Clinical Outcomes of Intermediate-Length Cephalomedullary Nails for Intertrochanteric Femur Fracture Repair in Older Adults.
Hip fracture is a major cause of morbidity and mortality in older adults. Intertrochanteric hip fractures often are treated surgically using cephalomedullary nails (CMN), in either a short or long length. Their outcomes are documented in the literature; however, outcomes of the intermediate-length CMN have not been well described. A retrospective review was conducted of older adults with intertrochanteric hip fractures that were treated with cephalomedullary nail fixation using an intermediate-length (235 mm Synthes Trochanteric Fixation® nail or 240 mm Stryker Gamma 3®) nail. Outcome data were collected during the inpatient stay and 16 months post-operatively. Seventy-seven patients met inclusion criteria and were reviewed during inpatient stay; however, only 42 had documented post-operative outcomes. Of those, two patients died post-discharge and were not included in the 16-month follow-up. Comparison of results to published literature suggested that intermediate-length nails are comparable to short-length nails with regard to time in the operating room and estimated blood loss. The rate of blood transfusion was lower and length of hospital stay was shorter than in comparable studies of both short- and long-length nails. There were no post-operative peri-prosthetic fractures in the 16-month follow-up. This rate was lower than published rates for short and long nails. The hardware failure rate (3/42, 7.1%) of intermediate-length nails was higher than comparison studies of both short- and long-length nails. Patient outcomes for intermediate-length nails were similar to outcomes of shorter length nails. Utilization of the intermediate-length nail appears to be an effective treatment option for repair of intertrochanteric femur fractures. However, direct comparison is difficult since peri-prosthetic fracture rate may increase over time and nail length and hardware failure are not defined consistently in the literature. Further study is needed with a larger sample size followed over a longer period of time to confirm our findings.


Pharmacological challenges in chronic pancreatitis.
Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion. Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases food intake is more or less substituted with alcohol, tobacco and coffee. Alcohol and drug interaction are known to influence the pharmacokinetics by altering either drug absorption or by affecting liver metabolism. Since patients suffering from chronic pancreatitis experience severe pain, opioids are often prescribed as pain treatment. Opioids have intrinsic effects on gastrointestinal motility and hence can modify the absorption of other drugs taken at the same time. Furthermore, the increased fluid absorption caused by opioids will decrease water available for drug dissolution and may hereby affect absorption of the drug. As stated above many factors can influence drug absorption and metabolism in patients with chronic pancreatitis. The factors may not have clinical relevance, but may explain inter-individual variations in responses to a given drug, in patients with chronic pancreatitis.


Multisite phosphorylation and the integration of stress signals at p53.
The p53 tumour suppressor protein is a potent transcription factor that plays a major role in the defence against tumour development. p53 exists in a latent form that can be activated by a range of stresses including DNA damage, hypoxia, cytokines, metabolic changes, viral infection, and activated oncogenes. Activation of p53 can lead to cellular growth arrest prior to entry into either S phase or mitosis or can trigger cell death through apoptosis. The modification of p53 by multisite phosphorylation provides a potential link between stress signalling and the regulation of p53 activity, and there is now striking evidence that agents that activate p53 can lead to selective changes in its phosphorylation status. Topologically, the phosphorylation sites in p53 fall into two discrete functional domains. Four phosphorylation events take place within the N-terminal 83 amino acids containing the transactivation domain and a region involved in transcription-independent growth suppression. At least three of these modifications occur in response to agents that cause cellular stress such as DNA damage. At the C-terminus, there are three phosphorylation events, each of which can independently regulate the specific DNA-binding function of p53, suggesting convergent control by different signalling pathways. The multiplicity of these covalent modifications and their responsiveness to a wide range of signals suggest that p53 activity is tightly and coordinately controlled in response to stresses and changes in the cellular environment.


Melting of charge stripes in vibrationally driven La(1.875)Ba(0.125)CuO4: assessing the respective roles of electronic and lattice order in frustrated superconductors.
We report femtosecond resonant soft x-ray diffraction measurements of the dynamics of the charge order and of the crystal lattice in nonsuperconducting, stripe-ordered La1.875Ba0.125CuO4. Excitation of the in-plane Cu-O stretching phonon with a midinfrared pulse has been previously shown to induce a transient superconducting state in the closely related compound La1.675Eu0.2Sr0.125CuO4. In La1.875Ba0.125CuO4, we find that the charge stripe order melts promptly on a subpicosecond time scale. Surprisingly, the low temperature tetragonal (LTT) distortion is only weakly reduced, reacting on significantly longer time scales that do not correlate with light-induced superconductivity. This experiment suggests that charge modulations alone, and not the LTT distortion, prevent superconductivity in equilibrium.


How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites.
Plasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites. An analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. The analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12-78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse. Site-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.


A community survey of antibiotic consumption among children in Madagascar and Senegal: the importance of healthcare access and care quality.
Antibiotic resistance is growing in low-income countries (LICs). Children in LICs are particularly at risk. Information on antibiotic consumption is needed to control the development and spread of resistant bacteria. To measure antibiotic consumption and related factors, a community survey was undertaken in two sites in Madagascar (Antananarivo and Moramanga) and in Senegal (Guediawaye) among children under 2. Face-to-face interviews were conducted with parents or caregivers of eligible children. Regression analysis was used to determine variables associated with reported antibiotic consumption. Availability of health structures and health policies were also investigated. Population estimates for antibiotic consumption in the last 3 months were 37.2% (95% CI 33.4%-41.2%) in Guediawaye, 29.3% (95% CI 25.0%-34.1%) in Antananarivo and 24.6% (95% CI 20.6%-29.1%) in Moramanga. In all sites, the large majority of antibiotics were taken with a prescription (92.2%, 87.0% and 92.0% for Antananarivo, Moramanga and Guediawaye, respectively) and purchased in pharmacies (89.4%, 73.5% and 78.5%, respectively). Living in houses without flushing toilets and baby age were significantly associated with any antibiotic consumption after adjusting for site. A higher density of public health structures was associated with lower antibiotic consumption levels, while a higher density of private pharmacies was associated with higher levels across sites. These data are crucial for the implementation of local programmes aimed at optimizing antibiotic consumption. Factors such as density of healthcare facilities, prescriber training and national policy must be taken into account when developing strategies to optimize antibiotic consumption in LICs.


MEDICAL GROUP PRACTICE IN CALIFORNIA.
A 1950 study of group practice in California reveals 52 "true general medical groups" among 123 medical organizations surveyed, involving 634 full-time and 215 part-time physicians. The groups, in contrast to the national patterns, tend to be larger, younger and more urban. There is also a greater tendency toward unit hospital affiliation (30 groups) and operation of group prepayment plans (10 groups). In general similarity to the national scene, California groups are most frequently organized as private partnerships with a salary method of remuneration sometimes augmented by a share of net earnings. The range of medical and technical services offered varies widely with the size of the group. The combination of group prepayment, medical group practice, and coordinated medical-hospital centers seems to offer special opportunities for satisfactory practice and adequate medical care.


Metformin Affects Heme Function as a Possible Mechanism of Action.
Metformin elicits pleiotropic effects that are beneficial for treating diabetes, as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30-50%; the heme-targeting drug artemisinin operates at a greater potency. Significantly, metformin prevents oxidation of heme in three protein scaffolds, cytochrome c, myoglobin and hemoglobin, with Kd values < 3 mM suggesting a dual oxidation and reduction role in the regulation of heme redox transition. Since heme- and porphyrin-like groups operate in diverse enzymes that control important metabolic processes, we suggest that metformin acts, at least in part, through stabilizing appropriate redox states in heme and other porphyrin-containing groups to control cellular metabolism.


Body mass index and cognitive decline among community-living older adults: the modifying effect of physical activity.
To examine the associations between BMI categories and subsequent 3-year cognitive decline among older adults, and to test whether physical activity modifies the associations. Study sample included n = 1028 cognitively unimpaired older adults participating in the Étude sur la Santé des Aînés (ESA)-Services longitudinal study and followed 3 years later. Cognitive decline was defined as a decrease of > 3 points in MMSE scores between baseline and follow-up. BMI categories (normal weight (reference), underweight, overweight, obese) were derived from self-reported weight and height. Moderate to vigorous physical activity of ≥20 min (# of times per week) was self-reported. The presence of chronic disorders was ascertained from administrative and self-reported data. Logistic regression analyses were used to study the risk of cognitive decline associated with BMI categories stratified by weekly physical activity (≥140 min), the presence of metabolic, cardiovascular and anxio-depressive disorders. In the overall sample, there was no evidence that underweight, overweight, or obesity, as compared to normal weight, was associated with cognitive decline, after adjusting for sociodemographic, lifestyle factors, and comorbidities. Individuals with overweight reporting high physical activity had lower odds of cognitive decline (OR = 0.25, 95% CI = 0.07-0.89), whereas no association was observed in individuals with overweight reporting low physical activity (OR = 0.85, 95% CI = 0.41-1.75). Among participants with metabolic and cardiovascular disorders, individuals with overweight reporting high physical activity had lower odds of cognitive decline (OR = 0.09, 95% CI = 0.01-0.59 and OR = 0.03, 95% CI = 0.01-0.92 respectively), whereas no association was observed in those with low physical activity. Physical activity modifies the association between overweight and cognitive decline in older adults overall, as in those with metabolic and cardiovascular disorders. Results highlight the importance of promoting and encouraging regular physical activity in older adults with overweight as prevention against cognitive decline.


Bones in Multiple Myeloma: Imaging and Therapy.
Bone disease is the most frequent disease-defining clinical feature of multiple myeloma (MM), with 90% of patients developing bone lesions over the course of their disease. For this reason, imaging plays a major role in the management of disease in patients with MM. Although conventional radiography has traditionally been the standard of care, its low sensitivity in detecting osteolytic lesions has called for more advanced imaging modalities. In this review, we discuss the advantages, indications, and applications of whole-body low-dose CT (WBLDCT), 18F-fluorodeoxyglucose (FDG)-PET/CT, MRI, and other novel imaging modalities in the management of disease in patients with plasma cell dyscrasias. We also review the state of the art in treatment of MM bone disease (MMBD) and the role of bisphosphonates and denosumab, a monoclonal antibody that binds and blocks the activity of receptor activator of nuclear factor-kappa B ligand (RANKL), which was recently approved by the U.S. Food and Drug Administration for MMBD.


