One-step double immunolabeling of mouse interdigitating reticular cells: simultaneous application of pre-formed complexes of monoclonal rat antibody M1-8 with horseradish peroxidase-linked anti-rat immunoglobulins and of monoclonal mouse anti-Ia antibody with alkaline phosphatase-coupled anti-mouse immunoglobulins.
A novel one-step double immunolabeling method was elaborated on the basis of the simultaneous application of preformed molecular complexes of two primary antibodies with their specific secondary antibodies labeled with different enzymes. Treatment with a rat monoclonal antibody (MAb), M1-8, pre-coupled with horseradish peroxidase-linked sheep anti-rat immunoglobulins, and enzyme reaction revealed by the 3-amino-9-ethylcarbazole/hydrogen peroxide reaction, resulted in red-brown intracytoplasmic staining of interdigitating reticular cells in the lymph nodes of Balb/c mice. Another molecular complex, made of mouse anti-Ia MAb with alkaline phosphatase-linked rabbit anti-mouse immunoglobulins, applied at the same time and then developed with naphthol AS-BI-phosphate/fast blue BB as substrate, yielded blue surface staining of this cell type in addition to labeling of B-lymphocytes. The method described provides the possibility of relatively rapid double antigen detection where the binding sites of the secondary antibodies are saturated by the specific primary immunoglobulins. This approach seems to avoid nonspecific binding of primary antibodies to Fc receptors, and the unwanted binding of secondary antibodies with cell surface immunoglobulins on B-lymphocytes or with crossreactive primary antibodies used in the other sequence, if the primary antibodies and the tissue are the same or crossreactive animal species.


Surveillance of Creutzfeldt-Jakob disease in Australia: 2010 update.
Surveillance of all human prion diseases in Australia has been the responsibility of the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) on behalf of the Australian Government Department of Health and Ageing since the Registry's inception in October 1993. The ANCJDR was established in response to the identification of 4 CJD deaths in recipients of human-derived pituitary hormone. The initial brief was to perform focused surveillance for any further iatrogenic cases of CJD; however the scope of surveillance was soon expanded to include all cases of CJD occurring in Australia both prospectively and retrospectively to 1970. The activities of the ANCJDR have evolved from: routine surveillance responsibilities to detailed epidemiological analysis at both national and international levels; expert advice in relation to, and management of, infection control issues; and the provision of a number of tests to aid the diagnosis and classification of CJD in suspect cases. In this brief report, surveillance outcomes are examined with the inclusion of figures from the reporting period of 1 April 2009 to 31 March 2010 and the diagnostic services offered by the ANCJDR are outlined to provide a greater insight into this aspect of the Registry.


Association of hyperphosphatemia with an increased risk of sudden death in patients on hemodialysis: Ten-year outcomes of the Q-Cohort Study.
Sudden death is one of the most common causes of death among patients on hemodialysis. Although hyperphosphatemia is a well-known risk factor for cardiovascular and all-cause deaths, the studies focusing on the relationship between serum phosphate levels and the risk of sudden death are limited. This study aimed to clarify the relationship between serum phosphate levels and the risk of sudden death in patients on hemodialysis. This is a multicenter, longitudinal, and observational study. A total of 3505 patients, registered in the Q-Cohort Study, who underwent maintenance hemodialysis, and were followed up for 10 years, were included. Patients were divided into quartiles on the basis of baseline serum phosphate levels: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 908), 4.9-5.6 mg/dL; and Q4 (n = 874), ≥5.7 mg/dL. Associations between baseline serum phosphate levels and sudden death were analyzed using the Cox proportional hazards model and the Fine-Gray regression model. During the follow-up period, 227 patients died from sudden death. The risk for sudden death was significantly higher in the highest quartile (Q4) than in the lowest quartile (Q1) as the reference group (multivariable-adjusted hazard ratios and 95% confidence intervals: Q1, 1.00; Q2, 1.15 [0.77-1.70], Q3, 1.31 [0.89-1.93], and Q4, 1.72 [1.14-2.59]; hazard ratio for every 1-mg/dL increase in the serum phosphate level, 1.23 [1.09-1.39]; p < 0.001). Hyperphosphatemia is independently associated with an elevated risk of sudden death in patients on hemodialysis.


Prevalence of pulmonary nodules suggestive of metastasis at presentation in dogs with cutaneous or subcutaneous soft tissue sarcoma.
To investigate the prevalence of pulmonary nodules suggestive of metastasis at the time of initial presentation in dogs with cutaneous or subcutaneous soft tissue sarcomas (STSs) and no previous related thoracic diagnostic imaging. 146 client-owned dogs with a cutaneous or subcutaneous STS. Medical records were retrospectively searched to identify dogs with STSs that underwent initial thoracic diagnostic imaging when presented for referral examination between September 2014 and March 2018. Data collected included patient and tumor characteristics. Results were evaluated for dogs grouped on the basis of variables of interest (eg, STS grade, duration, or history). Initial thoracic imaging was performed with CT (131/146 [89.7%]) or radiography (15 [10.3%]). Although the presence or absence of pulmonary nodules suggestive of metastasis on thoracic imaging was uncertain in 9 dogs, it was certain in the remaining 137 dogs, with nodules present in 16 (11.7%) dogs (5/77 [6%] with grade 1 STSs, 2/36 [6%] with grade 2 STSs, and 9/24 [38%] with grade 3 STSs). The odds of such pulmonary nodules being present on initial examination were higher (OR, 10.8 and 3.14, respectively) for dogs with grade 3 STSs (vs grade 1 or 2 STSs) and for dogs with an STS duration > 3 months (versus ≤ 3 months). Results indicated that pulmonary staging was a low-yield diagnostic procedure for dogs with grade 1 or 2 cutaneous or subcutaneous STSs, especially when tumors had been present for ≤ 3 months.


Evaluation of beef eating quality by Irish consumers.
A consumer's decision to purchase beef is strongly linked to its sensory properties and consistent eating quality is one of the most important attributes. Consumer taste panels were held according to the Meat Standards Australia guidelines and consumers scored beef according to its palatability attributes and completed a socio-demographic questionnaire. Consumers were able to distinguish between beef quality on a scale from unsatisfactory to premium with high accuracy. Premium cuts of beef scored significantly higher on all of the scales compared to poorer quality cuts. Men rated grilled beef higher on juiciness and flavour scales compared to women. Being the main purchaser of beef had no impact on rating scores. Overall the results show that consumers can judge eating quality with high accuracy. Further research is needed to determine how best to communicate inherent benefits that are not visible into extrinsic eating quality indicators, to provide the consumer with consistent indications of quality at the point of purchase.


The yeast v-SNARE Vti1p mediates two vesicle transport pathways through interactions with the t-SNAREs Sed5p and Pep12p.
Membrane traffic in eukaryotic cells requires that specific v-SNAREs on transport vesicles interact with specific t-SNAREs on target membranes. We identified a novel Saccharomyces cerevisiae v-SNARE (Vti1p) encoded by the essential gene, VTI1. Vti1p interacts with the prevacuolar t-SNARE Pep12p to direct Golgi to prevacuolar traffic. vti1-1 mutant cells missorted and secreted the soluble vacuolar hydrolase carboxypeptidase Y (CPY) rapidly and reversibly when vti1-1 cells were shifted to the restrictive temperature. However, overexpression of Pep12p suppressed the CPY secretion defect exhibited by vti1-1 cells at 36 degrees C. Characterization of a second vti1 mutant, vti1-11, revealed that Vti1p also plays a role in membrane traffic at a cis-Golgi stage. vti1-11 mutant cells displayed a growth defect and accumulated the ER and early Golgi forms of both CPY and the secreted protein invertase at the nonpermissive temperature. Overexpression of the yeast cis-Golgi t-SNARE Sed5p suppressed the accumulation of the ER form of CPY but did not lead to CPY transport to the vacuole in vti1-11 cells. Overexpression of Sed5p allowed growth in the absence of Vti1p. In vitro binding and coimmunoprecipitation studies revealed that Vti1p interacts directly with the two t-SNAREs, Sed5p and Pep12p. These data suggest that Vti1p plays a role in cis-Golgi membrane traffic, which is essential for yeast viability, and a nonessential role in the fusion of Golgi-derived vesicles with the prevacuolar compartment. Therefore, a single v-SNARE can interact functionally with two different t-SNAREs in directing membrane traffic in yeast.


Trends in the HIV Epidemic Among African American Men Who Have Sex with Men, San Francisco, 2004-2011.
African American men who have sex with men have been disproportionately affected by the HIV epidemic in the United States and remain to this day one of the groups with highest HIV prevalence and incidence. Our goal was to clarify the current state of HIV risk, sexual behaviors, and structural/network-network level factors that affect black MSM's population risk of HIV, enabling the formulation of targeted and up-to-date public health messages/campaigns directed at this vulnerable population. Our approach maximized the use of local data through a process of synthesis and triangulation of multiple independent and overlapping sources of information that are sometimes separately published and often not examined side-by-side. Among African American MSM, we observed stable HIV incidence despite increases in reported individual risk behavior and STDs. An increasing proportion of African American MSM are reporting HIV testing in the past 6 months and seroadaptive behaviors, which may play a role in this observed decline in HIV among MSM in San Francisco, California. Our analysis suggests that currently the HIV epidemic is stable among African American MSM in San Francisco. However, we suggest that the observed stability is due to factors prohibiting expansion of new infections rather than decreasing risks for HIV infection among African American MSM.


