Impact of sirolimus-eluting stent fracture on 4-year clinical outcomes.
Although stent fracture (SF) after sirolimus-eluting stent (SES) implantation has been recognized as one of the predisposing factors of in-stent restenosis, it remains uncertain whether SF can increase the risk of major adverse cardiac events (MACE), especially beyond 1 year after SES implantation. The aim of this study was to assess the impact of SF relative to non-SF on 4-year clinical outcomes after treatment with SES of comparable unselected lesions. A total of 874 lesions in 793 patients undergoing SES implantation and subsequent angiography 6 to 9 months after index procedure were analyzed. At 6- to 9-month angiographic follow-up, SF was identified in 70 of 874 lesions (8.0%). In-stent late loss was significantly higher in SF lesions versus non-SF lesions (0.42±0.59 mm versus 0.13±0.49 mm, P<0.001), resulting in a significantly higher in-stent restenosis rate (21.4% versus 4.1%, P<0.001). At 4 years, SF versus non-SF was associated with a significantly higher MACE rate (23.2% versus 12.6%, P=0.014), mainly driven by significantly higher target-lesion revascularization (18.8% versus 10.2%, P=0.029) rate. Adverse effects of SF on clinical outcomes occurred mostly within the first year (17.4% versus 6.6%, P=0.001), with similar MACE rate between 1 and 4 years (5.8% versus 5.9%, P=0.611). No significant differences between SF versus non-SF patients were observed in the cumulative frequency of very late stent thrombosis (2.9% versus 1.4%, P=0.281), death (0% versus 2.1%, P=0.252), or myocardial infarction (5.8% versus 2.9%, P=0.165). SF of SES was associated with higher MACE rate up to 1 year, mainly driven by higher target-lesion revascularization, whereas no significant association was evident between years 1 and 4.


Personal experiences of taking part in clinical trials - a qualitative study.
To investigate people's experiences of and attitudes to participation in clinical trials. 42 in-depth qualitative interviews, covering different types of trial and intervention, analysed thematically using a modified grounded theory approach. Many participants argued for a right to participate in research. This may be partly because personal benefit was a common primary motivation for taking part - but the benefits cited were not only personal health outcomes. Whilst most were satisfied with information received, some felt it was too complex. Gaps in understanding were evident, especially around randomisation, but trust in trial staff was high. Desire for feedback of trial results was common. Unintended consequences may arise from efforts to give full information and challenge therapeutic misconceptions. People wanted 'enough' information to help them decide, but their definition of 'enough', and the relative importance of written information versus discussion/advice from trusted professionals, varied by individual. In seeking to minimise misunderstanding we stress uncertainty and risk but have perhaps lost sight of the value people derive from trial participation. Better information on trial availability, shorter trial leaflets and greater emphasis on face-to-face discussion are suggested. Recruitment literature could appeal to a wider range of benefits.


A high-throughput assay for modulators of NNT activity in permeabilized yeast cells.
Nicotinamide nucleotide transhydrogenase (NNT) mutant mice show glucose intolerance with impaired insulin secretion during glucose tolerance tests. Uncoupling of the β cell mitochondrial metabolism due to such mutations makes NNT a novel target for therapeutics in the treatment of pathologies such as type 2 diabetes. The authors propose that increasing NNT activity would help reduce deleterious buildup of reactive oxygen species in the inner mitochondrial matrix. They have expressed human Nnt cDNA for the first time in Saccharomyces cerevisiae, and transhydrogenase activity in mitochondria isolated from these cells is six times greater than is seen in wild-type mitochondria. The same mitochondria have partially uncoupled respiration, and the cells have slower growth rates compared to cells that do not express NNT. The authors have used NNT's role as a redox-driven proton pump to develop a robust fluorimetric assay in permeabilized yeast. Screening in parallel a library of known pharmacologically active compounds (National Institute of Neurological Disorders and Stroke collection) against NNT ± cells, they demonstrate a robust and reproducible assay suitable for expansion into larger and more diverse compound sets. The identification of NNT activators may help in the elucidation of the role of NNT in mammalian cells and assessing its potential as a therapeutic target for insulin secretion disorders.