Recent advances into understanding some aspects of the structure and function of mammalian and avian lungs.
Recent findings are reported about certain aspects of the structure and function of the mammalian and avian lungs that include (a) the architecture of the air capillaries (ACs) and the blood capillaries (BCs); (b) the pulmonary blood capillary circulatory dynamics; (c) the adaptive molecular, cellular, biochemical, compositional, and developmental characteristics of the surfactant system; (d) the mechanisms of the translocation of fine and ultrafine particles across the airway epithelial barrier; and (e) the particle-cell interactions in the pulmonary airways. In the lung of the Muscovy duck Cairina moschata, at least, the ACs are rotund structures that are interconnected by narrow cylindrical sections, while the BCs comprise segments that are almost as long as they are wide. In contrast to the mammalian pulmonary BCs, which are highly compliant, those of birds practically behave like rigid tubes. Diving pressure has been a very powerful directional selection force that has influenced phenotypic changes in surfactant composition and function in lungs of marine mammals. After nanosized particulates are deposited on the respiratory tract of healthy human subjects, some reach organs such as the brain with potentially serious health implications. Finally, in the mammalian lung, dendritic cells of the pulmonary airways are powerful agents in engulfing deposited particles, and in birds, macrophages and erythrocytes are ardent phagocytizing cellular agents. The morphology of the lung that allows it to perform different functions-including gas exchange, ventilation of the lung by being compliant, defense, and secretion of important pharmacological factors-is reflected in its "compromise design."


Automated FiO2-SpO2 control system in neonates requiring respiratory support: a comparison of a standard to a narrow SpO2 control range.
Managing the oxygen saturation of preterm infants to a target range has been the standard of care for a decade. Changes in target ranges have been shown to significantly impact mortality and morbidity. Selecting and implementing the optimal target range are complicated not only by issues of training, but also the realities of staffing levels and demands. The potential for automatic control is becoming a reality. Results from the evaluation of different systems have been promising and our own experience encouraging. This study was conducted in two tertiary level newborn nurseries, routinely using an automated FiO2-SpO2 control system (Avea-CLiO2, Yorba Linda CA, USA). The aim of this study was to compare the performance of the system as used routinely (set control range of 87-93% SpO2), to a narrower higher range (90-93%). We employed a 12-hour cross-over design with the order of control ranges randomly assigned for each of up to three days. The primary prospectively identified end points were time in the 87-93% SpO2 target range, time at SpO2 extremes and the distribution of the SpO2 exposure. Twenty-one infants completed the study. The infants were born with a median EGA of 27 weeks and studied at a median age of 17 days and weight of 1.08 kg. Their median FiO2 was 0.32; 8 were intubated, and the rest noninvasively supported (7 positive pressure ventilation and 6 CPAP). The control in both arms was excellent, and required less than 2 manual FiO2 adjustments per day. There were no differences in the three primary endpoints. The narrower/higher set control range resulted in tighter control (IQR 3.0 vs. 4.3 p < 0.001), and less time with the SpO2 between 80-86 (6.2% vs. 8.4%, p = 0.006). We found that a shift in the median of the set control range of an automated FiO2-SpO2 control system had a proportional effect on the median and distribution of SpO2 exposure. We found that a dramatic narrowing of the set control range had a disproportionally smaller impact. Our study points to the potential to optimize SpO2 targeting with an automated control system.


Evaluation of a commercial multitest system for identification of yeasts.
A new commercial yeast identification system, the Randolph Multitest Mycology Plate, was evaluated. This system is based on the assimilation of carbohydrates, growth on birdseed agar, resistance to cycloheximide, hydrolysis of urea, and reduction of nitrate. The 184 clinical isolates used in the evaluation included 20 species of the genera Candida, Cryptococcus, Saccharomyces, Torulopsis, Trichosporon, Rhodotorula, and Geotrichum. Agreement with the standard Wickerham carbohydrate assimilation and other conventional biochemical results was found in 84 percent of the tests, and 91 percent of the yeasts were correctly identified with the aid of microscopy, cultural characteristics, and germ-tube formation. Identification of the tested strains was achieved within 96 hours.


Acute Myocardial Infarction and Pulmonary Diseases Result in Two Different Degradation Profiles of Elastin as Quantified by Two Novel ELISAs.
Elastin is a signature protein of the arteries and lungs, thus it was hypothesized that elastin is subject to enzymatic degradation during cardiovascular and pulmonary diseases. The aim was to investigate if different fragments of the same protein entail different information associated to two different diseases and if these fragments have the potential of being diagnostic biomarkers. Monoclonal antibodies were raised against an identified fragment (the ELM-2 neoepitope) generated at the amino acid position '552 in elastin by matrix metalloproteinase (MMP) -9/-12. A newly identified ELM neoepitope was generated by the same proteases but at amino acid position '441. The distribution of ELM-2 and ELM, in human arterial plaques and fibrotic lung tissues were investigated by immunohistochemistry. A competitive ELISA for ELM-2 was developed. The clinical relevance of the ELM and ELM-2 ELISAs was evaluated in patients with acute myocardial infarction (AMI), no AMI, high coronary calcium, or low coronary calcium. The serological release of ELM-2 in patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF) was compared to controls. ELM and ELM-2 neoepitopes were both localized in diseased carotid arteries and fibrotic lungs. In the cardiovascular cohort, ELM-2 levels were 66% higher in serum from AMI patients compared to patients with no AMI (p<0.01). Levels of ELM were not significantly increased in these patients and no correlation was observed between ELM-2 and ELM. ELM-2 was not elevated in the COPD and IPF patients and was not correlated to ELM. ELM was shown to be correlated with smoking habits (p<0.01). The ELM-2 neoepitope was related to AMI whereas the ELM neoepitope was related to pulmonary diseases. These results indicate that elastin neoepitopes generated by the same proteases but at different amino acid sites provide different tissue-related information depending on the disease in question.


Multiproxy paleoceanographic study from the western Barents Sea reveals dramatic Younger Dryas onset followed by oscillatory warming trend.
The Younger Dryas (YD) is recognized as a cool period that began and ended abruptly during a time of general warming at the end of the last glacial. New multi-proxy data from a sediment gravity core from Storfjordrenna (western Barents Sea, 253 m water depth) reveals that the onset of the YD occurred as a single short-lived dramatic environment deterioration, whereas the subsequent warming was oscillatory. The water masses in the western Barents Sea were likely strongly stratified at the onset of the YD, possibly due to runoff of meltwater combined with perennial sea-ice cover, the latter may last up to several decades without any brake-up. Consequently, anoxic conditions prevailed at the bottom of Storfjordrenna, leading to a sharp reduction of benthic biota and the appearance of vivianite microconcretions which formation is favoured by reducing conditions. While the anoxic conditions in Storfjordrenna were transient, the unfavorable conditions for benthic foraminifera lasted for c. 1300 years. We suggest that the Pre-Boreal Oscillation, just after the onset of the Holocene, may have been a continuation of the oscillatory warming trend during the YD.


Dependence of the velocity and attenuation of ultrasound in bone on the mineral content.
Measurements of the attenuation and velocity of ultrasound from 0.3 to 0.8 MHz have been performed on a number of bovine cancellous bone samples. The influence of bone mineral content has been isolated by measuring the acoustic properties of the samples at various stages of demineralization resulting from controlled nitric acid attack. The correlation coefficient r, between the attenuation at different frequencies and bone density was found to be in the range 0.68-0.97. Broadband ultrasonic attenuation (BUA) was also calculated and produced r values between 0.84 and 0.99. The velocity measurements indicated a correlation greater than 0.97 in all cases. Thus velocity is the parameter most sensitive to changes in bone mineral density alone. Attenuation and BUA are less well correlated presumably because of a sensitivity to minor structural change.


Flavonoids: A complementary approach to conventional therapy of COVID-19?
COVID-19, the highly contagious novel disease caused by SARS-CoV-2, has become a major international concern as it has spread quickly all over the globe. However, scientific knowledge and therapeutic treatment options for this new coronavirus remain limited. Although previous outbreaks of human coronaviruses (CoVs) such as SARS and MERS stimulated research, there are, to date, no antiviral therapeutics available that specifically target these kinds of viruses. Natural compounds with a great diversity of chemical structures may provide an alternative approach for the discovery of new antivirals. In fact, numerous flavonoids were found to have antiviral effects against SARS-and MERS-CoV by mainly inhibiting the enzymes 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). In this review, we specifically focused on the search for flavonoids, polyphenolic compounds, which are proven to be effective against human CoVs. We therefore summarized and analyzed the latest progress in research to identify flavonoids for antiviral therapy and proposed strategies for future work on medicinal plants against coronaviruses such as SARS-CoV-2. We discovered quercetin, herbacetin, and isobavachalcone as the most promising flavonoids with anti-CoV potential.


Shape and material characteristics of the trachea in the leatherback sea turtle promote progressive collapse and reinflation during dives.
The leatherback turtle regularly undertakes deep dives and has been recorded attaining depths in excess of 1200 m. Its trachea is an almost solid, elliptical-section tube of uncalcified hyaline cartilage with minimal connective tissue between successive rings. The structure appears to be advantageous for diving and perfectly designed for withstanding repeated collapse and reinflation. This study applies Boyle's law to the respiratory system (lungs, trachea and larynx) and estimates the changes in tracheal volume during a dive. These changes are subsequently compared with the results predicted by a corresponding finite element (FE) structural model, itself based on laboratory studies of the trachea of an adult turtle. Boyle's law predicts that the lungs will collapse first during the initial stages of a dive with tracheal compression beginning at much deeper depths after complete air mass expulsion from the lungs. The FE model reproduces the changes extremely well (agreeing closely with Boyle's law estimations) and provides visual representation of the deformed tracheal luminal area. Initially, the trachea compresses both ventrally and dorsally before levelling ventrally. Bulges are subsequently formed laterally and become more pronounced at deeper depths. The geometric configuration of the tracheal structure confers both homogeneity and strength upon it, which makes it extremely well suited for enduring repeated collapse and re-expansion. The structure actually promotes collapse and is an adaptation to the turtle's natural environment in which large numbers of deep dives are performed annually.