Cancer risk factors among Southeast Asian American residents of the U.S. Central Gulf Coast.
This study profiles aggregate-specific cancer risk factors of Southeast Asian Americans residing along the Central Gulf Coast in the United States. An investigator-designed cross-sectional survey was conducted with 332 volunteer Southeast Asian community residents aged 18 years and above. Aggregate-specific cancer risk factors include high prevalence of hepatitis, high smoking and drinking rates in men, extended ultraviolet light exposure without protection, low colorectal and prostate cancer screening rates, and knowledge deficits of cancer and cancer screenings. Based on the study findings, progress toward the targets of the Alabama Comprehensive Cancer Control Plan: 2001-2005 is evaluated and compared to available national data. Implications for public health nursing practice and future research are also addressed. In particular, the study findings underscore the importance of developing culturally tailored interventions to reduce cancer risk factors in this underserved Asian American population.


Effect of an occupational intervention on printing in children with economic disadvantages.
The purpose of this study was to evaluate whether an occupational therapy intervention improved an academic outcome (D'Nealian printing) in a school setting. The study specifically examined improvement in printing skills in economically disadvantaged first graders who were at risk academically and socially. The intervention was based on an occupational framework including biomechanical, sensorimotor, and teaching-learning strategies. The final sample consisted of 59 first-grade children from a low socioeconomic urban elementary school-based health center who were randomly assigned to an occupational therapy intervention or a control condition. In addition to regular academic instruction, the intervention group received 10 weeks of training twice a week for 30-minute sessions. The control group received only regular academic instruction. Subjects were pretested and posttested on the Minnesota Handwriting Test, which assesses legibility, space, line, size, and form (the main variables in this study) as well as speed. Multivariate analysis of variance confirmed that the gain scores in the occupational therapy intervention group were significantly greater than those in the control group. The Hotelling-Lawley Trace value was 0.606, with F(5, 53) = 6.43, p < .0001). The estimated effect size (eta2) was .378, with an observed power of .994. Largest gains for the intervention group were in the areas of space, line, and size. The intervention group demonstrated a significant increase in scores on the posttest of the Minnesota Handwriting Test when compared to the scores of the control group. Occupational intervention was effective in improving the academic outcome of printing in children who are economically disadvantaged.


[The assessment of biological maturation for talent selection - which method can be used?].
The biological maturity status plays an important role in sports, since it influences the performance level and the talent selection in various types of sport. More mature athletes are favorably selected for regional and national squads. Therefore, the biological maturity status should be considered during the talent selection process. In this context, the relative age effect (RAE), which exists when the relative age quarter distribution of selected sports groups shows a biased distribution with an over-representation of athletes born in the first months after the specific cut-off-date for the competition categories, represents another problem in the talent development. From an ethical point of view, discrimination of young talented kids does exist: the relatively younger athletes have little to no chance of reaching the elite level, despite their talents and efforts. The causal mechanisms behind the RAE are still unclear and have to be assessed. In this context, the biological maturation seems to be a possible influential factor for the existence of a RAE in sport, which has to be examined. Several methods for estimating the biological maturity status exist; however, they are often expensive and not practicable. Consequently, the aim of the present study was to assess the concordance of a simple, yet accurate method of estimating biological maturation (prediction equation of age at peak height velocity, APHV) of Mirwald and co-workers, and the gold standard method of estimating skeletal age (SA, the x-ray of the left wrist). In total, 75 Austrian students (40♂, 35♀) aged 10 - 13 years, were examined. Thirty of the participants (17♂, 13♀) were students of a well-known Austrian ski boarding school, and 45 (23♂, 22♀) of a non-sportive secondary modern school of the same region. The participants included in the study had not experienced a rupture of the carpal bones of the left wrist. Parents and participants were informed of the study aims, requirements and risks before providing written informed consent. The study was performed according to the Declaration of Helsinki. The study was approved by the Board for Ethical Questions in Science (Nr.: 2/2014) and the Institutional Ethics Review Boards for Human Research. For the prediction equations, the body height, the body mass and the sitting height were examined 8. The actual CA at time of measurement, and the leg length as the difference between body height and sitting height were calculated. These parameters were used to predict MO as time before or after PHV for boys and girls using the prediction equations of Mirwald et al. 19. According to Malina and Koziel 8, the participants were classified as late, on time (average) or early maturing on the basis of their APHV relative to the sample mean and standard deviation separated by sex. Participants within plus/minus the standard deviation of the mean were considered on time; participants with APHV > mean + standard deviation were classified late, while those with APHV < mean - standard deviation were classified early. An expert in pediatric endocrinology evaluated the x-rays of the left-hand wrist with the Greulich-Pyle-Method for assessing SA, the most widely used method of determining SA 24. The difference between SA and CA were calculated (= difference SA-CA). Consistent with other studies, the participants were divided into three groups according to their maturity status: on time or average maturity status was a SA within ±1 year of CA, late maturating was a SA behind CA of more than 1 year, and early maturating was a SA in advance of CA of more than 1 year 5 19 25. The most accurate method used to compare two methods of measurement is the Bland-Altman plot and the 95 % limits of agreement 26 27 28. Bland-Altman plots of the difference between difference in APHV (from the literature mean) and difference SA-CA (y-axis) and the mean of difference in APHV and difference SA-CA (x-axis) were performed. Approximately 95 % of the points in the plot should lie within the limits; then the concordance between the two methods of measurement is given 28. Additionally, intraclass correlation coefficients (ICC(3,1); two-way-mixed, total agreement) were calculated between difference in APHV and difference SA-CA. Chi²-tests were used to assess the difference in the percentage of pupils classified as on time, early or late maturing between the classifications based on the SA and on APHV, respectively. The level of significance was set at p < 0.05 and for highly significant at p < 0.01. All of the calculations were performed using PASW Statistics V.21.0. Chi²-tests did not show any significant differences (p = 0.404) in the percentage of participants classified as on time, early or late maturing between the two classifications based on SA and on APHV, respectively, neither for the total sample, nor for the two groups ski racers and non-athletes. The Bland-Altman analysis showed that more than 95 % of the points in the plot lie within the limits; consequently, there is concordance between the two methods with regard to estimating biological maturation. The ICC(3,1) statistics showed a highly significant correlation: p = 0.002, ICC (95 % CI) = 0.48 (0.13 - 0.69). The prediction equations to determine APHV seem to be a valid method of assessing the biological maturity status of youths aged 10 - 13 years. The percentage of pupils classified as on time, early or late maturing did not differ significantly between the classifications based on the two methods. Also the Bland-Altman analysis proved the concordance between the two methods. The RAE could be influenced and strengthened by the biological age in sports in which advantages in maturity parameters are important. Athletes born early in the selection year, who are also at the same time advanced in maturity, might be advantaged in the selection process. However, since the prediction equations seem to be valid, this method can be used in the future in the talent selection process in order to not disadvantage late-maturing athletes, which in turn could result in the reduction of the occurrence of the RAE in various types of sports in the future. In talent selection processes the growth spurt and the implemented changes in proportions between core and the extremities are often not considered; although it was shown that during this period, athletes showed poor performances in physical fitness. Since physical fitness is an important criterion in talent selection processes, athletes who go through their individual peak growth spurt at the time of selection have disadvantages due to the diverse proportions. As a consequence, it seems important to know the athlete's APHV in order to consider the variations in physical performance caused by developmental changes. The prediction equations to determine APHV include the leg length and sitting height in order to consider the diverse proportions between core and extremities; hence, this method seems to be accurate and should be implemented in the talent selection process.


Measurements of H-->D-->(gamma-->,pi) and implications for the convergence of the Gerasimov-Drell-Hern integral.
We report new measurements of inclusive pi production from frozen-spin HD for polarized photon beams covering the Delta(1232) resonance. These provide data simultaneously on both H and D with nearly complete angular distributions of the spin-difference cross sections entering the Gerasimov-Drell-Hearn (GDH) sum rule. Recent results from Mainz and Bonn exceed the GDH prediction for the proton by 22 microb, suggesting as yet unmeasured high-energy components. Our pi0 data reveal a different angular dependence than assumed in Mainz analyses and integrate to a value that is 18 microb lower, suggesting a more rapid convergence. Our results for deuterium are somewhat lower than published data, considerably more precise, and generally lower than available calculations.


Antimicrobial resistance in urinary tract pathogens in Canada from 2007 to 2009: CANWARD surveillance study.
From January 2007 to December 2009, an annual Canadian national surveillance study (CANWARD) tested 2,943 urinary culture pathogens for antimicrobial susceptibilities according to Clinical and Laboratory Standards Institute guidelines. The most frequently isolated urinary pathogens were as follows (number of isolates, percentage of all isolates): Escherichia coli (1,581, 54%), enterococci (410, 14%), Klebsiella pneumoniae (274, 9%), Proteus mirabilis (122, 4%), Pseudomonas aeruginosa (100, 3%), and Staphylococcus aureus (80, 3%). The rates of susceptibility to trimethoprim-sulfamethoxazole (SXT) were 78, 86, 84, and 93%, respectively, for E. coli, K. pneumoniae, P. mirabilis, and S. aureus. The rates of susceptibility to nitrofurantoin were 96, 97, 33, and 100%, respectively, for E. coli, enterococci, K. pneumoniae, and S. aureus. The rates of susceptibility to ciprofloxacin were 81, 40, 86, 81, 66, and 41%, respectively, for E. coli, enterococci, K. pneumoniae, P. mirabilis, P. aeruginosa, and S. aureus. Statistical analysis of resistance rates (resistant plus intermediate isolates) by year for E. coli over the 3-year study period demonstrated that increased resistance rates occurred only for amoxicillin-clavulanate (from 1.8 to 6.6%; P < 0.001) and for SXT (from 18.6 to 24.3%; P = 0.02). For isolates of E. coli, in a multivariate logistic regression model, hospital location was independently associated with resistance to ciprofloxacin (P = 0.026) with higher rates of resistance observed in inpatient areas (medical, surgical, and intensive care unit wards). Increased age was also associated with resistance to ciprofloxacin (P < 0.001) and with resistance to two or more commonly prescribed oral agents (amoxicillin-clavulanate, ciprofloxacin, nitrofurantoin, and SXT) (P = 0.005). We conclude that frequently prescribed empirical agents for urinary tract infections, such as SXT and ciprofloxacin, demonstrate lowered in vitro susceptibilities when tested against recent clinical isolates.


