METHODS
Motor evoked potentials (MEPs) were recorded from external urethral sphincter (EUS), and anterior tibial (TA) muscles following high voltage rTES in 9 consecutive patients undergoing spine surgery. Anesthesia was achieved by continuous propofol/narcotic infusion without paralytic agents. Anodal cortical stimulation was delivered at C4/C3, C2/C1, and Cz/Fz locations in each patient. Latency and amplitude of the MEP was measured and compared for each bipolar stimulation montage.
RESULTS
The mean latency was 20.24 +/- 1.3 msec. for Cz/Fz; 20.19 +/- 1.1 msec. for C4/C3 and 20.19 +/- 1.1 msec. for C2/C1. Statistical analysis showed no significant difference in latency between the three sites (F(2,15) = 0.004; p > 0.05). The mean amplitude was 37.14 +/- 24.3 microV for Cz/Fz; 113.33 +/- 100.6 microV for C4/C3; and 85 +/- 73.9 microV for C2/C1. A significant difference between the amplitudes at three sites was observed (F(2,8) = 5.2; p < 0.05). The amplitude at C4/C3 was significantly greater than amplitude at CzlFz (t (8) = 3.08; p < 0.05), but data did not give enough evidence to believe that difference between amplitudes for site C4/C3 & C2/C1 was significant (p > 0.05).
CONCLUSIONS
This study shows that the intraoperative MEP monitoring of the EUS is a feasible method. Furthermore, activation of descending axonal outflow to the EUS muscle is best achieved by cortical stimulation directed from C4 to C3 or C2 to C1 points. | pubmed_588_5770 |
pubmed_217_4406 | Mutations in the α-subunit of cardiac sodium channel gene SCN5A can lead to the overlapping phenotypes of both the Brugada and type 3 long QT syndromes. However, the combination of Brugada and a short QT phenotype resulting from mutation in SCN5A has not previously been described. A man with concomitant Brugada-like and short QT electrocardiogram (ECG) was identified and the SCN5A gene was sequenced. Whole-cell patch clamp analysis of human embryo kidney (HEK) 293 cells expressing a SCN5A channel with the patient's sequence was used to investigate the biophysical properties of the channel. The patient with the family history of sudden death showed Brugada-like and short QT interval ECG. Sequence analysis of the coding region of the SCN5A gene, identified a G to A heterozygous missense mutation at nucleotide site 2066 that resulted in a amino-acid substitution of arginine to histidine at amino-acid site 689 (R689H). Patch clamp analysis showed that the R689H failed to generate current when heterologously expressed in HEK293 cells, indicating it was a loss-of-function mutation. Our finding firstly shows that a heterozygous missense mutation R689H in SCN5A gene results in the loss of protein function and the coexistents of the Brugada-like and short QT interval ECG phenotypes. | 10.1038/ejhg.2012.63 |
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