Real-time PCR detection and quantification of fish probiotic Phaeobacter strain 27-4 and fish pathogenic Vibrio in microalgae, rotifer, Artemia and first feeding turbot (Psetta maxima) larvae.
To develop a SYBR Green quantitative real-time PCR protocol enabling detection and quantification of a fish probiotic and two turbot pathogenic Vibrio spp. in microcosms. Phaeobacter 27-4, Vibrio anguillarum 90-11-287 and Vibrio splendidus DMC-1 were quantified as pure and mixed cultures and in presence of microalgae (Isochrysis galbana), rotifers (Brachionus plicatilis), Artemia nauplii or turbot (Psetta maxima) larvae by real-time PCR based on primers directed at genetic loci coding for antagonistic and virulence-related functions respectively. The optimized protocol was used to study bioencapsulation and maintenance of the probiont and pathogens in rotifers and for the detection and quantification of Phaeobacter and V. anguillarum in turbot larvae fed rotifers loaded with the different bacteria in a challenge trial. Our real-time PCR protocol is reproducible and specific. The method requires separate standard curve for each host organism and can be used to detect and quantify probiotic Phaeobacter and pathogenic Vibrio bioencapsulated in rotifers and in turbot larvae. Our method allows monitoring and quantification of a turbot larvae probiotic bacteria and turbot pathogenic vibrios in in vivo trials and will be useful tools for detecting the bacteria in industrial rearing units.


3D porous chitosan-chondroitin sulfate scaffolds promote epithelial to mesenchymal transition in prostate cancer cells.
Prostate cancer (PCa) is a common cancer in men that is curable prior to metastasis, when its prognosis worsens. Chondroitin sulfate (CS) is found in the extracellular matrix of normal prostate tissue and PCa, with greater content in metastatic PCa. Biomaterial scaffolds containing CS have yet to be evaluated for tumor microenvironment applications. Three-dimensional porous chitosan-CS (C-CS) scaffolds were developed and evaluated for PCa culture. Three C-CS scaffold compositions were prepared with 4 w/v% chitosan and 0.1, 0.5, and 1.0 w/v% CS and named 4-0.1, 4-0.5, and 4-1, respectively. The C-CS scaffolds had 90-95% porosity, average pore sizes between 143 and 166 μm, and no significant difference in scaffold stiffness. PC-3 and 22Rv1 PCa cells were cultured on the C-CS scaffolds to study the effect of CS on PCa growth and epithelial to mesenchymal transition (EMT). All C-CS scaffold compositions supported PCa growth and the 4-1 scaffolds had the greatest cell numbers for both PC-3 and 22Rv1. The C-CS scaffolds promoted upregulated EMT marker expression compared to 2D cultures with the greatest EMT marker expression in 4-1 scaffolds. Increasing CS concentration promoted upregulated vimentin expression in PC-3 cultures and N-cadherin and MMP-2 expression in 22Rv1 cultures. C-CS scaffolds promoted docetaxel drug resistance in PC-3 and 22Rv1 cultures and the 4-1 scaffold cultures had the greatest drug resistance. These results indicate that C-CS scaffolds are a promising in vitro platform for PCa.


Neuro-QOL: quality of life item banks for adults with neurological disorders: item development and calibrations based upon clinical and general population testing.
Neuro-QOL provides a clinically relevant and psychometrically robust health-related quality of life (HRQL) assessment tool for both adults and children with common neurological disorders. We now report the psychometric results for the adult tools. An extensive research, survey and consensus process was used to produce a list of 5 priority adult neurological conditions (stroke, multiple sclerosis, Parkinson's disease, epilepsy and ALS). We identified relevant health related quality of life (HRQL) domains through multiple methods and data sources including a comprehensive review of the literature and literature search, expert interviews and surveys and patient and caregiver focus groups. The final domain framework consisted of 17 domains of Physical, Mental and Social health. There were five phases of item development: (1) identification of 3,482 extant items, (2) item classification and selection, (3) item review and revision, (4) cognitive interviews with 63 patients to assess their understanding of individual items and (5) field testing of 432 representative items. PARTICIPANTS AND PROCEDURES: Participants were drawn from the US general population and clinical settings, and included both English and Spanish speaking subjects (N = 3,246). Confirmatory factor analysis (CFA) was used to evaluate the dimensionality of unidimensional domains. Where the domain structure was previously unknown, the dataset was split and first analyzed with exploratory factor analysis and then CFA. Samejima's graded response model (GRM) was used to calculate IRT parameters. We further evaluated differential item functioning (DIF) on gender, education and age. Thirteen unidimensional calibrated item banks consisting of 297 items were developed. All of the tested item banks had high reliability and few or no locally dependent items. The range of item slopes and thresholds with good information are reported for each of the item banks. The banks can support CAT and the development of short forms. The Neuro-QOL measurement system provides item banks and short forms that enable PRO measurement in neurological research, minimizes patient burden and can be used to create multiple instrument types minimizing standard error. The 17 adult measures include 13 calibrated item banks, 3 item pools available for calibration work by others, and 1 stand-alone scale (index). The Neuro-QOL instruments provide a "common metric" of representative concepts for use across patient groups in different studies.


Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study.
The Food and Drug Administration has issued a boxed warning concerning increased suicidal ideation and behavior associated with antidepressant drug treatment in children and adolescents. It is unknown whether antidepressant agents increase the risk of suicide death in children or adults. To estimate the relative risk of suicide attempt and suicide death in severely depressed children and adults treated with antidepressant drugs vs those not treated with antidepressant drugs. Matched case-control study. Outpatient treatment settings in the United States. Medicaid beneficiaries from all 50 states who received inpatient treatment for depression, excluding patients treated for pregnancy, bipolar disorder, schizophrenia or other psychoses, mental retardation, dementia, or delirium. Controls were matched to cases for age, sex, race or ethnicity, state of residence, substance use disorder, recent suicide attempt, number of days since hospital discharge, and recent treatment with antipsychotic, anxiolytic/hypnotic, mood stabilizer, and stimulant medications. Suicide attempts and suicide deaths. In adults (aged 19-64 years), antidepressant drug treatment was not significantly associated with suicide attempts (odds ratio [OR], 1.10; 95% confidence interval [CI], 0.86-1.39 [521 cases and 2394 controls]) or suicide deaths (OR, 0.90; 95% CI, 0.52-1.55 [86 cases and 396 controls]). However, in children and adolescents (aged 6-18 years), antidepressant drug treatment was significantly associated with suicide attempts (OR, 1.52; 95% CI, 1.12-2.07 [263 cases and 1241 controls]) and suicide deaths (OR, 15.62; 95% CI, 1.65-infinity [8 cases and 39 controls]). In these high-risk patients, antidepressant drug treatment does not seem to be related to suicide attempts and death in adults but might be related in children and adolescents. These findings support careful clinical monitoring during antidepressant drug treatment of severely depressed young people.


Detection of persistent signals and its relation to coherent feed-forward loops.
Many studies have shown that cells use the temporal dynamics of signalling molecules to encode information. One particular class of temporal dynamics is persistent and transient signals, i.e. signals of long and short duration, respectively. It has been shown that the coherent type-1 feed-forward loop with an AND logic at the output (or C1-FFL for short) can be used to discriminate a persistent input signal from a transient one. This has been done by modelling the C1-FFL, and then using the model to show that persistent and transient input signals give, respectively, a non-zero and zero output. The aim of this paper is to make a connection between the statistical detection of persistent signals and the C1-FFL. We begin by first formulating a statistical detection problem of distinguishing persistent signals from transient ones. The solution of the detection problem is to compute the log-likelihood ratio of observing a persistent signal to a transient signal. We show that, if this log-likelihood ratio is positive, which happens when the signal is likely to be persistent, then it can be approximately computed by a C1-FFL. Although the capability of C1-FFL to discriminate persistent signals is known, this paper adds an information processing interpretation on how a C1-FFL works as a detector of persistent signals.


Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells.
Epstein-Barr virus (EBV) is a ubiquitous oncogenic virus that is associated with B cell lymphomas, including Burkitt lymphoma and Hodgkin lymphoma. Previous studies have shown that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in EBV-associated lymphomas and can be a novel therapeutic target. An oral dual inhibitor of PI3Kγ and PI3Kδ, duvelisib, is in clinical trials for the treatment of lymphoid malignancies. In this study, we evaluated how duvelisib affects the activity of the PI3K/Akt signaling pathway and if it has antitumor effects in EBV-associated lymphoma cell lines. We found that the PI3K/Akt signaling pathway was activated in most of the B and T cell lymphoma cell lines tested. Additionally, duvelisib treatment inhibited cellular growth in the tested cell lines. Overall, B cell lines were more susceptible to duvelisib than T and NK cell lines in vitro regardless of EBV infection. However, the additional influence of duvelisib on the tumor microenvironment was not assessed. Duvelisib treatment induced both apoptosis and cell cycle arrest in EBV-positive and -negative B cell lines, but not in T cell lines. Furthermore, duvelisib treatment reduced the expression of EBV lytic genes (BZLF1 and gp350/220) in EBV-positive B cell lines, suggesting that duvelisib suppresses the lytic cycle of EBV induced by B cell receptor signaling. However, duvelisib did not induce a remarkable change in the expression of EBV latent genes. These results may indicate that there is therapeutic potential for duvelisib administration in the treatment of EBV-associated B cell lymphomas and other B cell malignancies.