Measures of Functioning in Patients With Episodic Migraine: Findings From a Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial With Galcanezumab.
Objective - To evaluate 12-week changes from baseline of 2 disease-specific patient-reported outcome (PRO) measures in adults with migraine treated with galcanezumab, an investigational humanized antibody binding calcitonin gene-related peptide (CGRP), or placebo. Background - Preventing headache-related functional impairment is an important goal of migraine preventive treatment and a measurement target for PROs. Understanding which drugs have the potential to improve patient functioning in addition to preventing migraine headaches is vital to lessening patient burden. Design/Methods - This Phase 2b double-blind, randomized, placebo-controlled study enrolled adults with episodic migraine. Galcanezumab (120 mg subcutaneous injection; n = 60) or placebo (n = 127) was administered every 28 days for 12 weeks. Post hoc secondary analyses were conducted for those who completed 12 weeks of treatment on 2 PROs: The Migraine-Specific Quality of Life Questionnaire (MSQ) v2.1 and the Headache Impact Test™ (HIT-6). Results - Analysis of covariance revealed significant differences in least square mean changes from baseline between galcanezumab and placebo for all MSQ domains including total mean change placebo of 18.63, galcanezumab of 27.36 (95% CI 2.449, 15.008; P-value of .0067); Role Function-Restrictive mean change placebo of 22.40, galcanezumab of 31.92 (95% CI 2.636, 16.518; P-value of .0071); Role Function-Preventive mean change placebo of 13.43, galcanezumab of 19.76 (95% CI 0.476, 12.185; P-value of .0342); and Emotional Function mean change placebo of 16.88, galcanezumab of 26.61 (95% CI 2.789, 16.674; P-value of .0063). At baseline, mean number of migraine headache days (MHDs) did not correlate with MSQ total scores or HIT-6. At 12 weeks post-treatment, MHD correlated with MSQ and HIT-6 scores (all P < .0001). Change in MHD was associated with change in MSQ domains and change in HIT-6 scores (all P < .0001). Conclusions - In comparison with placebo, treatment with galcanezumab was associated with significant functional improvements as reflected by changes in MSQ scores. Change in MHD was associated with improvements in MSQ and reductions in HIT-6 scores, indicating the clinical importance of these changes in relation to PROs that measure function.


Is hospital admission valuable in managing syncope? Results from the STePS study.
The proper way to test the usefulness of hospitalization in syncope patients would be to conduct a randomized controlled trial. However, this approach is characterized by major theoretical and ethical limitations which make this procedure unfeasible. Data from observational studies indirectly show that hospitalization might help reduce the short-term risk of death and adverse events by promptly identifying and treating life-threatening events or conditions. Future research should focus on identifying which patients will benefit from hospitalization. In this regard, we should be able both to correctly risk-stratify patients and to analyze syncope observation units and protocols, which may provide a safe alternative for the evaluation of intermediate-risk patients.


Chemotherapy-Induced Nausea and Vomiting: Incidence and Management in Jordan.
Cancer patients experience a considerable number of symptoms during the course of their disease. Of these symptoms, chemotherapy-induced nausea and vomiting (CINV) is one of the most reported and it increases the cancer burden on patients. This study aims to assess the current status of CINV among Jordanian cancer patients, with regard to its incidence and management. A descriptive cross-sectional survey design was used. The study sample was 185 cancer patients. The mean age of participants was 46.6 years ( SD = 15.5, range = 18-76) and were mainly female (56.8%). The incidence of nausea and vomiting was high at 71.4% and 57.3%, respectively. Most of the patients (89.7%) received a 5-HT3 antagonist therapy combined with corticosteroids therapy (81.1%). This study demonstrated a high incidence rate of all types of CINV, which was undertreated. Antiemetic treatment could be improved by encouraging nurses to introduce the internationally agreed guidelines into their daily clinical practice.


Phenotypic modulation of the mesangium reflected by contractile proteins in diabetes.
The phenotypic change of the mesangial cell is considered to play a pivotal role in the accumulation of extracellular matrix in diabetic nephropathy. This investigation was undertaken to evaluate the expression of the various isoforms of contractile proteins in the streptozocin (STZ)-induced diabetic rat kidney and in renal biopsy specimens from patients with diabetic nephropathy. Specific antibodies to myosin heavy chain isoforms (SM1, SM2, SMemb), caldesmon, and alpha-smooth muscle actin and cDNAs for SMemb were used. Increased expression of SMemb at the mRNA and protein levels was demonstrated at 1 week after STZ administration in the rat. Both levels were increased at 4 weeks. Mesangial staining of caldesmon was observed at 4 weeks and that of alpha-smooth muscle actin at 24 weeks. Immunohistochemical mesangial staining of the contractile proteins was pronounced in patients with diabetic nephropathy in contrast to the trace mesangial staining in normal control subjects. These results indicate that the phenotypic change in mesangial cells occurs in the early stages of diabetes and that several stages in phenotypic changes may exist. Expression of the contractile protein isoforms, especially SMemb, should serve as a new marker for the subsequent glomerular hypertrophy and sclerosis.


Physical activity of mice on dietary sulfur amino acid restriction is influenced by age of diet initiation and biological sex.
Sulfur amino acid restriction (SAAR)-the reduction of methionine and cysteine concentrations either in the diet or by genetic manipulation-promotes health span and extends lifespan, but its effects on physical activity remain unclear. We investigated whether age of diet initiation and biological sex could influence physical activity in mice fed either a control diet (CF, 0.86% methionine w/w) or SAAR (0.12% methionine w/w). Quadriceps femoris muscle mass is smaller in SAAR than in CF mice. Young mice fed a chronic SAAR diet at 8 weeks of age exhibited improved wire hang and running wheel activities compared to young CF mice, while aged mice showed comparable results. The effects of chronic SAAR on physical activity was mildly influenced by sex as observed in middle-aged male SAAR mice who showed minor improvements than CF males while middle-aged females displayed no discernible effects. Muscle mass is minimally affected by changes in markers of protein synthesis, autophagy and atrophy. Improvements to physical activity in young SAAR mice could be partially attributed to increased skeletal muscle mitochondrial activity. Furthermore, SAAR in C2C12 myotubes increased citrate synthase protein expression and enhanced succinyl dehydrogenase enzyme activity compared to CF myotubes. Overall, our data reveal that SAAR can improve mouse physical activity without compromising muscle proteostasis. This is partially due to enhanced mitochondrial activity, but the effects are influenced by age of diet initiation and sex.


[Neural stem cell marker MSI-1 expression in rat telencephalon].
The aim of the study was to examine the distribution of cells expressing Msi-1 (Musashi-1) protein which is believed to be a marker of neural stem cells, in rat telencephalon. These cells were found to be concentrated in the subventricular proliferative zone and diffusely scattered in striatum and hippocampus. Moreover, neurons with extensive Msi-1 reaction were found in habenular nuclei. The data obtained are not in full agreement with current views on the localization of neural stem cells in the brain.


A new mathematical model for chemotactic bacterial colony growth.
A new continuum model for the growth of a single species biofilm is proposed. The geometry of the biofilm is described by the interface between the biomass and the surrounding liquid. Nutrient transport is given by the solution of a semi-linear Poisson equation. In this model we study the morphology of a chemotactic bacterial colony, which grows in the direction of increasing nutrient concentration. Numerical simulations using the level set method and finite difference schemes are presented. The results show rich heterogeneous morphology.


Pten signaling in gliomas.
In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas.


Use of sodium taurocholate to enhance spore recovery on a medium selective for Clostridium difficile.
Isolation of Clostridium difficile from fecal specimens has been facilitated by the development of a selective and differential medium, cefoxitin-cycloserinefructose agar (CCFA). We substituted 0.1% sodium taurocholate for the 2.5% egg yolk in CCFA and compared the growth of 15 isolates of C. difficile on the resulting medium with growth on conventional CCFA. The taurocholate-containing medium (TCCFA) quantitatively recovered vegetative forms of C. difficile in the same numbers as CCFA medium. Recovery of spores was a mean 1.7 log(10) higher on TCCFA than on CCFA. Thirty-six of 60 patient stool specimens growing C. difficile gave a heavier growth on TCCFA than on CCFA, and 9 failed to yield C. difficile on CCFA. TCCFA detected spores of 75 colony-forming units per ml from artificially inoculated fecal specimens when conventional stool culturing techniques were used. Fluorescence of colonies of C. difficile was more intense on TCCFA than on CCFA. TCCFA was simpler to prepare and, overall, was more sensitive than CCFA.