Time course of physiologic variables in response to ventilator-induced lung injury.
The time course of the physiological derangements that result from ventilator-induced lung injury has not been adequately described. Similarly, the regional topographies of pleural pressure and tissue edema have not been carefully mapped for this injury process. Lung injury was induced in 9 normal pigs by ventilating for 6 hours at a transpulmonary pressure of 35 cm H(2)O, with the animals in the supine position. Eight additional normal pigs received right thoracotomy to place pleural-surface-pressure sensors prior to an identical period and intensity of injurious ventilation. Gas exchange and lung mechanics were tracked in all the animals. Cytokines (tumor necrosis factor alpha, interleukin 6, and interleukin 8) in peripheral blood were assayed at 2 hour intervals, beginning at the onset of mechanical ventilation, from all the animals. After a brief "induction" period, P(aO(2)) and tidal volume declined steadily in the animals that were ventilated to induce lung injury. The rate of decline was greater in the animals that received thoracotomy. The pleural pressure gradient steadily increased from ventral to dorsal. The serum cytokine levels did not evolve with developing injury, but cytokines were elevated at the onset of ventilation. Tissue edema, as assessed by the ratio of wet weight to dry weight, was greater in the thoracotomized animals than in the nonthoracotomized animals, and tissue edema tended to be greater in the caudal lung regions than in the cephalad lung regions. Following the induction period, the development of ventilator-induced lung injury progressed steadily and then plateaued, as assessed by quantitative physiology variables during 6 hours of ventilation at a transpulmonary pressure of 35 cm H(2)O. Greater injury developed in animals that had a coexisting potential insult (thoracotomy). Injury development was not paralleled by bloodborne inflammatory cytokines.


BactImAS: a platform for processing and analysis of bacterial time-lapse microscopy movies.
The software available to date for analyzing image sequences from time-lapse microscopy works only for certain bacteria and under limited conditions. These programs, mostly MATLAB-based, fail for microbes with irregular shape, indistinct cell division sites, or that grow in closely packed microcolonies. Unfortunately, many organisms of interest have these characteristics, and analyzing their image sequences has been limited to time consuming manual processing. Here we describe BactImAS - a modular, multi-platform, open-source, Java-based software delivered both as a standalone program and as a plugin for Icy. The software is designed for extracting and visualizing quantitative data from bacterial time-lapse movies. BactImAS uses a semi-automated approach where the user defines initial cells, identifies cell division events, and, if necessary, manually corrects cell segmentation with the help of user-friendly GUI and incorporated ImageJ application. The program segments and tracks cells using a newly-developed algorithm designed for movies with difficult-to-segment cells that exhibit small frame-to-frame differences. Measurements are extracted from images in a configurable, automated fashion and an SQLite database is used to store, retrieve, and exchange all acquired data. Finally, the BactImAS can generate configurable lineage tree visualizations and export data as CSV files. We tested BactImAS on time-lapse movies of Mycobacterium smegmatis and achieved at least 10-fold reduction of processing time compared to manual analysis. We illustrate the power of the visualization tool by showing heterogeneity of both icl expression and cell growth atop of a lineage tree. The presented software simplifies quantitative analysis of time-lapse movies overall and is currently the only available software for the analysis of mycobacteria-like cells. It will be of interest to the community of both end-users and developers of time-lapse microscopy software.


Singlet and triplet excited-state dynamics study of the keto and enol tautomers of cytosine.
The photoinduced excited-state dynamics of the keto and enol forms of cytosine have been investigated by using ab initio surface-hopping to gain an understanding of the outcome of molecular beam femtosecond pump-probe photoionisation spectroscopy experiments. Both singlet and triplet states were included in the dynamics. The results show that triplet states play a significant role in the relaxation of the keto tautomer, whereas they are less important in the enol tautomer. In both forms, the T1 state minimum was found to be too low in energy to be detected in standard photoionisation spectroscopy experiments and therefore experimental decay times should arise from simultaneous relaxation to the ground state and additional intersystem crossing followed by internal conversion to the T1 state. In agreement with available experimental lifetimes, we observed three decay constants of 7, 270 and 1900 fs, the first two coming from the keto tautomer and the third from the enol form. Deactivation of the enol tautomer is due to internal conversion to the ground state through two ethylenic-type S1/S0 conical intersections.