American Society of Clinical Oncology Clinical Practice Guidelines: formal systematic review-based consensus methodology.
The American Society of Clinical Oncology (ASCO) guidelines program employs a systematic review-based methodology to produce evidence-based guidelines. This is consistent with the stance of the Institute of Medicine on guideline development, which is that high-quality evidence syntheses form the basis for recommendation development. In the absence of high-quality evidence, recommendation development becomes more complex. One option is to provide no recommendations or withdraw a guideline topic. However, it is often the areas of greatest uncertainty in which the evidentiary base is incomplete, and thus, guidelines are needed most. To provide recommendations in such circumstances, an explicit methodology is needed to ensure that a credible process is undertaken, and rigorous, reliable advice is provided. In 2010, the ASCO Board of Directors approved development of guideline recommendations using consensus methodology. A modified Delphi approach to recommendation development, based on the best available data identified in a systematic review, was piloted with an ASCO guideline. Consensus was achieved through the rating of a series of recommendations by a large group of clinicians, including academic and community-based content and methodology experts. A prespecified threshold of agreement was determined to indicate when consensus was achieved. Consensus was defined as agreement by ≥ 75% of raters. The formal consensus methodology used by ASCO enabled development of guideline recommendations on a challenging clinical issue based on limited evidence using a rigorous, transparent, and explicit method. This methodology is proposed for development of future ASCO guidelines on topics for which limited evidence is available.


Genome Partitioner: A web tool for multi-level partitioning of large-scale DNA constructs for synthetic biology applications.
Recent advances in lower-cost DNA synthesis techniques have enabled new innovations in the field of synthetic biology. Still, efficient design and higher-order assembly of genome-scale DNA constructs remains a labor-intensive process. Given the complexity, computer assisted design tools that fragment large DNA sequences into fabricable DNA blocks are needed to pave the way towards streamlined assembly of biological systems. Here, we present the Genome Partitioner software implemented as a web-based interface that permits multi-level partitioning of genome-scale DNA designs. Without the need for specialized computing skills, biologists can submit their DNA designs to a fully automated pipeline that generates the optimal retrosynthetic route for higher-order DNA assembly. To test the algorithm, we partitioned a 783 kb Caulobacter crescentus genome design. We validated the partitioning strategy by assembling a 20 kb test segment encompassing a difficult to synthesize DNA sequence. Successful assembly from 1 kb subblocks into the 20 kb segment highlights the effectiveness of the Genome Partitioner for reducing synthesis costs and timelines for higher-order DNA assembly. The Genome Partitioner is broadly applicable to translate DNA designs into ready to order sequences that can be assembled with standardized protocols, thus offering new opportunities to harness the diversity of microbial genomes for synthetic biology applications. The Genome Partitioner web tool can be accessed at https://christenlab.ethz.ch/GenomePartitioner.


Data-driven, two-stage machine learning algorithm-based prediction scheme for assessing 1-year and 3-year mortality risk in chronic hemodialysis patients.
Life expectancy is likely to be substantially reduced in patients undergoing chronic hemodialysis (CHD). However, machine learning (ML) may predict the risk factors of mortality in patients with CHD by analyzing the serum laboratory data from regular dialysis routine. This study aimed to establish the mortality prediction model of CHD patients by adopting two-stage ML algorithm-based prediction scheme, combined with importance of risk factors identified by different ML methods. This is a retrospective, observational cohort study. We included 800 patients undergoing CHD between December 2006 and December 2012 in Shin-Kong Wu Ho-Su Memorial Hospital. This study analyzed laboratory data including 44 indicators. We used five ML methods, namely, logistic regression (LGR), decision tree (DT), random forest (RF), gradient boosting (GB), and eXtreme gradient boosting (XGB), to develop a two-stage ML algorithm-based prediction scheme and evaluate the important factors that predict CHD mortality. LGR served as a bench method. Regarding the validation and testing datasets from 1- and 3-year mortality prediction model, the RF had better accuracy and area-under-curve results among the five different ML methods. The stepwise RF model, which incorporates the most important factors of CHD mortality risk based on the average rank from DT, RF, GB, and XGB, exhibited superior predictive performance compared to LGR in predicting mortality among CHD patients over both 1-year and 3-year periods. We had developed a two-stage ML algorithm-based prediction scheme by implementing the stepwise RF that demonstrated satisfactory performance in predicting mortality in patients with CHD over 1- and 3-year periods. The findings of this study can offer valuable information to nephrologists, enhancing patient-centered decision-making and increasing awareness about risky laboratory data, particularly for patients with a high short-term mortality risk.


IL-1alpha and IL-1beta are endogenous mediators linking cell injury to the adaptive alloimmune response.
Preoperative or perioperative ischemic injury of allografts predisposes to graft arteriosclerosis, the major cause of late graft failure. We hypothesize that injured tissues release mediators that increase the production of pathogenic cytokines by alloreactive T cells. We find that freeze-thaw lysates of human endothelial cells (EC) increase both IFN-gamma and IL-17 production by human CD4(+) T cells activated by HLA-DR(+) allogeneic EC. Immunoadsorption of high-mobility group box 1 protein (HMGB1) reduces this activity in the lysates by about one-third, and recombinant HMGB1 increases T cell cytokine production. HMGB1 acts by inducing IL-1beta secretion from contaminating monocytes via TLR4 and CD14. Upon removal of contaminating monocytes, the remaining stimulatory activity of EC lysates is largely attributable to IL-1alpha. Recombinant IL-1 directly augments IFN-gamma and IL-17 production by activated memory CD4(+) T cells, which express IL-1R1. Furthermore, IL-1 increases the frequency of alloreactive memory CD4(+) T cells that produce IL-17, but not those that produce IFN-gamma, in secondary cultures. Our results suggest that IL-1, released by injured EC or by HMGB1-stimulated monocytes, is a key link between injury and enhanced alloimmunity, offering a new therapeutic target for preventing late graft failure.


Drug policy for visceral leishmaniasis: a cost-effectiveness analysis.
To facilitate the choice of the best visceral leishmaniasis (VL) treatment strategy for first-line health services in (VL)-endemic areas, we compared in a formal decision analysis the cost and the cost-effectiveness of the different available options. We selected four drug regimens for VL on the basis of frequency of use, feasibility and reported efficacy studies. The point estimates and the range of plausible values of effectiveness and cost were retrieved from a literature review. A decision tree was constructed and the strategy minimizing the cost per death averted was selected. Treatment with amphotericin B deoxycholate was the most effective approach in the baseline analysis and averted 87.2% of all deaths attributable to VL. The least expensive and the most cost-effective treatment was the miltefosine regimen, and the most expensive and the least cost-effective was AmBisome treatment. The cost of drug and medical care are the main determinants of the cost-effectiveness ranking of the alternative schemes. Sensitivity analysis showed that antimonial was competitive with miltefosine in the low-resistance regions. In areas with >94% response rates to antimonials, generic sodium stibogluconate remains the most cost-effective option for VL treatment, mainly due to low drug cost. In other regions, miltefosine is the most cost-effective option of treatment, but its use as a first-line drug is limited by its teratogenicity and rapid resistance development. AmBisome in mono- or combination therapy is too expensive to compete in cost-effectiveness with the other regimens.


Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis.
An association between deficiency of tissue factor pathway inhibitor (TFPI) and thrombosis has not been clearly demonstrated in humans, but previous studies have focused on the measurement of plasma TFPI, which is only a small part of the total body TFPI. The major fraction of this natural anticoagulant can be measured in plasma after release by heparin injection. To investigate if deficiency of heparin-releasable TFPI is associated with thrombosis. we measured TFPI activity in plasma before and 10 min after intravenous injection of 7500 IU unfractionated heparin in 64 young patients with venous thrombosis, 49 young patients with arterial thrombosis and 38 healthy individuals. Post-heparin TFPI activity levels were significantly lower in the group of patients with venous thrombosis than in controls (mean+/-SD: 230%+/-39 vs 260%+/-34, p = 0.0002), whereas there was no difference for patients with arterial thrombosis. Defining the normal range as the mean+/-2 SD of TFPI activity in controls, twelve patients had low post-heparin TFPI activity levels, seven with venous and five with arterial thrombosis. Low levels of TFPI activity were confirmed by immunoassay in six of the seven patients with venous thrombosis and two of the five patients with arterial thrombosis, and were present also in at least one first degree relative of six patients, suggesting that the defect might be inheritable. However, the causative role of low heparin-releasable TFPI remains uncertain, because co-segregation of the defect with thrombotic symptoms could not be demonstrated in the small number of families studied.


[Biochemical changes in rats under the influence of cesium chloride].
Cesium is lately accumulated actively in the environment, but its influence on human and animal organism is the least studied among heavy metals. It is shown that the action of cesium chloride in rats caused significant changes in blood chemistry, which are characterized by a decrease of total protein content, pH, an increase in the level of urea, creatinine, glucose and total hemoglobin. The results showed that potassium content in all the studied organs and tissues of poisoned rats decreases under the action of cesium chloride. Histological examination of the heart tissue in rats poisoned with cesium chloride indicates the onset of pathology of cardiovascular system. It was found out that use of the drug "Asparkam" reduces the negative effect of cesium chloride on the body of rats.


Structures and energetics of the deprotonated adenine-uracil base pair, including proton-transferred systems.
The B3LYP/DZP++ level of theory has been employed to investigate the structures and energetics of the deprotonated adenine-uracil base pairs, (AU-H)-. Formation of the lowest-energy structure, [A(N9)-U]- (which corresponds to deprotonation at the N9 atom of adenine), through electron attachment to the corresponding neutral is accompanied by proton transfer from the uracil N3 atom to the adenine N1 atom. The driving force for this proton transfer is a significant stabilization from the base pairing in the proton transferred form. Such proton transfer upon electron attachment is also observed for the [A(N6b)-U]- and [A(C2)-U]- anions. Electron attachment to the A-U(N3) radical causes strong lone pair repulsion between the adenine N1 and the uracil N3 atoms, driving the two bases apart. Similarly, lone pair repulsion in the anion A(N6a)-U causes the loss of coplanarity of the two base units. The computed adiabatic electron attachment energies for nine AU-H radicals range from 1.86 to 3.75 eV, implying that the corresponding (AU-H)- anions are strongly bound. Because of the large AEAs of the (AU-H) radicals, the C-H and N-H bond dissociation in the AU- base pair anions requires less energy than the neutral AU base pair. The computed C-H and N-H bond dissociation energies for the AU- anion (i.e., the AU base pair plus one electron) are in the range 1.0-3.2 eV, while those for neutral AU are 4.08 eV or higher.