Sexually dimorphic expression of estrogen receptors, but not of androgen receptors in human fetal external genitalia.
Using immunohistochemistry, we investigated the distribution of androgen receptors (AR) and estrogen receptors (ER) in the external genitalia of human male and female fetuses at 18-22 weeks gestation. In the male, the corpus cavernosum, and the stroma of the inner prepuce, scrotum, and periphery of the glans were AR rich. The corpus spongiosum, a well defined structure that surrounds the penile urethra in the neonate, was not yet developed at this fetal age, but the periurethral mesenchyme (presumably the primordium of the corpus spongiosum) was intensely AR positive. In contrast, the epithelium of the preputial skin, penile shaft skin, and scrotal skin were AR negative. The urethral plate in the distal glans was nonpatent and was filled with a meshwork of AR-negative epithelial cells. Canalization of the AR-negative urethral plate was observed to begin where it joined the patent distal penile urethra, which was AR positive. Male external genitalia lacked ER, ruling out a direct influence of maternal estrogen on male genital development. Interestingly, female external genital structures contained AR, and the distribution of AR and staining intensity were strikingly similar to that in the male. The distribution of AR in the female provides a mechanism to explain how female external genitalia become masculinized if exposed to elevated androgen levels in the first trimester. Moreover, it implies that in the male, these AR indeed mediate androgen-dependent male external genital development. Female fetal external genitalia were also intensely ER positive in the stroma of the labia minora and in the periphery of the glans and inner prepuce. The presence of ER suggests that maternal estrogen may play a direct role in female external genital development, challenging the widely held view that female external genital development is passive because it can occur in the absence of fetal gonadal hormones.


Filter radiometer: the selective interferometer.
This paper describes a new type of filter radiometer-the Selective Interferometer Filter (SIF)-which has extremely high selectivity to the radiation from a given gas. The basic device is a double output Michelson interferometer, with mirrors fixed at zero geometrical path difference. It is shown that if a cell containing a gas is placed in each of the arms, the ensemble can be made to operate as a highly selective filter, passing radiation only very near the center frequencies corresponding to the absorption lines of this gas. This is a result of direct absorption effects and of the variation of refractive index with frequency and consequent modification of the optical path difference of the two arms of the interferometer. The device may, therefore, after calibration be operated as a highly selective ir radiometer; and a feature of importance in atmospheric and space applications is that it requires no internal moving parts to achieve this selectivity. Details of the device are presented, and a thorough examination of the practical realization of it is given.


Basic and aromatic residues in the C-terminal domain of PriC are involved in ssDNA and SSB binding.
In bacterial organisms, the oriC-independent primosome plays an essential role in replication restart after dissociation of the replication DNA-protein complex following DNA damage. PriC is a key protein component in the oriC-independent replication restart primosome. Our previous study suggested that PriC was divided into an N-terminal domain and a C-terminal domain, with the latter domain being the major contributor to single-stranded DNA (ssDNA) binding capacity. In this study, we prepared several PriC mutants in which basic and aromatic amino acid residues were mutated to alanine. Five of these residues, Arg107, Lys111, Phe118, Arg121 and Lys165 in the C-terminal domain, were shown to be involved in ssDNA binding. Moreover, we evaluated the binding of the PriC mutants to the ssDNA-binding protein (SSB) complex. Five residues, Phe118, Arg121, Arg129, Tyr152 and Arg155 in the C-terminal domain of PriC, were shown to be involved in SSB binding in the presence of ssDNA. On the basis of these results, we propose a structural model of the C-terminal domain of PriC and discuss how the interactions of PriC with SSB and ssDNA may contribute to the regulation of PriC-dependent replication restart.


On 'natural' learning and pruning in multi-layered perceptrons.
Several studies have shown that natural gradient descent for on-line learning is much more efficient than standard gradient descent. In this article, we derive natural gradients in a slightly different manner and discuss implications for batch-mode learning and pruning, linking them to existing algorithms such as Levenberg-Marquardt optimization and optimal brain surgeon. The Fisher matrix plays an important role in all these algorithms. The second half of the article discusses a layered approximation of the Fisher matrix specific to multilayered perceptrons. Using this approximation rather than the exact Fisher matrix, we arrive at much faster "natural" learning algorithms and more robust pruning procedures.


High prevalence of Entamoeba moshkovskii in a Tanzanian HIV population.
Entamoeba moshkovskii and Entamoeba dispar are microscopically indistinguishable from the pathogenic species Entamoeba histolytica. There are limited data on the prevalence of these commensal infections from Africa. We utilized PCR and antigen detection to evaluate the carriage rate of E. moshkovskii, E. dispar, and E. histolytica infection in stool from a cohort of HIV-suspected or confirmed inpatients from Tanzania. E. histolytica was detected by ELISA in 4% (5/118) while E. moshkovskii and E. dispar were detected by PCR in 13% (18/136) and 5% (7/136) of individuals, respectively (P<0.05). Supporting their commensal nature, neither E. moshkovskii nor E. dispar infection was statistically associated with HIV status, CD4 count, or the presence of diarrhea. These data suggest E. moshkovskii is a common infection in HIV-infected individuals in northern Tanzania and supports the concept that the microscopic detection of Entamoeba should be interpreted cautiously.


Identification and Management of Acute Neuromuscular Respiratory Failure in the ICU.
Respiratory failure is a common and potentially life-threatening complication of neuromuscular diseases. Prompt recognition and accurate diagnosis of new or worsening chronic neuromuscular disease have important clinical management and prognostic implications. In this article, we present an approach to the acute presentation of undifferentiated neuromuscular respiratory failure in the ICU and guidance for determination and respiratory management of the underlying disorder.


Are all Granulomatous Mastitis Cases Tuberculous?: A Study on the Role of Cytology in Evaluation of Granulomatous Mastitis.
Granulomatous mastitis is a rare inflammatory condition of the breast clinically mimicking breast carcinoma and pyogenic abscess, thereby creating a diagnostic dilemma. Tuberculous mastitis is a rare clinical entity accounting for approximately 3% of all mammary lesions. All cases of granulomatous mastitis diagnosed cytologically over a period of 3 years were evaluated to ascertain the cases with tuberculous etiology. Fine needle aspiration cytology of the breast lump was performed and all the cytological parameters were evaluated. Wherever histopathology was available, the diagnosis was confirmed on Hematoxylin & Eosin stained sections and the Ziehl Neelsen (ZN) stain was applied. A total of 10 cases of granulomatous mastitis were diagnosed on cytology during the 3-year period. On cytological smears, four cases showed presence of ill-formed granulomas and one case had scattered epithelioid histiocytes; however, the rest of the cases had well-formed granulomas. Finally, four out of ten cases were labeled as tuberculous mastitis based on the ZN stain/Tuberculosis-Polymerase chain reaction (TB-PCR) and the other six cases were granulomatous mastitis. Cytology plays a significant role in the diagnosis of granulomatous mastitis. This study re-emphasizes the role of the cytopathologist in the accurate and early diagnosis of these lesions so that unnecessary surgery can be avoided, and also highlights the fact that all granulomatous mastitis cases are not tuberculous.


The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial.
Malignant pleural mesothelioma is usually a fatal cancer for which operation has been the mainstay of treatment because chemotherapy and radiation are relatively ineffective. The choice of operation for malignant pleural mesothelioma remains controversial. Extrapleural pneumonectomy has been advocated because it allows complete removal of gross tumor and can be associated with long-term survival. To evaluate extrapleural pneumonectomy, we conducted a prospective multiinstitutional trial in patients with biopsy-proved previously untreated malignant pleural mesothelioma. Criteria for extrapleural pneumonectomy were (1) potentially completely resectable unilateral disease by computed tomography scan, (2) predicted postresection forced expiratory volume in 1 second greater than 1 L/sec, and (3) no other major medical problems. Patients who were not candidates for extrapleural pneumonectomy had a more limited operation with or without adjuvant therapy or had nonsurgical treatment. From September 1985 to June 1988 83 eligible patients (64 male, 19 female) were entered. The mean age for all patients was 59.7 years. Only 20 of the 83 patients (24%) underwent extrapleural pneumonectomy. Three of these 20 patients (15%) died postoperatively. The recurrence-free survival was significantly longer for the patients undergoing extrapleural pneumonectomy than for the other two groups (p = 0.03), but there was no difference in overall survival among the three groups. In univariate analyses, epithelial versus sarcomatoid and mixed histologic findings and platelet count less than 400,000 were associated with a better overall survival (p = 0.02), and performance status (Karnofsky less than 80) was predictive of recurrence (p = 0.02). In a multivariate analysis, histologic findings, sex, age, extrapleural pneumonectomy, weight loss, and performance status all had no significant impact on survival. Extrapleural pneumonectomy was associated with a greater likelihood of relapse in distant sites than were limited operation and nonsurgical treatment. We conclude that (1) only a small proportion of all patients with malignant pleural mesothelioma are candidates for extrapleural pneumonectomy, (2) extrapleural pneumonectomy carries a significant operative mortality and does not seem to improve overall survival compared with more conservative forms of treatment, (3) extrapleural pneumonectomy alters the patterns of relapse, and (4) factors previously thought to have an impact on survival in other series did not affect outcome in this trial.


The molecular biology of rotaviruses. VI. RNA species-specific terminal conservation in rotaviruses.
The use of T1 RNase fingerprinting of terminally labelled genomic double-stranded RNA species from various rotavirus isolates, to analyse the near terminal G-residue positions, has revealed an RNA species-specific fingerprint pattern covering approximately 40 nucleotides at the termini. These RNA species-specific terminal fingerprint patterns were found to be conserved in both rotavirus RNAs isolated from various animal species, and in isolates from a single animal species where gross divergence of internal RNA sequence for a particular RNA species was evident. This conservation of near terminal G-residue positions suggests that, internal to the short regions of absolute terminal sequence conservation that we have previously shown to be present on all rotavirus RNA species, there is a region of conserved sequence which is specific for a particular RNA species.


Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress.
Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.