Episodic outbreaks bias estimates of age-specific force of infection: a corrected method using measles as an example.
Understanding age-specific differences in infection rates can be important in predicting the magnitude of and mortality in outbreaks and targeting age groups for vaccination programmes. Standard methods to estimate age-specific rates assume that the age-specific force of infection is constant in time. However, this assumption may easily be violated in the face of a highly variable outbreak history, as recently observed for acute immunizing infections like measles, in strongly seasonal settings. Here we investigate the biases that result from ignoring such fluctuations in incidence and present a correction based on the epidemic history. We apply the method to data from a measles outbreak in Niamey, Niger and show that, despite a bimodal age distribution of cases, the estimated age-specific force of infection is unimodal and concentrated in young children (<5 years) consistent with previous analyses of age-specific rates in the region.


Mitochondrial Neurogastrointestinal Encephalomyopathy Presenting as Anorexia Nervosa.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystemic autosomal recessive disorder mainly caused by mutations in the nuclear gene TYMP, encoding thymidine phosphorylase. It generally appears in childhood and is clinically characterized by severe gastrointestinal dysmotility, cachexia, ptosis, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy on brain magnetic resonance imaging. The disease is clinically heterogeneous with the main symptoms being gastrointestinal, with an important weight loss. Symptoms might worsen rapidly, and a timely diagnosis is vital. However, patients report retrospectively their first symptoms before the age of 12 years, but the delay in diagnosis varies from 5 to 10 years. In the present study, we report a case of an adolescent with MNGIE, which was initially, and erroneously, diagnosed as anorexia nervosa. To make a timely and accurate differential diagnosis, we will discuss the clinical differences and similarities between MNGIE and anorexia nervosa and the importance of a multidisciplinary evaluation.


Effectiveness of zinc supplementation on diarrhea and average daily gain in pre-weaned dairy calves: A double-blind, block-randomized, placebo-controlled clinical trial.
The objective of this clinical trial was to evaluate the effectiveness of zinc supplementation on diarrhea and average daily weight gain (ADG) in pre-weaned dairy calves. A total of 1,482 healthy Holstein heifer and bull calves from a large California dairy were enrolled at 24 to 48 hours of age until hutch exit at approximately 90 days of age. Calves were block-randomized by time to one of three treatments: 1) placebo, 2) zinc methionine (ZM), or 3) zinc sulfate (ZS) administered in milk once daily for 14 days. Serum total protein at enrollment and body weight at birth, treatment end, and hutch exit were measured. Fecal consistency was assessed daily for 28 days post-enrollment. For a random sample of 127 calves, serum zinc concentrations before and after treatment and a fecal antigen ELISA at diarrhea start and resolution for Escherichia coli K99, rotavirus, coronavirus, and Cryptosporidium parvum were performed. Linear regression showed that ZM-treated bull calves had 22 g increased ADG compared to placebo-treated bulls (P = 0.042). ZM-treated heifers had 9 g decreased ADG compared to placebo-treated heifers (P = 0.037), after adjusting for average birth weight. Sex-stratified models showed that high birth weight heifers treated with ZM gained more than placebo-treated heifers of the same birth weight, which suggests a dose-response effect rather than a true sex-specific effect of ZM on ADG. Cox regression showed that ZM and ZS-treated calves had a 14.7% (P = 0.015) and 13.9% (P = 0.022) reduced hazard of diarrhea, respectively, compared to placebo-treated calves. Calves supplemented for at least the first five days of diarrhea with ZM and ZS had a 21.4% (P = 0.027) and 13.0% (P = 0.040) increased hazard of cure from diarrhea, respectively, compared to placebo-treated calves. Logistic regression showed that the odds of microbiological cure at diarrhea resolution for rotavirus, C. parvum, or any single fecal pathogen was not different between treatment groups. Zinc supplementation delayed diarrhea and expedited diarrhea recovery in pre-weaned calves. Additionally, zinc improved weight gain differentially in bulls compared to heifers, indicating a research need for sex-specific dosing.