Protein kinase C alpha signaling inhibits cyclin D1 translation in intestinal epithelial cells.
Cyclin D1 is a key regulator of cell proliferation, acting as a mitogen sensor and linking extracellular signaling to the cell cycle machinery. Strict control of cyclin D1 levels is critical for maintenance of tissue homeostasis. We have reported previously that protein kinase C alpha (PKCalpha), a negative regulator of cell growth in the intestinal epithelium, promotes rapid down-regulation of cyclin D1 (Frey, M. R., Clark, J. A., Leontieva, O., Uronis, J. M., Black, A. R., and Black, J. D. (2000) J. Cell Biol. 151, 763-778). The current study explores the mechanisms underlying PKCalpha-induced loss of cyclin D1 protein in non-transformed intestinal epithelial cells. Our findings exclude several mechanisms previously implicated in down-regulation of cyclin D1 during cell cycle exit/differentiation, including alterations in cyclin D1 mRNA expression and protein turnover. Instead, we identify PKCalpha as a novel repressor of cyclin D1 translation, acting at the level of cap-dependent initiation. Inhibition of cyclin D1 translation initiation is mediated by PKCalpha-induced hypophosphorylation/activation of the translational suppressor 4E-BP1, association of 4E-BP1 with the mRNA cap-binding protein eIF4E, and sequestration of cyclin D1 mRNA in 4E-BP1-associated complexes. Together, these post-transcriptional effects ensure rapid disappearance of the potent mitogenic molecule cyclin D1 during PKCalpha-induced cell cycle withdrawal in the intestinal epithelium.


Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation.
Efficient osteogenic differentiation and bone formation from mesenchymal stem cells (MSCs) should have clinical applications in treating nonunion fracture healing. MSCs are adherent bone marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We have identified bone morphogenetic protein 9 (BMP-9) as one of the most osteogenic BMPs. Here we investigate the effect of insulin-like growth factor 2 (IGF-2) on BMP-9-induced bone formation. We have found that endogenous IGF-2 expression is low in MSCs. Expression of IGF-2 can potentiate BMP-9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers. IGF-2 has been shown to augment BMP-9-induced ectopic bone formation in the stem cell implantation assay. In perinatal limb explant culture assay, IGF-2 enhances BMP-9-induced endochondral ossification, whereas IGF-2 itself can promote the expansion of the hypertropic chondrocyte zone of the cultured limb explants. Expression of the IGF antagonists IGFBP3 and IGFBP4 leads to inhibition of the IGF-2 effect on BMP-9-induced ALP activity and matrix mineralization. Mechanistically, IGF-2 is further shown to enhance the BMP-9-induced BMPR-Smad reporter activity and Smad1/5/8 nuclear translocation. PI3-kinase (PI3K) inhibitor LY294002 abolishes the IGF-2 potentiation effect on BMP-9-mediated osteogenic signaling and can directly inhibit BMP-9 activity. These results demonstrate that BMP-9 crosstalks with IGF-2 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs. Taken together, our findings suggest that a combination of BMP-9 and IGF-2 may be explored as an effective bone-regeneration agent to treat large segmental bony defects, nonunion fracture, and/or osteoporotic fracture.


Adsorption behavior of serum proteins on anodized titanium is driven by surface nanomorphology.
Protein adsorption behavior can play a critical role in defining the outcome of a material by affecting the subsequent in vivo response to it. To date, the effect of surface properties on protein adsorption behavior has been mainly focused on surface chemistry, but research on the effect of nanoscale surface topography remains limited. In this study, the adsorption behavior of human serum albumin, immunoglobulin G, and fibrinogen in terms of the adsorbed amount and conformational changes were investigated on bare and anodized titanium (Ti) samples (40 and 60 V applied voltages). While the surface chemistry, RMS surface roughness, and arithmetic surface roughness of the anodized samples were similar, they had distinctly different nanomorphologies identified by atomic force microscopy and scanning electron microscopy, and the surface statistical parameters, surface skewness Ssk and kurtosis Sku. The Feret pore size distribution was more uniform on the 60 V sample, and surface nanostructures were more symmetrical with higher peaks and deeper pores. On the other hand, the 40 V sample surface presented a nonuniform pore size distribution and asymmetrical surface nanostructures with lower peaks and shallower pores. The amount of surface-adsorbed protein increased on the sample surfaces in the order of Ti < 40 V < 60 V with the predominant factor affecting the amount of surface-adsorbed protein being the increased surface area attained by pore formation. The secondary structure of all adsorbed proteins deviated from that of their native counterparts. While comparing the secondary structure components of proteins on anodized surfaces, it was observed that all three proteins retained more of their secondary structure composition on the surface with more uniform and symmetrical nanofeatures than the surface having asymmetrical nanostructures. Our results suggest that the nanomorphology of the peaks and outer walls of the nanotubes can significantly influence the conformation of adsorbed serum proteins, even for surfaces having similar roughness values.


A new method to estimate the real upper limit of the false alarm rate in a 3 accelerometry-based fall detector for the elderly.
Falls are a major concern for the elderly and their ability to remain healthy. Fall detection systems may notify emergency responders when no one apart from the injured is present. However, their real-world application is limited by a number of factors such as high false positive rates, low-compliance, poor-usability and short battery lifetime. In order to improve these aspects we have developed a miniaturized 3D accelerometer integrated in a belt buckle, the actibelt(®), and a fall detection algorithm. We have used a new evaluation method to assess the upper limit of the false alarm rate of our algorithm using a large set of long term standardized acceleration measurements recorded under real life conditions. Our algorithm has a false alarm rate of seventeen false alarms per month and has the potential to be reduced down to at most three false alarms per month when activities which require the sensor to be removed are eliminated. In laboratory settings, the algorithm has a sensitivity of 100%. The algorithm was sucessfully validated using data from a real-world fall.


Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism.
Review literature on the effect of decreasing cholesteryl ester transfer protein (CETP) activity through pharmacological inhibition or modulation in preclinical and clinical settings compared to human CETP deficiency on lipoprotein characteristics, HDL remodelling and function. Torcetrapib, anacetrapib and dalcetrapib inhibited the heterotypic transfer of cholesteryl ester from HDL to LDL and/or VLDL with similar potency, although the potency of dalcetrapib was time dependent. Homotypic transfer of cholesteryl ester from HDL3 to HDL2 via recombinant human CETP was inhibited by torcetrapib and anacetrapib (CETP inhibitors, CETPi) but not by dalcetrapib (CETP modulator, CETPm). In a hamster model of reverse cholesterol transport, only dalcetrapib increased efflux of fecal sterols from macrophages to feces. In clinical studies, dose-responses of CETPi and CETPm demonstrate qualitative and quantitative changes in HDL and LDL particle composition and distribution. Recent studies of the CETPi torcetrapib and anacetrapib and the CETPm dalcetrapib have shown differences in the resulting increase in HDL-cholesterol and in the level of HDL remodelling and potential for effective reverse cholesterol transport. Results from ongoing clinical outcomes studies with anacetrapib and dalcetrapib will clarify the relevance of CETP inhibition versus modulation towards HDL remodelling in the treatment of cardiovascular diseases.


Strengthening the laboratory diagnosis of pathogenic Corynebacterium species in the Vaccine era.
Over the last three decades, successful implementation of the diphtheria vaccination in the developed and developing countries has reduced the infections caused by the toxigenic strains of Corynebacterium diphtheriae, but a concomitant increase in the invasive infections due to the nontoxigenic strains was seen. In addition, the recent reports on the emergence of nontoxigenic toxin gene-bearing strains, having the potential to revert back to toxigenic form poses a significant threat to human beings. Besides infections caused by C. diphtheriae, the emergence of the respiratory, cutaneous and invasive infections by related pathogenic Corynebacterium species like C. ulcerans and C. pseudotuberculosis, complicate the diagnosis and management of infection. These observations together with the widespread prevalence of diphtheria in the vaccine era, necessitates the strengthening of the epidemiological surveillance and laboratory diagnosis of the pathogen. This review provides the overview of the advantages and limitations of different molecular methods and the role of MALDI-TOF in the laboratory diagnosis of Diphtheria. The contribution of next generation sequencing technology and different genotyping techniques in understanding the pathogenicity, transmission dynamics and epidemiology of the C. diphtheriae is discussed.


Aquaporin-3 functions as a glycerol transporter in mammalian skin.
The AQPs (aquaporins) are a family of homologous water transporting proteins expressed in many mammalian epithelial, endothelial and other cell types. Phenotype analysis of mice lacking individual AQPs has been informative in elucidating their role in mammalian physiology. For example, phenotype analysis has indicated an important role of AQPs in the renal urinary concentrating mechanism (AQP1-AQP4), brain water balance and neural signal transduction (AQP4), exocrine gland secretion (AQP5) and ocular fluid balance (AQP1, AQP5). In skin, the aquaglyceroporin AQP3 is expressed in the basal layer of epidermal keratinocytes. Mice deficient in AQP3 have dry skin with reduced SC (stratum corneum) hydration, decreased elasticity and impaired biosynthesis. Mechanistic analysis of the altered skin phenotype in AQP3 deficiency suggested that the glycerol rather than the water transporting function of AQP3 is important in skin physiology. The glycerol content of SC and epidermis of AQP3 deficient mice is reduced, whereas that of dermis and serum is normal. The dry, relatively inelastic skin in AQP3 null mice is probably related to the humectant properties of glycerol, and the impaired SC repair to impaired epidermal biosynthetic function. The key role of AQP3 in epidermal physiology might be exploited in the development of improved cosmetics and new therapies for skin diseases associated with altered skin water content.