Evidence of developmental niche construction in dung beetles: effects on growth, scaling and reproductive success.
Niche construction occurs when organisms modify their environments and alter selective conditions through their physiology and behaviours. Such modifications can bias phenotypic variation and enhance organism-environment fit. Yet few studies exist that experimentally assess the degree to which environmental modifications shape developmental and fitness outcomes, how their influences may differ among species and identify the underlying proximate mechanisms. Here, we experimentally eliminate environmental modifications from the developmental environment of Onthophagus dung beetles. We show that these modifications (1) differentially influence growth among species, (2) consistently shape scaling relationships in fitness-related traits, (3) are necessary for the maintenance of sexual dimorphism, (4) influence reproductive success among females of at least one species and (5) implicate larval cultivation of an external rumen as a possible mechanism for environmental modification. Our results present evidence that Onthophagus larvae engage in niche construction, and that this is a fundamental component of beetle development and fitness.


Mitogen-Activated Protein (MAP) kinases in plant metal stress: regulation and responses in comparison to other biotic and abiotic stresses.
Exposure of plants to toxic concentrations of metals leads to disruption of the cellular redox status followed by an accumulation of reactive oxygen species (ROS). ROS, like hydrogen peroxide, can act as signaling molecules in the cell and induce signaling via mitogen-activated protein kinase (MAPK) cascades. MAPK cascades are evolutionary conserved signal transduction modules, able to convert extracellular signals to appropriate cellular responses. In this review, our current understanding about MAPK signaling in plant metal stress is discussed. However, this knowledge is scarce compared to research into the role of MAPK signaling in the case of other abiotic and biotic stresses. ROS production is a common response induced by different stresses and undiscovered analogies may exist with metal stress. Therefore, further attention is given to MAPK signaling in other biotic and abiotic stresses and its interplay with other signaling pathways to create a framework in which the involvement of MAPK signaling in metal stress may be studied.


Lipoprotein lipase activities in adipose tissues and muscle in the obese Zucker rat.
Activity of lipoprotein lipase (LPL) was determined in whole adipose tissue and isolated adipocytes, and in heart and skeletal muscle that contained predominantly red or white fiber types in lean and obese Zucker rats. In rats of both sexes at 9-11 and 26-30 wk of age, no differences were observed between lean and obese rats when LPL activity of the perirenal (PR), subcutaneous (SC), and mesenteric (M) adipose tissues was expressed per millimole of tissue triglyceride. Within each sex, data relating the LPL content of isolated adipocytes to cell size was a linear function in which data for lean and obese rats fell on the same regression line. Measurement of the distribution of adipose tissue LPL activity between adipocytes and other tissue constituents showed no differences between lean and obese rats, a finding that is inconsistent with the hypothesis that obesity results in part by an alteration in adipose tissue enzyme distribution. Activity of LPL in the myocardium and red fiber types in the younger group of both sexes showed significant decreases in obese animals. This was also true for white fibers of males but not females. No differences in heart or muscle LPL between lean and obese rats were observed in the older group of either sex.


Alcohol and laryngeal cancer: an update.
Epidemiological studies provide definite evidence that alcohol drinking is an independent risk factor for laryngeal cancer. This risk increases with the amount of alcohol consumed: in a meta-analysis of 20 studies conducted in North America, Europe, Japan and Korea the multivariate relative risks were about 2 for 50 g ( approximately 4 drinks)/day and about 4 for 100 g/day compared to nondrinkers, in the absence of evidence of a threshold. Genetic polymorphisms in the alcohol-metabolizing enzyme aldehyde dehydrogenases have been found to be associated with upper aerodigestive tract cancer, including the larynx. Further, the risk increases by concomitant tobacco smoking, each agent approximately multiplying the effect of the other. In the absence of smoking, the relative and absolute risks are small for moderate alcohol consumption, but there is an increased risk for elevated alcohol consumption. After stopping drinking, some fall in risk becomes apparent only in the long term. The supraglottis is more closely related to alcohol consumption, as compared to the glottis/subglottis. In various populations, the most commonly used alcoholic beverage appears to be the one most strongly associated with laryngeal cancer risk, suggesting that no meaningful difference exists for different types of alcoholic beverages.


Hybrid atomistic-coarse-grained treatment of thin-film lubrication. II.
A new hybrid atomistic-coarse-grained (HACG) treatment of reversible processes in multiple-scale systems involving fluid-solid interfaces was tested through isothermal-isobaric Monte Carlo simulations of the quasistatic shearing of a model two-dimensional lubricated contact comprising two planar Lennard-Jones solid substrates that sandwich a softer Lennard-Jones film. Shear-stress profiles (plots of shear stress T(yx) versus lateral displacement of the substrates) obtained by the HACG technique, which combines an atomistic description of the interfacial region with a continuum description of regions well removed from the interface, are compared with "exact" profiles (obtained by treating the whole system at the atomic scale) for a selection of thermodynamic states that correspond to systematic variations of temperature, load (normal stress), film-substrate coupling strength, and film thickness. The HACG profiles are in excellent agreement overall with the exact ones. The HACG scheme provides a reliable description of quasistatic shearing under a wide range of conditions. It is demonstrated that the elastic response of the remote regions of the substrates can have a significant impact on the static friction profile (plot of maximum magnitude of T(yx) versus load).


New antiarrhythmic agents for atrial fibrillation and atrial flutter: United States drug market response as an indicator of acceptance.
To determine how well dofetilide and Betapace AF (sotalol, approved solely for atrial fibrillation and atrial flutter), with their detailed dosing and monitoring guidelines for safety, were accepted into clinical practice during the 2 calendar years after their introduction. We reviewed the number of new, refill, and total prescriptions of all antiarrhythmic agents in the United States from April 2000-December 2001 to assess use of dofetilide and Betapace AF in the drug market. Both were prescribed very infrequently throughout the study period. In addition, the infrequent reported use of these drugs for patients with atrial fibrillation and flutter indicated poor acceptance of these agents by prescribing physicians. We speculated that the restricted distribution and required educational program for dofetilide, as well as the availability of generic sotalol products, may have discouraged physicians from prescribing both dofetilide and Betapace AE CONCLUSION: A common goal for both the dofetilide risk-management program and the creation of a sotalol product indicated solely for atrial fibrillation and atrial flutter was to provide safer treatment for patients with these arrhythmias. Unfortunately, limited penetration of dofetilide and Betapace AF into the U.S. market suggests that drugs without a risk-management program or detailed dosing guidelines were more likely than dofetilide or Betapace AF to be selected for treatment of atrial fibrillation and atrial flutter.


Molecular cloning and biochemical characterization of rabbit factor XI.
Human factor XI, a plasma glycoprotein required for normal haemostasis, is a homodimer (160 kDa) formed by a single interchain disulphide bond linking the Cys-321 of each Apple 4 domain. Bovine, porcine and murine factor XI are also disulphide-linked homodimers. Rabbit factor XI, however, is an 80 kDa polypeptide on non-reducing SDS/PAGE, suggesting that rabbit factor XI exists and functions physiologically either as a monomer, as does prekallikrein, a structural homologue to factor XI, or as a non-covalent homodimer. We have investigated the structure and function of rabbit factor XI to gain insight into the relation between homodimeric structure and factor XI function. Characterization of the cDNA sequence of rabbit factor XI and its amino acid translation revealed that in the rabbit protein a His residue replaces the Cys-321 that forms the interchain disulphide linkage in human factor XI, explaining why rabbit factor XI is a monomer in non-reducing SDS/PAGE. On size-exclusion chromatography, however, purified plasma rabbit factor XI, like the human protein and unlike prekallikrein, eluted as a dimer, demonstrating that rabbit factor XI circulates as a non-covalent dimer. In functional assays rabbit factor XI and human factor XI behaved similarly. Both monomeric and dimeric factor XI were detected in extracts of cells expressing rabbit factor XI. We conclude that the failure of rabbit factor XI to form a covalent homodimer due to the replacement of Cys-321 with His does not impair its functional activity because it exists in plasma as a non-covalent homodimer and homodimerization is an intracellular process.


RhoA Activation Sensitizes Cells to Proteotoxic Stimuli by Abrogating the HSF1-Dependent Heat Shock Response.
The heat shock response (HSR) is an ancient and highly conserved program of stress-induced gene expression, aimed at reestablishing protein homeostasis to preserve cellular fitness. Cells that fail to activate or maintain this protective response are hypersensitive to proteotoxic stress. The HSR is mediated by the heat shock transcription factor 1 (HSF1), which binds to conserved heat shock elements (HSE) in the promoter region of heat shock genes, resulting in the expression of heat shock proteins (HSP). Recently, we observed that hyperactivation of RhoA conditions cardiomyocytes for the cardiac arrhythmia atrial fibrillation. Also, the HSR is annihilated in atrial fibrillation, and induction of HSR mitigates sensitization of cells to this disease. Therefore, we hypothesized active RhoA to suppress the HSR resulting in sensitization of cells for proteotoxic stimuli. Stimulation of RhoA activity significantly suppressed the proteotoxic stress-induced HSR in HL-1 atrial cardiomyocytes as determined with a luciferase reporter construct driven by the HSF1 regulated human HSP70 (HSPA1A) promoter and HSP protein expression by Western Blot analysis. Inversely, RhoA inhibition boosted the proteotoxic stress-induced HSR. While active RhoA did not preclude HSF1 nuclear accumulation, phosphorylation, acetylation, or sumoylation, it did impair binding of HSF1 to the hsp genes promoter element HSE. Impaired binding results in suppression of HSP expression and sensitized cells to proteotoxic stress. These results reveal that active RhoA negatively regulates the HSR via attenuation of the HSF1-HSE binding and thus may play a role in sensitizing cells to proteotoxic stimuli.