Consistency of topological moves based on the balanced minimum evolution principle of phylogenetic inference.
Many phylogenetic algorithms search the space of possible trees using topological rearrangements and some optimality criterion. FastME is such an approach that uses the balanced minimum evolution (BME) principle, which computer studies have demonstrated to have high accuracy. FastME includes two variants: balanced subtree prune and regraft (BSPR) and balanced nearest neighbor interchange (BNNI). These algorithms take as input a distance matrix and a putative phylogenetic tree. The tree is modified using SPR or NNI operations, respectively, to reduce the BME length relative to the distance matrix, until a tree with (locally) shortest BME length is found. Following computer simulations, it has been conjectured that BSPR and BNNI are consistent, i.e. for an input distance that is a tree-metric, they converge to the corresponding tree. We prove that the BSPR algorithm is consistent. Moreover, even if the input contains small errors relative to a tree-metric, we show that the BSPR algorithm still returns the corresponding tree. Whether BNNI is consistent remains open.


Legal requirements and wastewater discharges to Polish water bodies, 1945-2003.
The postwar development of water protection legislation and wastewater discharges is poorly known for the Baltic Sea region as a whole. This article presents national efforts to govern wastewater discharges in Poland using legal tools over the twentieth century with an emphasis on the postwar period, 1945-2003. The study also attempts to evaluate how the state authority responded to changing legal demands in terms of urban and industrial wastewater discharges in the postwar period. It outlines the main changes during the socialist regime in Poland and after it regained independence. Also the implications of Poland's integration into the European Union are briefly discussed. Mathematical calculations are used to illustrate some changes in legal requirements over time.


Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study.
To evaluate the safety and immunologic and antiviral effects of combination therapy with zidovudine and dideoxycytidine (ddC) in patients with advanced human immunodeficiency virus type 1 (HIV) infection. A phase I/II open-label, dose-ranging study. Two AIDS Clinical Trials Group units. Patients (56) with advanced HIV disease. Patients were randomly assigned to one of three paired regimens of zidovudine and ddC. We evaluated six dosing regimens, each involving oral administration of the study drugs at 8-hour intervals. Pharmacokinetics, toxicity, CD4 counts, p24 antigenemia and clinical end points. The median follow-up period was 40.6 weeks (range, 0.3 to 70 weeks). Neither drug affected the pharmacokinetic profile of the other. Episodes of serious hematologic toxicity were infrequent, occurring in only 17.9% of patients, and did not differ among the regimens (P = 0.15). Severe sensory peripheral neuropathy occurred in two patients (one patient each in regimens 1 and 4). One patient receiving regimen 4 died. The mean maximal increase in CD4 counts exceeded 109 cells/mm3, and 69% of patients receiving combinations containing 300 or 600 mg of zidovudine daily had an increase in CD4 counts of 50 cells/mm3 or greater. Regimens containing 600 mg of zidovudine daily (regimens 2 and 5) were also more likely to result in persistent increases in CD4 counts above pretreatment values than were the two lowest dose regimens (P = 0.003). The decline in CD4 counts was more rapid, and the suppression of the p24 antigenemia was less rapid and less sustained in patients receiving the lowest zidovudine dose alone (regimen 6). The addition of ddC to regimen 6 (regimen 3) resulted in a slower decline in the CD4 counts (P = 0.06). Combination therapy with zidovudine and ddC at the doses tested was well tolerated and did not result in toxicity. A daily oral dose of 150 mg of zidovudine appeared to produce a suboptimal effect on p24 antigenemia and CD4 counts. Combination therapy with ddC and higher doses of zidovudine produced greater and more persistent effects in patients with advanced HIV infection compared with other study regimens and with the results of previous trials of zidovudine monotherapy.


Extraordinarily rapid life-history divergence between Cryptasterina sea star species.
Life history plays a critical role in governing microevolutionary processes such as gene flow and adaptation, as well as macroevolutionary processes such speciation. Here, we use multilocus phylogeographic analyses to examine a speciation event involving spectacular life-history differences between sister species of sea stars. Cryptasterina hystera has evolved a suite of derived life-history traits (including internal self-fertilization and brood protection) that differ from its sister species Cryptasterina pentagona, a gonochoric broadcast spawner. We show that these species have only been reproductively isolated for approximately 6000 years (95% highest posterior density of 905-22 628), and that this life-history change may be responsible for dramatic genetic consequences, including low nucleotide diversity, zero heterozygosity and no gene flow. The rapid divergence of these species rules out some mechanisms of isolation such as adaptation to microhabitats in sympatry, or slow divergence by genetic drift during prolonged isolation. We hypothesize that the large phenotypic differences between species relative to the short divergence time suggests that the life-history differences observed may be direct responses to disruptive selection between populations. We speculate that local environmental or demographic differences at the southern range margin are possible mechanisms of selection driving one of the fastest known marine speciation events.