The use of tobacco-free betel-quid in conjunction with alcohol/tobacco impacts early-onset age and carcinoma distribution for upper aerodigestive tract cancer.
Recognition of how risk factors affect the age when cancers are first diagnosed may help to establish more appropriate cancer screening and preventive strategies. To investigate the independent and synergistic effects of alcohol, tobacco-free betel-quid (TF-BQ), and cigarette use on diagnosis age and dissemination of upper aerodigestive tract squamous cell carcinoma (UADT-SCC), we recruited pathology-proven 1522 patients with UADT-SCC for study. A 49-, 53-, 57-, and 62-year-old stepwise older median age at carcinoma diagnosis was, respectively, found among patients with oral, pharyngeal, esophageal, and laryngeal cancer. Oral cavity (53.2%) and larynx (11.6%) were separately the dominant and recessive sites where the UADT-SCC occurred. Although alcohol and tobacco bestowed increased risks of earlier tumor occurrence only for oral/pharyngeal and oral cancers, respectively, TF-BQ was consistently observed to confer elevated age-associated risks for each UADT-SCC [adjusted hazard ratio (aHR) = 1.6-2.3]. Alcohol and TF-BQ joint consumers experienced a stepwise increased cumulative risk (CR) of contracting carcinomas of the larynx (46.2%), esophagus (47.5%), pharynx (53.5%), and oral cavity (60.5-71.0%), with >68% of CRs found among drinkers who started chewing before age 20. Alcohol + Betel + Cigarette and Alcohol + Betel users exhibited earlier diagnosis ages than non-users: 10 years ahead for oral cancer, 7, 17, and 12 years earlier for pharyngeal, esophageal, and laryngeal cancers. Noticeably, higher cumulative cancer risks regarding earlier tumor occurrence were correspondingly identified for these users aged 43, 49, 43, and 44 upward. Tobacco-free betel-quid, in conjunction with alcohol and/or tobacco consumption, impacts early cancer occurrence for specific UADT-SCC and influences tumor site incidence pattern of these neoplasms.


Layered structures in proton-transfer compounds of 5-sulfosalicylic acid with the aromatic polyamines 2,6-diaminopyridine and 1,4-phenylenediamine.
The crystal structures of two proton-transfer compounds of 3-carboxy-4-hydroxybenzenesulfonic acid (5-sulfosalicylic acid) with the aromatic polyamines 2,6-diaminopyridine [namely 2,6-diaminopyridinium 3-carboxy-4-hydroxybenzenesulfonate monohydrate, C5H8N3+.C7H5O6S-.H2O, (I)] and 1,4-phenylenediamine [namely 1,4-phenylenediaminium 3-carboxylato-4-hydroxybenzenesulfonate, C6H10N2(2+).C7H4O6S2-, (II)] have been determined. Both compounds feature extensively hydrogen-bonded three-dimensional layered polymer structures having significant interlayer pi-pi interactions between the cation and anion species. In (I), the pyridine N atom of the Lewis base is protonated and forms a direct hydrogen-bonding interaction with the water molecule, which together with the two amine groups of the cation and the carboxylic acid group of the anion also give additional interactions with O-atom acceptors of the sulfonate group. In (II), a dianionic species results from deprotonation of both the sulfonic and the carboxylic acid groups, and all available O-atom acceptors interact with all dication donors, which lie about inversion centres.


[Secondary splenomegaly in cholestasis and disorders of portal blood flow in an experiment detectable by intravenous liposome splenography].
The paper is concerned with the results showing high diagnostic potentialities of i.v. liposome lienography for the detection of the splenomegalic syndrome in acute cholestasis, cholestatic hepatitis and disturbances of the extrahepatic portal blood flow. The authors managed to establish the dependence of the value of secondary splenomegaly on the period of cholestasis and a degree of occlusion of the portal vein. In acute cholestasis splenomegaly was manifested in 5 days by a two-fold increase in the spleen with reverse development within 2.5 mos. A rapid 2-fold increase in the spleen for 24 h was noted in occlusion of the portal vein by 40%, and a three-fold increase was noted in 5 mos. with subsequent death of the animals. A decrease in the extrahepatic portal blood flow by 25% also resulted in splenomegaly but without death of the animals. The authors have assumed that the use of i.v. liposome lienography ensures timely diagnosis of the splenomegalic syndrome and provides an opportunity to assess function of the reticuloendothelial system of the spleen.


Accepting loss: the temporal limits of reciprocity in brown capuchin monkeys.
Delayed reciprocity is a potentially important mechanism for cooperation to occur. It is however rarely reported among animals, possibly because it requires special skills like the ability to plan a loss. We tested six brown capuchin monkeys (Cebus apella) in such skills. Subjects were studied in exchange tasks in which they had to retain a food item for a given time lag before returning it to an experimenter and obtaining a more desirable reward. Experiments showed that the subjects could wait for several minutes when allowed to return only part of the initial item. When required to return the full item intact, however, most subjects could not sustain a time lag longer than 10 s. Although the duration of waiting increased with the amount of return expected by subjects, in most cases it did not extend beyond 20 s even when the eperimenter offered a food amount 40 fold the initial item. The failure of capuchin monkeys to sustain long-lasting waiting periods may be explained by limited self-control abilities. This would prevent them achieving reciprocal altruism.


The Vivity Extended Range of Vision IOL vs the PanOptix Trifocal, ReStor 2.5 Active Focus and ReStor 3.0 Multifocal Lenses: A Comparison of Patient Satisfaction, Visual Disturbances, and Spectacle Independence.
To compare patient-reported outcomes (PROs) after intraocular lens (IOL) implantation with the AcrySof IQ Vivity IOL or Vivity Toric IOL to those achieved with other multifocal IOLs. Prospective, open-label, multicenter analysis of PROs, including spectacle independence, dysphotopsia, and overall satisfaction among patients who underwent cataract surgery at least 1 month previously with bilateral Vivity or Vivity Toric lenses (n=60). Results were compared to outcomes from two similar prospective studies of bilateral AcrySof IQ PanOptix or PanOptix Toric trifocal IOLs (n = 59), blended AcrySof ReSTOR 2.5/3.0 IOLs (n=72) or bilateral ReSTOR ActiveFocus 2.5 D IOLs with a mini-monovision target [n = 95]). Patients in the Vivity cohort were significantly less likely to notice glare and halo in dim light (85% "none" or "just a little") compared to PanOptix (69%, p<0.03), 2.5 mini-monovision (75%, p< 0.05) or 2.5/3.0 (71%, p< 0.05) patients. Complete spectacle independence for all visual activities combined (never need glasses) with Vivity was comparable to the mini-monovision and 2.5/3.0 groups (33%, 36%, and 31%, respectively) but significantly lower than in the PanOptix cohort (83%, p < 0.0001). Satisfaction was high across all groups. There were no statistically significant differences in best-corrected visual acuity, and no new safety concerns were reported. The AcrySof IQ Vivity extended depth of focus IOL offers an expanded range of vision and better spectacle independence than has typically been achieved with traditional monofocal IOLs, with high rates of satisfaction and a favorable dysphotopsia profile compared to diffractive multifocal IOLs.


Comparison of tethering and rolling of eosinophils and neutrophils through selectins and P-selectin glycoprotein ligand-1.
We compared the abilities of selectins and the selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), to support tethering and rolling of eosinophils and neutrophils under physiologic flow conditions. Eosinophils and neutrophils accumulated on P-selectin at similar site densities and rolled at similar velocities, but fewer eosinophils than neutrophils accumulated at any P-selectin density. Compared with neutrophils, few eosinophils accumulated on E-selectin except at high densities, and those cells that did accumulate rolled faster than neutrophils. Examination of the mechanisms for accumulation revealed that eosinophils and neutrophils formed similar numbers of primary tethers to P-selectin, whereas eosinophils formed fewer primary tethers to E-selectin than did neutrophils. Compared with neutrophils, adherent eosinophils also supported fewer leukocyte-leukocyte interactions, resulting in diminished secondary tethers to either P- or E-selectin. Studies with mAbs to L-selectin and PSGL-1 demonstrated that neither cell type used L-selectin to form primary tethers to P- or E-selectin. Both eosinophils and neutrophils used the NH2 terminus of PSGL-1 to form primary tethers to P-selectin, but not to E-selectin. Both cell types used L-selectin and PSGL-1 to promote leukocyte-leukocyte interactions and secondary tethers to P- or E-selectin. However, eosinophils developed significantly fewer secondary interactions, probably because they express less L-selectin than do neutrophils.


Global analysis of Salmonella alternative sigma factor E on protein translation.
The alternative sigma factor E (σ(E)) is critical for response to extracytoplasmic stress in Salmonella. Extensive studies have been conducted on σ(E)-regulated gene expression, particularly at the transcriptional level. Increasing evidence suggests however that σ(E) may indirectly participate in post-transcriptional regulation. In this study, we conducted sample-matched global proteomic and transcriptomic analyses to determine the level of regulation mediated by σ(E) in Salmonella. Samples were analyzed from wild-type and isogenic rpoE mutant Salmonella cultivated in three different conditions: nutrient-rich and conditions that mimic early and late intracellular infection. We found that 30% of the observed proteome was regulated by σ(E) combining all three conditions. In different growth conditions, σ(E) affected the expression of a broad spectrum of Salmonella proteins required for miscellaneous functions. Those involved in transport and binding, protein synthesis, and stress response were particularly highlighted. By comparing transcriptomic and proteomic data, we identified genes post-transcriptionally regulated by σ(E) and found that post-transcriptional regulation was responsible for a majority of changes observed in the σ(E)-regulated proteome. Further, comparison of transcriptomic and proteomic data from hfq mutant of Salmonella demonstrated that σ(E)-mediated post-transcriptional regulation was partially dependent on the RNA-binding protein Hfq.