Stimulus-dependent pacemaker activity in the distal canine lower esophageal sphincter.
Electrical and mechanical properties of the distal canine lower esophageal sphincter were studied in vitro to investigate possible means of inducing pacemaker activity. Both direct excitation and block of potassium conductance were investigated. The acetylcholine analog, carbachol, induced tissue depolarization and increase in tone but no electrical slow waves. Tetraethylammonium (TEA) chloride induced depolarization and evoked continuous spiking activity and increase in tone. BaCl did not depolarize the tissue but low amplitude spiking activity developed and increased tone. The putative potassium channel blocker, aminacrine at 2 X 10(-4) M, induced electrical slow wave activity in the distal lower esophageal sphincter, with or without superimposed spikes, accompanied by phasic contractile activity. This activity closely resembled the spontaneous pacemaker activity observed previously in the proximal lower esophageal sphincter. The aminacrine-induced activity was abolished by calcium influx blockers. Aminacrine, but not TEA or BaCl, abolished the nonadrenergic nerve-mediated inhibitory junction potentials. In conclusion, block of inhibitory innervation, and induction of electrical slow waves as a control mechanism for phasic contractile activity, seems to require blockade of an aminacrine- but not TEA-sensitive potassium conductance.


The 2019 n2c2/OHNLP Track on Clinical Semantic Textual Similarity: Overview.
Semantic textual similarity is a common task in the general English domain to assess the degree to which the underlying semantics of 2 text segments are equivalent to each other. Clinical Semantic Textual Similarity (ClinicalSTS) is the semantic textual similarity task in the clinical domain that attempts to measure the degree of semantic equivalence between 2 snippets of clinical text. Due to the frequent use of templates in the Electronic Health Record system, a large amount of redundant text exists in clinical notes, making ClinicalSTS crucial for the secondary use of clinical text in downstream clinical natural language processing applications, such as clinical text summarization, clinical semantics extraction, and clinical information retrieval. Our objective was to release ClinicalSTS data sets and to motivate natural language processing and biomedical informatics communities to tackle semantic text similarity tasks in the clinical domain. We organized the first BioCreative/OHNLP ClinicalSTS shared task in 2018 by making available a real-world ClinicalSTS data set. We continued the shared task in 2019 in collaboration with National NLP Clinical Challenges (n2c2) and the Open Health Natural Language Processing (OHNLP) consortium and organized the 2019 n2c2/OHNLP ClinicalSTS track. We released a larger ClinicalSTS data set comprising 1642 clinical sentence pairs, including 1068 pairs from the 2018 shared task and 1006 new pairs from 2 electronic health record systems, GE and Epic. We released 80% (1642/2054) of the data to participating teams to develop and fine-tune the semantic textual similarity systems and used the remaining 20% (412/2054) as blind testing to evaluate their systems. The workshop was held in conjunction with the American Medical Informatics Association 2019 Annual Symposium. Of the 78 international teams that signed on to the n2c2/OHNLP ClinicalSTS shared task, 33 produced a total of 87 valid system submissions. The top 3 systems were generated by IBM Research, the National Center for Biotechnology Information, and the University of Florida, with Pearson correlations of r=.9010, r=.8967, and r=.8864, respectively. Most top-performing systems used state-of-the-art neural language models, such as BERT and XLNet, and state-of-the-art training schemas in deep learning, such as pretraining and fine-tuning schema, and multitask learning. Overall, the participating systems performed better on the Epic sentence pairs than on the GE sentence pairs, despite a much larger portion of the training data being GE sentence pairs. The 2019 n2c2/OHNLP ClinicalSTS shared task focused on computing semantic similarity for clinical text sentences generated from clinical notes in the real world. It attracted a large number of international teams. The ClinicalSTS shared task could continue to serve as a venue for researchers in natural language processing and medical informatics communities to develop and improve semantic textual similarity techniques for clinical text.


Delivery of nucleic acids using nanomaterials.
The increasing number of approved nucleic acid therapeutics demonstrates the potential for the prevention and treatment of a broad spectrum of diseases. This trend underscores the significant impact and promise of nucleic acid-based treatments in the field of medicine. Nevertheless, employing nucleic acids as therapeutics is challenging due to their susceptibility to degradation by nucleases and their unfavorable physicochemical characteristics that hinder delivery into cells. Appropriate vectors play a pivotal role in improving nucleic acid stability and delivering nucleic acids into specific cells. The maturation of delivery systems has led to breakthroughs in the development of therapeutics based on nucleic acids such as DNA, siRNA, and mRNA. Non-viral vectors have gained prominence among the myriad of nanomaterials due to low immunogenicity, ease of manufacturing, and simplicity of cost-effective, large-scale production. Here, we provide an overview of the recent advancements in nanomaterials for nucleic acid delivery. Specifically, we give a detailed introduction to the characteristics of polymers, lipids, and polymer-lipid hybrids, and provide comprehensive descriptions of their applications in nucleic acid delivery. Also, biological barriers, administration routes, and strategies for organ-selective delivery of nucleic acids are discussed. In summary, this review offers insights into the rational design of next-generation delivery vectors for nucleic acid delivery.


Production of a heparin-binding angiogenesis factor by the embryonic kidney.
Embryonic mouse kidneys induce angiogenesis when transplanted on the quail chorioallantoic membrane (Ekblom, P., H. Sariola, M. Karkinen, and L. Saxén, 1982, Cell Differ., 11:35-39). In these experiments all blood vessels were derived from the quail host, suggesting that kidney endothelium is derived from outside blood vessels. We have now analyzed whether kidney angiogenesis is regulated by kidney-derived soluble factors that stimulate the growth of new blood vessels. In the rabbit cornea, 11-d embryonic kidneys induced angiogenesis, whereas uninduced 11-d kidney mesenchymes did not. To characterize and purify this activity from an embryonic organ, we dissected between 600 and 1,000 14-17-d-old embryonic mouse kidneys for each purification experiment. Growth factor activity for capillary endothelial cells was found to bind to heparin-Sepharose and eluted at 0.9-1.1 M sodium chloride. Gel filtration revealed a molecular weight of 16,000-20,000 of this factor. A major 18,000-mol-wt band was seen after gel electrophoresis and silver staining of partially purified growth factor material. The chromatographed factor is mitogenic for endothelial cells but not for smooth muscle cells and stimulates angiogenesis in vivo in the rabbit cornea. Adult kidneys contained two heparin-binding endothelial cell growth factors. The differentiation-dependent production of an angiogenesis factor by the embryonic kidney suggests an important role of angiogenesis in organogenesis.


The association of chest radiographic findings and severity scoring with clinical outcomes in patients with COVID-19 presenting to the emergency department of a tertiary care hospital in Pakistan.
While chest x-rays (CXRs) represent a cost-effective imaging modality for developing countries like Pakistan, their utility for the prognostication of COVID-19 has been minimally explored. Thus, we describe the frequency and distribution of CXR findings, and their association with clinical outcomes of patients with COVID-19. All adult (≥ 18 years) patients presenting between 28th February-31st May to the emergency department of a tertiary care hospital in Pakistan, who were COVID-19 positive on RT-PCR with CXR done on presentation, were included. A CXR Severity Score (CXR-SS) of 0-8 was used to quantify the extent of pulmonary infection on CXR, with a score of 0 being negative and 1-8 being positive. The patients' initial CXR-SS and their highest CXR-SS over the hospital course were used for analysis, with cut-offs of 0-4 and 5-8 being used to assess association with clinical outcomes. A total of 150 patients, with 76.7% males and mean age 56.1 years, were included in this study. Initial CXR was positive in 80% of patients, and 30.7% of patients had an initial CXR-SS between 5-8. The mortality rate was 16.7% and 30.6% patients underwent ICU admission with intubation (ICU-Int). On multivariable analysis, initial CXR-SS (1.355 [1.136-1.616]) and highest CXR-SS (1.390 [1.143-1.690]) were predictors of ICU-Int, and ICU-Int was independently associated with both initial CXR-SS 5-8 (2.532 [1.109-5.782]) and highest CXR-SS 5-8 (3.386 [1.405-8.159]). Lastly, age (1.060 [1.009-1.113]), initial CXR-SS (1.278 [1.010-1.617]) and ICU-Int (5.047 [1.731-14.710]), were found to be independent predictors of mortality in our patients. In a resource-constrained country like Pakistan, CXRs may have valuable prognostic utility in predicting ICU admission and mortality. Additional research with larger patient samples is needed to further explore the association of CXR findings with clinical outcomes.


Altered small-world brain networks in temporal lobe in patients with schizophrenia performing an auditory oddball task.
The functional architecture of the human brain has been extensively described in terms of complex networks characterized by efficient small-world features. Recent functional magnetic resonance imaging (fMRI) studies have found altered small-world topological properties of brain functional networks in patients with schizophrenia (SZ) during the resting state. However, little is known about the small-world properties of brain networks in the context of a task. In this study, we investigated the topological properties of human brain functional networks derived from fMRI during an auditory oddball (AOD) task. Data were obtained from 20 healthy controls and 20 SZ; A left and a right task-related network which consisted of the top activated voxels in temporal lobe of each hemisphere were analyzed separately. All voxels were detected by group independent component analysis. Connectivity of the left and right task-related networks were estimated by partial correlation analysis and thresholded to construct a set of undirected graphs. The small-worldness values were decreased in both hemispheres in SZ. In addition, SZ showed longer shortest path length and lower global efficiency only in the left task-related networks. These results suggested small-world attributes are altered during the AOD task-related networks in SZ which provided further evidences for brain dysfunction of connectivity in SZ.