Disentangling the role of environmental filtering and biotic resistance on alien invasions in a reservoir area.
Large-scale water conservancy projects benefit human life but have modified the landscape and provided opportunities for alien plant invasions. Understanding the environmental (e.g., climate), human-related (e.g., population density, proximity to human activities), and biotic (e.g., native plant, community structure) factors driving invasions is essential in the management of alien plants and biodiversity conservation in areas with intense human pressure. To this end, we investigated the spatial patterns of alien plant species distribution in the Three Gorges Reservoir Area (TGRA) of China and distinguished the role of the external environment and community characteristics in determining the occurrence of alien plants with differing levels of known invasion impacts in China using random forest analyses and structural equation models. A total of 102 alien plant species belonging to 30 families and 67 genera were recorded, the majority being annual and biennial herbs (65.7%). The results showed a negative diversity-invasibility relationship and supported the biotic resistance hypothesis. Moreover, percentage coverage of native plants was found to interact with native species richness and had a predominant role in resisting alien plant species. We found alien dominance was mainly the result of disturbance (e.g., changes in hydrological regime), which drove native plant loss. Our results also demonstrated that disturbance and temperature were more important for the occurrence of malignant invaders than all alien plants. Overall, our study highlights the importance of restoring diverse and productive native communities in resistance to invasion.


Genetics of multiple sclerosis.
Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system affecting primarily young adults. Evidence from genetic epidemiological studies demonstrate that the observed familial clustering of MS is primarily due to shared genes between family members. Molecular investigations have failed to elucidate susceptibilty loci with the exception of the HLA DRB1*1501, DQA1*0102, DQB1*0602 haplotype of the major histocompatibility complex. Results from genomic screens stress the complexity of MS genetics and that there is no one single locus contributing significantly to familial risk. To overcome the confounding effects of genetic complexity, MS genetic research needs to take advantage of clinical and epidemiological information to better homogenize study samples. In addition, the continued collection and genotyping of MS families may shed some light on the mild to moderate susceptibility loci affecting the MS patient population.


Cancer statistics for Hispanics/Latinos, 2012.
Hispanics/Latinos are the largest and fastest growing major demographic group in the United States, accounting for 16.3% (50.5 million/310 million) of the US population in 2010. In this article, the American Cancer Society updates a previous report on cancer statistics for Hispanics using incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. In 2012, an estimated 112,800 new cases of cancer will be diagnosed and 33,200 cancer deaths will occur among Hispanics. In 2009, the most recent year for which actual data are available, cancer surpassed heart disease as the leading cause of death among Hispanics. Among US Hispanics during the past 10 years of available data (2000-2009), cancer incidence rates declined by 1.7% per year among men and 0.3% per year among women, while cancer death rates declined by 2.3% per year in men and 1.4% per year in women. Hispanics have lower incidence and death rates than non-Hispanic whites for all cancers combined and for the 4 most common cancers (breast, prostate, lung and bronchus, and colorectum). However, Hispanics have higher incidence and mortality rates for cancers of the stomach, liver, uterine cervix, and gallbladder, reflecting greater exposure to cancer-causing infectious agents, lower rates of screening for cervical cancer, differences in lifestyle and dietary patterns, and possibly genetic factors. Strategies for reducing cancer risk among Hispanics include increasing utilization of screening and available vaccines, as well as implementing effective interventions to reduce obesity, alcohol consumption, and tobacco use.