Combining pharmacometric models with predictive and prognostic biomarkers for precision therapy in Crohn's disease: A case study of brazikumab.
Pharmacometric models were used to investigate the utility of biomarkers in predicting the efficacy (Crohn's Disease Activity Index [CDAI]) of brazikumab and provide a data-driven framework for precision therapy for Crohn's disease (CD). In a phase IIa trial in patients with moderate to severe CD, treatment with brazikumab, an anti-interleukin 23 monoclonal antibody, was associated with clinical improvement. Brazikumab treatment effect was determined to be dependent on the baseline IL-22 (BIL22) or baseline C-reactive protein (BCRP; predictive biomarkers), and placebo effect was found to be correlated with the baseline CDAI (a prognostic biomarker). A maximal total inhibition on CDAI input function of 50.6% and 42.4% was predicted for patients with extremely high BIL22 or BCRP, compared to a maximal total inhibition of 20.9% and 17.8% for patients with extremely low BIL22 or BCRP, respectively, which were mainly due to the placebo effect. We demonstrated that model-derived baseline biomarker levels that achieve 50% of maximum unbound systemic concentration of 22.8 pg/mL and 8.03 mg/L for BIL22 and BCRP as the cutoffs to select subpopulations can effectively identify high-response subgroup patients with improved separation of responders when compared to using the median values as the cutoff. This work exemplifies the utility of pharmacometrics to quantify biomarker-driven responses in biologic therapies and distinguish between predictive and prognostic biomarkers, complementing clinical efforts of identifying subpopulations with higher likelihood of response to brazikumab.


Previous external beam radiation therapy for pelvic malignancy increases complications of total hip arthroplasty.
External beam radiation therapy (EBRT) has known effects on bone health. No large database studies have looked at the effects of pelvic EBRT on total hip arthroplasty (THA) outcomes. The purpose of this study was to evaluate 90-day and long-term (>2 years) complication rates following THA in patients with a history of pelvic malignancy and EBRT. Patients were retrospectively identified using a national insurance claims database. Subjects who underwent THA for osteoarthritis or avascular necrosis were included if they had at least 2-year follow-up and were stratified into 3 cohorts: (1) prior pelvic malignancy diagnosis (prostate, cervical, uterine, ovarian, or rectal) and EBRT (Group A); (2) prior malignancy diagnosis but no EBRT (Group B); and (3) neither prior malignancy diagnosis nor EBRT (Group C). Univariate and multivariate analyses were conducted to evaluate for an association between prior EBRT and the incidence of 90-day and 2-year complication rates using chi-square, student t-tests, and logistic regression analyses where appropriate. 671,554 patients met the inclusion criteria. Group A had higher odds of all-cause revision, septic revision, and loosening with revision after 2 years when compared to Group C and Group B (p < 0.001). Group A subjects had higher rates of 90-day deep vein thrombosis, sepsis, and stroke (p < 0.001) than groups B and C. Prior EBRT for pelvic malignancy was associated with significantly increased rates of all-cause revision, septic revision, and loosening as well as 90-day medical complications.


From pathogenesis to treatment of chronic lymphocytic leukaemia.
Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice.


A mixed methods approach to assess the likelihood of testing for STI using self-collected samples among behaviourally bisexual women.
Behaviourally bisexual women (women who have sex with women and men (WSWM)) are more likely to report a history of sexually transmitted infections (STI) than women who have sex exclusively with men or exclusively with women. Barriers to care may prohibit WSWM from seeking STI testing. The present study investigated participant willingness to self-collect oral, vaginal and anal samples for STI testing. Eighty WSWM were recruited from two midwestern locations. After completing an online questionnaire, a subset of the participants were interviewed (n=54) and provided the option to self-collect oral, vaginal and/or anal samples to screen for Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis. Over two-thirds (67.5%, n=54) of the participants completed the baseline scheduled and attended the interview. The majority of these participants provided vaginal (87.0%, n=47), oral (85.2%, n=46) and/or anal (61.1%, n=33) samples. Participants with a history of anal play were significantly more likely to provide an anal sample. C. trachomatis infection was identified in the samples of 6.8% (n=3) of the participants including 4.5% (n=2) of the vaginal samples and 3.3% (n=1) of the anal samples. None of the samples were positive for N. gonorrhoeae or T. vaginalis. Participants who reported a recent history of anal sexual behaviour with a male partner were significantly more likely to self-collect an anal sample. Given the comparatively high STI rates among WSWM, self-sampling in non-traditional settings may present a unique opportunity to provide needed care to this underserved population of women.


Effect of high and low rates of fluid intake on post-exercise rehydration.
The effect of a high (H) and a low (L) rate of post-exercise fluid consumption on plasma volume and fluid balance restoration was investigated. Eight well-trained cyclists were dehydrated at 3% of body weight (BW) by cycling at 28 degrees C. During the recovery period, they ingested a carbohydrate-electrolyte solution in a volume equivalent to 120% of BW loss. Randomly, they ingested 60%, 40%, and 20% in the 1st, 2nd, and 3rd hours of the recovery period, respectively (H), or 24% x h(-1) during 5 hours (L). BW loss was similar for both trials and resulted in a total drink intake of 2.6 +/- 0.1 kg. Urine output in H exceeded significantly that of L in the 2nd and 3rd hours. This was reversed in the 5th and 6th hours. Plasma volume and fluid balance increased more rapidly in H compared to L. After 6 hours this difference disappeared. It is concluded that H results in a faster rate of plasma volume and fluid balance restoration compared to L, despite a temporary large urine output.


Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate.
An essential event in the progression of adenocarcinoma is the loss of organized epithelial attachment (both to the basement membrane and to adjoining epithelial cells). The E-cadherin cell adhesion molecule has an established function in maintaining normal phenotype and tissue homeostasis, and loss of E-cadherin function has been implicated in tumorigenesis. Aberrations in E-cadherin are associated with prostate cancer progression; however, these aberrations are not simply a result of prodigious allelic loss. We have previously demonstrated a novel posttranslational truncation within the cytosolic domain of native Mr 120,000 E-cadherin to a membrane-bound Mr 97,000 species. We hypothesize that truncation of E-cadherin is an inactivating event that is significantly increased in localized prostate tumors and that it represents a novel molecular event that may distinguish prostate cancer from adjacent normal tissue. E-cadherin was characterized by Western blot analysis in matched normal and cancer tissue from 18 prostate cancer patients. Imaging and densitometry software were used to quantify the truncation of E-cadherin by measuring the ratio of Mr 97,000 E-cadherin to Mr 120,000 E-cadherin, which was significantly increased in the tumor aspect of the prostate gland. Herein, we report the first experiment comparing case-matched human normal and cancerous prostate tissue in the context of E-cadherin truncation.


A model predictive control strategy toward optimal structured treatment interruptions in anti-HIV therapy.
In this paper, model predictive control (MPC) strategies are applied to the control of human immunodeficiency virus infection, with the final goal of implementing an optimal structured treatment interruptions protocol. The MPC algorithms proposed in this paper use a dynamic model recently developed in order to mimic both transient responses and ultimate behavior, and to describe accordingly the different effect of commonly used drugs in highly active antiretroviral therapy (HAART). Simulation studies show that the proposed methods achieve the goal of reducing the drug consumption (thus minimizing the severe side effects of HAART drugs) while respecting the desired constraints on CD4+ cells and free virions concentration. Such promising results are obtained with realistic assumptions of infrequent (possibly noisy) measurements of a subset of model state variables. Furthermore, the control objectives are achieved even in the presence of mismatch between the dynamics of true patients and that of the MPC model.


Parental consanguinity and the Majewski syndrome.
We report a female infant with the Majewski syndrome, one of a group of conditions characterised by short ribs, polydactyly, dwarfism, and early neonatal death. This syndrome seems to be extremely rare, with only five well documented cases reported and, including this case, nine recorded in all. The Majewski syndrome is considered to be recessively inherited, and this report adds further support to this hypothesis, as the infant was born to consanguineous parents.


Does body mass index "dilute" the predictive property of prostate-specific antigen for tumor volume at radical prostatectomy?
To evaluate the effect of the body mass index (BMI) as it relates to the predictive value of the preoperative prostate-specific antigen (PSA) level regarding the tumor volume at radical prostatectomy. Stage migration with the widespread use of PSA screening is well documented; however, the association between the PSA level and tumor volume is less defined. Additionally, the effect of obesity on the serum PSA level might cause relative hemodilution and account for the decreased predictive ability of the PSA level to determine the tumor volume in the modern era. We identified 14 293 patients who had undergone radical prostatectomy for prostate cancer from 1987 to 2007 and had a documented BMI. Using the clinicopathologic variables, we examined the relationship among the BMI, preoperative PSA level, and tumor volume at radical prostatectomy using multiple linear regression analysis. An elevated BMI was associated with an increased pathologic Gleason score (P < .0001), increased tumor volume (P < .0001), and increased prostate size (P < .0001). The preoperative PSA level correlated significantly with the tumor volume (P < .0001). No significant correlation was found between the BMI and preoperative PSA level (P = .39). On multivariate analysis, controlling for the BMI, the preoperative PSA level remained a significant predictor of the tumor volume (P < .0001). The interaction between the preoperative PSA level and BMI in the prediction of the tumor volume was not statistically significant (P = .56), suggesting that the BMI does not affect the association between the PSA level and tumor volume. Our results have shown that the predictive ability of the PSA level for tumor volume is not affected by the BMI. There does not appear to be a need to correct the serum PSA level in relation to the BMI when used in preoperative prediction models of the tumor volume.


Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway.
Epidermal growth factor receptor (EGFR) exists in the nucleus of highly proliferative cells where it functions as a transcription factor. Although EGFR has transactivational activity, it lacks a DNA binding domain and, therefore, may require a DNA binding transcription cofactor for its transcriptional function. Here, we report that EGFR physically interacts with signal transducers and activators of transcription 3 (STAT3) in the nucleus, leading to transcriptional activation of inducible nitric oxide synthase (iNOS). In breast carcinomas, nuclear EGFR positively correlates with iNOS. This study describes a mode of transcriptional control involving cooperated efforts of STAT3 and nuclear EGFR. Our work suggests that the deregulated iNOS/NO pathway may partly contribute to the malignant biology of tumor cells with high levels of nuclear EGFR and STAT3.