Sexual dimorphism of messenger RNA isolated from neonatal rat brain.
The rat brain is sexually dimorphic with respect to structure and function, and there is evidence that these differences are effected in the fetus through changes in protein synthesis, some of which may result from the intervention of gonadal steroids. To investigate this, messenger RNA (mRNA) from the limbic system and cerebellum of neonatal rats was prepared, translated in a rabbit reticulocyte system in vitro and the products were analysed by two-dimensional electrophoresis and fluorography. Some of the results were further analysed using image analysis. There was a striking sexual dimorphism in the patterns of incorporation of [35S]methionine into proteins using mRNA from the limbic system, in that groups of proteins were apparently present in male-but not in female-derived fluorograms and vice versa. One protein, tentatively identified from its coordinates as alpha-tubulin, was more abundant in male-derived fluorograms. Although there were no clear-cut qualitative sex differences using mRNA derived from the cerebellum, that derived from the male cerebellum appeared to be consistently more active. These results provide direct evidence for a sexual dimorphism at the transcriptional level in the neonatal limbic system of the rat.


An African-American family with dystonia.
The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African-Americans or reports of THAP1 mutations in African-Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African-Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African-Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration.


Surface display on gram positive bacteria.
Heterologous surface display on Gram-positive bacteria was first described almost a decade ago and has since then developed into an active research area. Gram-positive bacterial surface display has today found a range of applications, in immunology, microbiology and biotechnology. Live bacterial vaccine delivery vehicles are being developed through the surface display of selected foreign antigens on the bacterial surfaces. In this field, "second generation" vaccine delivery vehicles are at present being generated by the addition of mucosal targeting signals through co-display of adhesins, in order to achieve targeting of the live bacteria to immunoreactive sites to thereby increase immune responses. Engineered Gram-positive bacteria are further being evaluated as novel microbial biocatalysts with heterologous enzymes immobilized as surface exposed on the bacterial cell surface. A discussion has started whether bacteria can find use as new types of whole-cell diagnostic devices since single-chain antibodies and other variants of tailor-made binding proteins can be displayed on bacteria. Bacteria with increased binding capacity for certain metal ions can be created and potential environmental or biosensor applications for such recombinant bacteria as biosorbents are being discussed. This article explains the basis of Gram-positive bacterial surface display, and discusses current uses and possible future trends of this emerging technology.


Predisposing factors for positive D-Xylose breath test for evaluation of small intestinal bacterial overgrowth: a retrospective study of 932 patients.
To investigate, in the largest cohort to date, patient characteristics and associated risk factors for developing small intestinal bacterial overgrowth (SIBO) using the D-Xylose breath test (XBT). We performed a retrospective cross-sectional study to analyze patient characteristics who underwent the XBT for evaluation of SIBO. Diagnostic testing with the XBT was performed based on a clinical suspicion for SIBO in patients with symptoms of bloating, abdominal pain, abdominal distension, weight loss, diarrhea, and/or constipation. Consecutive electronic medical records of 932 patients who completed the XBT at the University of Florida between 2005 and 2009 were reviewed. A two-way Analysis of Variance (ANOVA) was used to test for several associations including age, gender, and body mass index (BMI) with a +XBT. A two-way ANOVA was also performed to control for the differences and interaction with age and between genders. A similar analysis was repeated for BMI. Associations between medical conditions and prior surgical histories were conducted using the Mantel-Haenszel method for 2 by 2 contingency tables, stratified for gender. Reported odds ratio estimates reflect the odds of the prevalence of a condition within the +XBT group to that of the -XBT group. P values of less than 0.05 (two-sided) were considered statistically significant. In the 932 consecutive eligible subjects studied, 513 had a positive XBT. A positive association was found between female gender and a positive XBT (P = 0.0025), and females with a positive test were, on average, greater than 5 years older than those with a negative test (P = 0.024). The mean BMI of positive XBT subjects was normal (24.5) and significantly lower than the subjects with a negative XBT (29.5) (P = 0.0050). A positive XBT was associated with gastroesophageal reflux disease (GERD) (OR = 1.35; 95%CI: 1.02-1.80, P = 0.04), peptic ulcer disease (PUD) (OR = 2.61; 95%CI: 1.48-4.59, P < 0.01), gastroparesis (GP) (OR = 2.04; 95%CI: 1.21-3.41, P < 0.01) and steroid use (OR = 1.35; 95%CI: 1.02-1.80, P = 0.01). Irritable bowel syndrome, independent proton-pump inhibitor (PPI) usage, or previous abdominal surgery was not significantly associated with a positive XBT. No single subdivision by gender or PPI use was associated with a significant difference in the odds ratios between any of the subsets. Female gender, lower BMI, steroid use, PUD, GERD (independent of PPI use), and GP were more prevalent in patients with SIBO, determined by a positive XBT. Increasing age was associated with SIBO in females, but not in males.


The complexity of alternative splicing and landscape of tissue-specific expression in lotus (Nelumbo nucifera) unveiled by Illumina- and single-molecule real-time-based RNA-sequencing.
Alternative splicing (AS) plays a critical role in regulating different physiological and developmental processes in eukaryotes, by dramatically increasing the diversity of the transcriptome and the proteome. However, the saturation and complexity of AS remain unclear in lotus due to its limitation of rare obtainment of full-length multiple-splice isoforms. In this study, we apply a hybrid assembly strategy by combining single-molecule real-time sequencing and Illumina RNA-seq to get a comprehensive insight into the lotus transcriptomic landscape. We identified 211,802 high-quality full-length non-chimeric reads, with 192,690 non-redundant isoforms, and updated the lotus reference gene model. Moreover, our analysis identified a total of 104,288 AS events from 16,543 genes, with alternative 3' splice-site being the predominant model, following by intron retention. By exploring tissue datasets, 370 tissue-specific AS events were identified among 12 tissues. Both the tissue-specific genes and isoforms might play important roles in tissue or organ development, and are suitable for 'ABCE' model partly in floral tissues. A large number of AS events and isoform variants identified in our study enhance the understanding of transcriptional diversity in lotus, and provide valuable resource for further functional genomic studies.


Anticooperative effect induced by mixed solvation in H+ (CH3OH)m(H2O)n (m + n = 5 and 6): a theoretical and infrared spectroscopic study.
When a solvent molecule is replaced by another molecule with larger proton affinity, the strength of all other hydrogen bonds decreases. This is the concept of anticooperativity by successive substitution in a mixed solvation system. In the present study, this concept is demonstrated in H(+)(CH(3)OH)(m)(H(2)O)(n) (m + n = 5 and 6) mixed clusters by a joint theoretical and infrared (IR) spectroscopic approach. The observed IR spectra of the mixed clusters exhibit two high-frequency shifts of hydrogen-bonded OH stretch bands with increasing methanol content. These trends are well reproduced by first-principle IR spectra simulated by thermal averaging over a set of configurational isomers under the quantum harmonic superposition approach. Theoretical analysis on the magnitude of charge transfer from the protonated site to the solvent molecules is found to be in agreement with the spectroscopic measurement that the individual hydrogen bond in the mixed clusters is weakened with an increase of the mixing ratio of methanol to water.


Superficial cervical plexus blockade improves pain control after thyroidectomy: A randomized controlled trial.
The aim was to evaluate the ability of bilateral superficial cervical plexus blockade to control pain and to reduce the side effects of general anesthesia in patients submitted to thyroidectomy. In this randomized controlled trial, we prospectively studied 100 consecutive patients who underwent total thyroidectomy. The simple random patient sample was divided into two groups: 50 patients received general anesthesia alone (group 1 [G1]), and 50 patients received general anesthesia with bilateral superficial cervical plexus blockade (group 2 [G2]). Statistical analyses were performed, and a 5% significance level was adopted. The mean arterial blood pressure and heart rate were 12% lower in G2 patients than in G1 patients 60 minutes after surgery (101 mmHg for G1 vs. 92.3 mmHg for G2; p<0.001). G2 patients reported less pain than G1 patients, and opioid consumption was lower in G2 patients than in G1 patients, not upon postanesthesia care unit arrival, but at 30 minutes (2% vs. 34%; p<0.001, respectively), 45 minutes (0% vs. 16%; p=0.006, respectively), and 4 hours postoperatively (6% vs. 20%; p=0.037, respectively). The incidence of nausea and vomiting was lower in G2 patients than in G1 patients from 45 minutes (0% vs. 16%; p=0.006, respectively) to 8 hours postoperatively (0% vs. 14%; p=0.012, respectively). The present study demonstrated that the combination of bilateral superficial cervical plexus blockade with general anesthesia for thyroidectomy is feasible, safe, and effective for achieving pain control and improving patient outcomes.


Acute injuries and overuse syndromes in sport climbing and bouldering in Austria: a descriptive epidemiological study.
The increasing popularity of climbing activities is associated with a rise in the number of respective injuries and overuse syndromes. However, a comprehensive scrutiny of the incidence, kind and severity of climbing-related ailments in Austria is so far outstanding. We aimed to evaluate injuries and overuse syndromes in sport climbing and bouldering in Austria and to investigate whether the injury incidence differs between specific groups of climbers. Retrospective cross-sectional self-report study. A self-report questionnaire to assess (a) demographic and anthropometric characteristics, (b) climbing experience and skill level, and (c) detailed information on climbing-related injuries was made available in climbing halls and on the Internet. Data from 193 climbers (133 males and 60 females; age 30.4 ± 8.1 years; average climbing experience 9.3 ± 7.7 years) were acquired. A total of 374 injuries were reported by 130 participants (67.4 %). The single most common differential diagnoses, accounting for 56.7 % of all injuries, were strains and ruptures of annular ligaments of the fingers, lateral epicondylitis of the elbow, and sprains or fractures of the ankle joint. The odds for strains of the annular ligaments and lateral epicondylitis were greater in men and increased with older age and higher exposure to climbing stress. This is the first comprehensive study investigating climbing-related injuries in Austria. The incidence and kind of the ailments reported confirm results of previous studies. Moreover, our results suggest that the risk to suffer climbing-related overuse syndromes, but not acute injuries, is dependent on sex, age, and exposure to climbing stress.