Component Separation vs. Bridged Repair for Large Ventral Hernias: A Multi-Institutional Risk-Adjusted Comparison, Systematic Review, and Meta-Analysis.
Repair of large ventral hernia defects is associated with high rates of surgical site occurrences (SSO), including surgical site infection (SSI), site dehiscence, seroma, hematoma, and site necrosis. Two common operative strategies exist: Component separation (CS) with primary fascial closure and mesh reinforcement (PFC-CS) and bridged repair (mesh spanning the hernia defect). We hypothesized that: (1) ventral hernia repair (VHR) of large defects with bridged repair is associated with more SSOs than is PFC, and (2) anterior CS is associated with more SSOs than is endoscopic, perforator-sparing, or posterior CS. Part I of this study was a review of a multi-center database of patients who underwent VHR of a defect ≥8 cm from 2010-2011 with at least one month of follow-up. The primary outcome was SSO. The secondary outcome was recurrence. Part II of this study was a systematic review and meta-analysis of studies comparing bridged repair with PFC and studies comparing different kinds of CS. A total of 108 patients were followed for a median of 16 months (range 1-50 months), of whom 84 underwent PFC-CS and 24 had bridged repairs. Unadjusted results demonstrated no differences between the groups in SSO or recurrence; however, the study was underpowered for this purpose. On meta-analysis, PFC was associated with a lower risk of SSO (odds ratio [OR] = 0.569; 95% confidence interval [CI] = 0.34-0.94) and recurrence (OR = 0.138; 95% CI = 0.08-0.23) compared with bridged repair. On multiple-treatments meta-analysis, both endoscopic and perforator-sparing CS were most likely to be the treatments with the lowest risk of SSO and recurrence. Bridged repair was associated with more SSOs than was PFC, and PFC should be used whenever feasible. Endoscopic and perforator-sparing CS were associated with the fewest complications; however, these conclusions are limited by heterogeneity between studies and poor methodological quality. These results should be used to guide future trials, which should compare the risks and benefits of each CS method to determine in which setting each technique will give the best results.


Dynamical Computation of the Density of States and Bayes Factors Using Nonequilibrium Importance Sampling.
Nonequilibrium sampling is potentially much more versatile than its equilibrium counterpart, but it comes with challenges because the invariant distribution is not typically known when the dynamics breaks detailed balance. Here, we derive a generic importance sampling technique that leverages the statistical power of configurations transported by nonequilibrium trajectories and can be used to compute averages with respect to arbitrary target distributions. As a dissipative reweighting scheme, the method can be viewed in relation to the annealed importance sampling (AIS) method and the related Jarzynski equality. Unlike AIS, our approach gives an unbiased estimator, with a provably lower variance than directly estimating the average of an observable. We also establish a direct relation between a dynamical quantity, the dissipation, and the volume of phase space, from which we can compute quantities such as the density of states and Bayes factors. We illustrate the properties of estimators relying on this sampling technique in the context of density of state calculations, showing that it scales favorable with dimensionality-in particular, we show that it can be used to compute the phase diagram of the mean-field Ising model from a single nonequilibrium trajectory. We also demonstrate the robustness and efficiency of the approach with an application to a Bayesian model comparison problem of the type encountered in astrophysics and machine learning.


Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite.
Total sleep deprivation in rodents and in humans has been associated with hyperphagia. Over the past 40 years, self-reported sleep duration in the United States has decreased by almost 2 hours. To determine whether partial sleep curtailment, an increasingly prevalent behavior, alters appetite regulation. Randomized, 2-period, 2-condition crossover clinical study. Clinical Research Center, University of Chicago, Chicago, Illinois. 12 healthy men (mean age [+/-SD], 22 +/- 2 years; mean body mass index [+/-SD], 23.6 +/- 2.0 kg/m2). Daytime profiles of plasma leptin and ghrelin levels and subjective ratings of hunger and appetite. 2 days of sleep restriction and 2 days of sleep extension under controlled conditions of caloric intake and physical activity. Sleep restriction was associated with average reductions in the anorexigenic hormone leptin (decrease, 18%; P = 0.04), elevations in the orexigenic factor ghrelin (increase, 28%; P < 0.04), and increased hunger (increase, 24%; P < 0.01) and appetite (increase, 23%; P = 0.01), especially for calorie-dense foods with high carbohydrate content (increase, 33% to 45%; P = 0.02). The study included only 12 young men and did not measure energy expenditure. Short sleep duration in young, healthy men is associated with decreased leptin levels, increased ghrelin levels, and increased hunger and appetite.