New advances in Clostridium difficile infection: changing epidemiology, diagnosis, treatment and control.
Clostridium difficile infection and Clostridium difficile-associated diarrhea (CDAD) are growing worldwide health threats. Recent studies have identified new host risk factors, diagnostic approaches and therapies of CDAD. The present review focuses on scientific papers published in the past 18 months in an attempt to provide the latest information on the topic. We are seeing an increasing number of patients with Clostridium difficile infection developing their illness in the community, although many were recently discharged from a healthcare setting suggesting an acquisition of infection in the hospital environment. The use of gastric acid-altering drugs that facilitate intestinal transit of the bacteria, antibacterial drugs that deplete colonic flora and presence of inflammatory bowel disease are risk factors for CDAD. Fulminant CDAD is increasing, complicated by leukocytosis (peripheral white blood cell count >16,000/mm), hypoalbuminemia, renal failure and emergency colectomy, with overall rise in CDAD disease mortality rates. Although vancomycin is recommended for severe cases of CDAD, recurrence rates remain high. Control of Clostridium difficile infection in the hospital setting focuses on disinfection of the environment and antibiotic stewardship policies. Anti-Clostridium difficile vaccines are in development. CDAD is an increasing health problem throughout the United States, Canada and Europe with rising mortality rate. Occurrence of CDAD outside of healthcare settings and in pediatric populations represents newly emerging problems. New treatments are needed.


Phosphoric acid triester glutathione alkyltransferase. A mechanism for the detoxification of dimethyl phosphate triesters.
1. 2-Chloro-1-(2,4,5-trichlorophenyl)vinyl dimethyl phosphate (tetrachlorvinphos) is demethylated by mammalian liver supernatant (100000g) protein in the presence of GSH. 2. GSH acts as an acceptor of the transferred methyl group to form S-methyl glutathione. 3. The enzyme that catalyses this reaction is present in the soluble fraction of liver from mouse, rat, rabbit and pig at similar activity. The enzyme was purified 45-fold from pig liver, dimethyl 1-naphthyl phosphate being used as assay substrate. 4. Methyl groups are readily removed from most of the substrates studied; ethyl groups are removed at one-fiftieth to one-hundredth of the rate for methyl groups. It is likely that the enzyme plays an important role in the detoxification of the phosphate triester pesticides containing CH(3)-O-P groups.


Physical growth in the neonatal intensive-care unit and neuropsychological performance at preschool age in very preterm-born singletons.
We studied the associations between early postnatal growth gains and neuropsychological outcome in very preterm-born children. Specifically, we wished to establish whether relationships exist between gains in head circumference (relative to gains in body-weight or length), from birth to hospital discharge, and intellectual, language, or motor, performance at preschool age. We used data from 127 preschoolers, born <33 weeks, all graduates of the William Beaumont Hospital Neonatal Intensive-Care Unit (NICU) in Royal Oak, MI. Cognitive, motor, and language outcomes were evaluated using the Wechsler Preschool and Primary Scales of Intelligence-Revised, Peabody Developmental Scales - 2(nd) Edition, and the Preschool Language Scale - 3(rd) Edition, respectively. Differences between Z-scores at birth and hospital discharge, calculated for three anthropometric measures (head circumference, weight, length), were variables of interest in separate simultaneous multiple regression procedures. We statistically adjusted for sex, socioeconomic status, birth weight, length of hospitalization, perinatal complications, and intrauterine growth. Examination of the relationships between anthropometric indices and outcome measures revealed a significant association between NICU head growth and global intelligence, with the Z-difference score for head circumference accounting for a unique portion of the variance in global intelligence (ηp(2) =.04). Early postnatal head growth is significantly associated with neuropsychological outcome in very preterm-born preschoolers. To conclude, despite its relative brevity, NICU stay, often overlapping with the end of 2(nd) and with the 3(rd) trimester of pregnancy, appears to be a sensitive developmental period for brain substrates underlying neuropsychological functions.


Predictors of HIV disclosure to secondary partners and sexual risk behavior among a high-risk sample of HIV-positive MSM: results from six epicenters in the US.
This study sought to identify predictors of HIV disclosure and serodiscordant unprotected anal intercourse (SDUAI) among HIV-positive men who have sex with men (MSM). Between January 2005 and April 2006, 675 HIV-positive MSM were recruited into the Positive Connections intervention trial held in six US cities with intentional over-sampling of HIV-positive MSM of Color (74%) and men engaging in unprotected anal intercourse (UAI) in the previous year. Baseline survey data showed 30 and 31%, respectively, of participants disclosed to none or some of their secondary sex partners in the last 90 days. Greater disclosure to secondary partners was associated with having fewer sexual partners, being extremely out as MSM, longer HIV diagnosis, knowledge of CD4 count, detectable viral load and being white. Disclosure to all secondary partners was associated with lower SDUAI. Recommendations for prevention for HIV-positive MSM include the promotion of serodisclosure to all secondary partners and increasing comfort with, and outness about, one's sexuality.


Bone and joint tuberculosis in Glasgow: the present situation.
A retrospective survey of bone and joint tuberculosis in the City of Glasgow over the decade 1966-75 has been carried out. Its object is to chart the changing pattern of clinical presentation of this disease, and details of 129 patients are presented. The numbers of children and adolescents are relatively low: Asian immigrants and the elderly are now the higher risk groups. A positive culture was obtained from 60 per cent of the bone and joint lesions and in every case the organism was human Mycobacterium tuberculosis. Tuberculosis complicating a closed fracture is a very rare occurrence; this series includes one further such case. Delay in diagnosis was evident in a significant number (11%) of patients. We must bear in mind the fact that we still have with us not only the great Victorian architecture, but also the great Victorian disease.


Probability of exclusion in paternity testing: time to reassess.
The average exclusion probability is a measure of efficiency in paternity testing; it refers to the a priori ability of a battery of tests to detect paternity inconsistencies. This parameter measures the capacity of the system to detect a false accusation of paternity. Traditionally, this average exclusion probability has been estimated as the probability of excluding a man who is not the father by an inconsistency in at least one of the studied loci. We suggest that this criterion should be corrected, as currently the presumed father is excluded when at least three genetic inconsistencies are found with the child being tested, not just one. This change of criterion has occurred because of the use of microsatellite loci, whose mutation rates are much greater than those of the coding genes used previously in paternity studies. We propose the use of the average probability of exclusion for at least three loci (not only one), as an honest measure of the combined probability of exclusion of several loci, and we propose an algebraic expression to calculate it.


Mechanisms Underlying the Antidepressant Response of Acupuncture via PKA/CREB Signaling Pathway.
Protein kinase A (PKA)/cAMP response element-binding (CREB) protein signaling pathway, contributing to impaired neurogenesis parallel to depressive-like behaviors, has been identified as the crucial factor involved in the antidepressant response of acupuncture. However, the molecular mechanisms associated with antidepressant response of acupuncture, neurogenesis, and depressive-like behaviors ameliorating remain unexplored. The objective was to identify the mechanisms underlying the antidepressant response of acupuncture through PKA signaling pathway in depression rats by employing the PKA signaling pathway inhibitor H89 in in vivo experiments. Our results indicated that the expression of hippocampal PKA-α and p-CREB was significantly downregulated by chronic unpredicted mild stress (CUMS) procedures. Importantly, acupuncture reversed the downregulation of PKA-α and p-CREB. The expression of PKA-α was upregulated by fluoxetine, but not p-CREB. No significant difference was found between Acu and FLX groups on the expression of PKA-α and p-CREB. Interestingly, H89 inhibited the effects of acupuncture or fluoxetine on upregulating the expression of p-CREB, but not PKA-α. There was no significant difference in expression of CREB among the groups. Conclusively, our findings further support the hypothesis that acupuncture could ameliorate depressive-like behaviors by regulating PKA/CREB signaling pathway, which might be mainly mediated by regulating the phosphorylation level of CREB.


Beliefs About Wife Beating Among Social Work Students in Taiwan.
Based on an integrative framework, this study addresses the beliefs that a group of social work students from Taiwan had about wife beating. A self-administered questionnaire was filled out by 790 students (76.5% female, 23.5% male) spanning all 4 years of undergraduate studies. The results show that male students exhibited a greater tendency than their female counterparts to justify wife beating and to hold battered women responsible for violence against them. This tendency was also found among students who held traditional attitudes toward women, students who held patriarchal expectations of marriage, and students who had witnessed interparental violence in childhood. In addition, male students and students with traditional attitudes toward women exhibited the strongest tendency to believe that wives benefit from beating. Conversely, female students expressed more willingness than their male counterparts to help battered women, as did students who held liberal attitudes toward women and students who held egalitarian expectations of marriage. Furthermore, female students and those with liberal attitudes toward women tended to hold violent husbands responsible for their behavior, and to express support for punishing violent husbands. This article concludes with a discussion of the study's limitations and the results' implications for future research on the topic.


Islet cell cytoplasmic antibodies in Macaca nigra.
Islet cell antibodies (ICA) have been measured in mature Macaca nigra. Of 30 nondiabetic monkeys, 26 (87%) were ICA-negative; of 43 monkeys with evidence of mild to severe hormonal or glycemic abnormalities, 39 (91%) were ICA-positive. Pancreatic islets were examined from biopsy and autopsy sections to assess cell deterioration and amyloid infiltration. No ICA were found in 13 of 18 (72%) monkeys with no evidence of amyloid, whereas 30 of 35 (86%) monkeys with islet amyloid and concurrent cell deterioration were ICA-positive. Association of ICA with metabolic and islet abnormalities was significant at P less than or equal to 0.001. ICA were specific for the islet cells in pancreatic sections; plasma preincubated with insulin, glucagon, or acetone extracts of tissues retained their ICA-positive reaction. The relationships of ICA in older monkeys to the islet lesion and to metabolic abnormalities could be relevant to similar situations in aging diabetic persons.