PEA3, AP-1, and a unique repetitive sequence all are involved in transcriptional regulation of the breast cancer-associated gene, mammaglobin.
The breast cancer-associated gene mammaglobin is a member of the secretoglobin protein family and has demonstrated its utility as a breast cancer marker. However, the transcriptional regulation of mammaglobin has not been well-characterized. In this report, we used luciferase reporter assays to identify the 200 bp directly 5' of the transcriptional start site as the minimal promoter region of mammaglobin. Sequence scanning indicated that two PEA3 transcription sites were possibly involved in mammaglobin transcription. By transfecting a PEA3 expression vector into breast cancer cell lines MDA-MB-415 and MCF-7, we determined that exogenous PEA3 was able to drive transcription. Mutational analysis indicated that each PEA3 site was functional. Our reporter system and electrophorectic mobility shift assays (EMSAs) also identified the involvement of a unique repetitive element in mammaglobin transcription. Finally, AP-1 was determined via luciferase assays to be involved in regulating non-PEA3 dependent transcription. Elucidating these cis-acting elements will impact our understanding of transcription of normal breast and breast cancer-associated genes.


A survey on virtualization of Wireless Sensor Networks.
Wireless Sensor Networks (WSNs) are gaining tremendous importance thanks to their broad range of commercial applications such as in smart home automation, health-care and industrial automation. In these applications multi-vendor and heterogeneous sensor nodes are deployed. Due to strict administrative control over the specific WSN domains, communication barriers, conflicting goals and the economic interests of different WSN sensor node vendors, it is difficult to introduce a large scale federated WSN. By allowing heterogeneous sensor nodes in WSNs to coexist on a shared physical sensor substrate, virtualization in sensor network may provide flexibility, cost effective solutions, promote diversity, ensure security and increase manageability. This paper surveys the novel approach of using the large scale federated WSN resources in a sensor virtualization environment. Our focus in this paper is to introduce a few design goals, the challenges and opportunities of research in the field of sensor network virtualization as well as to illustrate a current status of research in this field. This paper also presents a wide array of state-of-the art projects related to sensor network virtualization.


Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison.
To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE). We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III). SRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies. These analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE. PLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).


Nurse practitioners in primary care. V. Development of the utilization and financial index to measure effects of their deployment.
The new Utilization and Financial Index (UF-Index) was developed to measure the economic effects of deployment of new health professionals or of other changes in the provision of health services. By means of several steps, information on concurrent use of various categories of health service is converted into a single quantitative index. The index has been used to evaluate the financial effects of introduction of nurse practitioners into primary care practices by means of two complementary studies.


The emerging role of endocrine disruptors in pathogenesis of insulin resistance: a concept implicating nonalcoholic fatty liver disease.
Endocrine disruptors or endocrine-disrupting chemicals (EDCs) represent a highly heterogeneous group of molecules found in the environment or in consumer products. Toxicology and epidemiology studies have suggested the involvement of diverse EDCs in an increasing number of metabolic disorders, including insulin resistance (IR) and IR-related co morbidities, such as obesity, type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Nonalcoholic fatty liver disease (NAFLD), another IR related condition, is emerging as a significant public health concern, affecting 30-45% of the general population in the Western world. To evaluate whether EDCs may also play a role in the pathogenesis of NAFLD, we reviewed the literature on well-studied EDCs, such as dioxins, bisphenol A, phthalates and other persistent organic pollutants, in relation to pathways that might contribute to the pathogenesis of fatty liver / NAFDL. Certain EDCs may be responsible for inducing alterations similar to those encountered in NAFLD either directly through a hepatotoxic effect and/or indirectly by triggering hepatic and systematic IR. Considering these effects, which act in concert with the effects of the epidemics of obesity and T2DM, EDCs may play a significant role in the pathogenesis of fatty liver, thereby increasing the prevalence of NAFLD worldwide. Translational studies and clinical trials investigating the association between EDCs and NAFLD are required to confirm and extent these studies.


The looming storm: Blood and cytokines in COVID-19.
A novel coronavirus termed as COVID-19 by WHO has been the causative agent of an unprecedented pandemic in the history of humanity. The global burden of mortality and morbidity associated with this pandemic continues to increase with each passing day as it is progressively leading to multiorgan dysfunction. In most cases, the cause of death has been attributed to respiratory failure, sepsis, cardiac failure, kidney injury, or coagulopathy. As more knowledge is being unfolded, an in-depth understanding of various systemic manifestations and complications of SARS-CoV2 is vital for optimum management of these patients. This novel virus is known to spread faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), demonstrating a case fatality ranging from 5 to 8% [1]. Hematological abnormalities such as lymphopenia, thrombocytopenia, elevated D-Dimer, elevated fibrinogen, elevated fibrinogen degradation products as well as cytokines such as IL-6 are emerging as important prognostic marker for worse outcome of COVID-19. Among various systemic manifestations, hematological complications such as venous thrombosis causing pulmonary embolism or deep vein thrombosis, and arterial thrombosis causing myocardial infarction, strokes or limb ischemia are being noted to be directly linked to high mortality from COVID-19. An attempt to understand the pathophysiology of various hematological abnormalities including cytokine storm, hypercoagulable state and some rare presentations of this disease hence becomes imperative. Through this review, we aim to provide an up-to-date summary of current evidence-based literature of hematological manifestations, their consequences and management including role of anticoagulation and drugs targeting cytokine storm in patients with SARS-CoV-2.


UVB radiation and DNFB skin painting induce suppressor cells universally in mice.
Ultraviolet radiation (UVR)3 from within the spectrum B (UVB) has the capacity to distort the induction of contact hypersensitivity (CH) in murine skin. A damaging effect of UVB on epidermal Langerhans cells (LC) appears to be universal in all genetically defined strains of mice tested. However, while UVB impairs the induction of CH in some strains of mice, it has no apparent effect on CH in others. Thus, a disparity exists between the effects of UVB on LC and on CH. This is a paradox because LC are generally regarded to serve as the antigen-presenting cells of the skin, placing them at the earliest stages of induction of CH. One possible explanation for this paradox has been that UVB-susceptible strains of mice may generate hapten-specific suppressor T cells, whereas their UVB-resistant counterparts may not, when their skin is treated with UVR and painted with haptens such as dinitrofluorobenzene (DNFB). This possibility was excluded by examining the capacity of UVR and hapten to generate suppressor T cells in several different inbred strains of mice. The results indicate that the induction of hapten-specific afferent T suppressor cells is a universal sequela to treatment of mice with UVB and hapten, irrespective of whether the mice display the phenotype of vigorous CH or not. Thus, the genetic basis of UVB-resistance does not reside in the ability of UVR to induce suppressor T cells. Rather, attention should now be focused on its ability to interrupt induction of effector mechanisms.


Different patterns of age-related central olfactory decline in men and women as quantified by olfactory fMRI.
Age-related olfactory decline, or presbyosmia, is a prevalent condition with potentially devastating consequences on both quality of life and safety. Despite clear evidence for this decline, it is unknown whether presbyosmia is sex-dependent and also whether it is due to central or peripheral olfactory system deterioration. Therefore, the goals of this study were to investigate the neurofunctional substrate of olfactory decline and examine its relationship to age and sex in thirty-seven (18 women, 19 men) healthy older participants using olfactory functional MRI (fMRI). The olfactory fMRI paradigm utilized unique odor+visual and visual-only conditions to contrast peripheral-to-central and central-to-central olfactory processing, respectively. Age was negatively correlated with fMRI activation in olfactory-related regions. Significant aging effects were identifiable in male participants in all target regions. Female participants, however, showed a different pattern of functional decline. Extended unified structural equation modeling (euSEM) analysis revealed that the effective functional connectivity profile was drastically different between male and female participants, with females manifesting a top-down mechanism to offset age-related olfactory activation decline. Our results support the hypotheses that the central olfactory system is involved in age-related olfactory decline, and that resilience to age-related olfactory decline in women may be due to their profuse olfactory network effective connectivity.


Mortality from COVID-19 in Amazonian and Andean original indigenous populations of Peru.
To compare the mortality rates from COVID-19 among indigenous populations of the Amazon and Andean regions of Peru during the years 2020, 2021 and 2022. Secondary analysis of 33,567 data from the COVID-19 Notification System of the National Epidemiology Center, Prevention and Control of Diseases (CDC-Peru), from the years 2020-2022. The variables were age, sex, belonging to the Andean or Amazonian ethnic group, number and type of symptoms and risk conditions, abnormal findings in chest X-rays, year of data collection for hospitalization and death from COVID-19. Poisson family generalized linear regression models with logarithmic linkage and robust variance were used to establish differences in mortality between ethnic groups. Crude and adjusted risk ratio (RR) with 95 % confidence intervals (CI) were calculated. 33,567 participants with an average age of 33.6 years were included, 44.4 % were men and 70.2 % belonged to the Amazonian ethnic group. Most of those affected by COVID-19 presented 2 symptoms (38.8 %), 4.8 % presented some risk condition, 1451 (4.3 %) were hospitalized, and 433 (1.3 %) died. The adjusted analysis showed that the Andean group, compared to the Amazonian, tended to have a higher probability of death, and this association was statistically significant, RR =7.6, 95 % CI (5.5-10.5). Patients from Andean indigenous communities had an almost 8 times higher risk of death from COVID-19.