Inhibition of hepatic and extrahepatic glutathione S-transferases by primary and secondary bile acids.
Glutathione S-transferases are a complex family of dimeric proteins that play a dual role in cellular detoxification; they catalyse the first step in the synthesis of mercapturic acids, and they bind potentially harmful non-substrate ligands. Bile acids are quantitatively the major group of ligands encountered by the glutathione S-transferases. The enzymes from rat liver comprise Yk (Mr 25 000), Ya (Mr 25 500), Yn (Mr 26 500), Yb1, Yb2 (both Mr 27 000) and Yc (Mr 28 500) monomers. Although bile acids inhibited the catalytic activity of all transferases studied, the concentration of a particular bile acid required to produce 50% inhibition (I50) varies considerably. A comparison of the I50 values obtained with lithocholate (monohydroxylated), chenodeoxycholate (dihydroxylated) and cholate (trihydroxylated) showed that, in contrast with all other transferase monomers, the Ya subunit possesses a relatively hydrophobic bile-acid-binding site. The I50 values obtained with lithocholate and lithocholate 3-sulphate showed that only the Ya subunit is inhibited more effectively by lithocholate than by its sulphate ester. Other subunits (Yk, Yn, Yb1 and Yb2) were inhibited more by lithocholate 3-sulphate than by lithocholate, indicating the existence of a significant ionic interaction, in the bile-acid-binding domain, between (an) amino acid residue(s) and the steroid ring A. By contrast, increasing the assay pH from 6.0 to 7.5 decreased the inhibitory effect of all bile acids studied, suggesting that there is little significant ionic interaction between transferase subunits and the carboxy group of bile acids. Under alkaline conditions, low concentrations (sub-micellar) of nonsulphated bile acids activated Yb1, Yb2 and Yc subunits but not Yk, Ya and Yn subunits. The diverse effects of the various bile acids studied on transferase activity enables these ligands to be used to help establish the quaternary structure of individual enzymes. Since these inhibitors can discriminate between transferases that appear to be immunochemically identical (e.g. transferases F and L), bile acids can provide information about the subunit composition of forms that cannot otherwise be distinguished.


Neisseria gonorrhoeae isolates with reduced susceptibility to cefixime and ceftriaxone: association with genetic polymorphisms in penA, mtrR, porB1b, and ponA.
The recent emergence and transmission of Neisseria gonorrhoeae isolates with reduced susceptibility to expanded-spectrum cephalosporins such as cefixime and ceftriaxone have been reported. The aim of this study was to determine the correlation of different polymorphisms in the penA, mtrR, porB1b (penB), and ponA genes of N. gonorrhoeae with reduced susceptibility to cefixime and ceftriaxone. Eighteen gonococcal isolates with reduced cefixime and ceftriaxone susceptibility (Cef(i)) and two susceptible isolates were characterized using serovar determination, antibiograms, N. gonorrhoeae multiantigen sequence typing (NG-MAST), and sequencing of penA, mtrR, porB1b, and ponA alleles. For the Cef(i) isolates (n = 18), the MICs of cefixime and ceftriaxone ranged between 0.032 to 0.38 mug/ml and 0.064 to 0.125 mug/ml, respectively. These isolates were assigned five different serovars and six divergent NG-MAST sequence types. Eleven isolates (61%) with higher MICs of cefixime and ceftriaxone contained a nearly identical penA mosaic allele and previously described polymorphisms in mtrR (a single nucleotide [A] deletion in the promoter), penB (mutations in porB1b encoding loop 3 of PorB1b), and ponA (ponA1 polymorphism). The remaining seven Cef(i) isolates (39%), which had somewhat lower MICs of cefixime and ceftriaxone, contained an aspartic acid insertion (Asp-345a) in PBP 2 in conjunction with alterations of 4 to 10 amino acid residues in the C-terminal region of the transpeptidase domain of penA. In conclusion, an unambiguous association between penA mosaic alleles, in conjunction with genetic polymorphisms in mtrR, porB1b, and ponA, and greater reduced susceptibility to cefixime and ceftriaxone was identified.


Impact of precautionary behaviors during outbreaks of pandemic influenza: modeling of regional differences.
Using time geographic theory for representation of population mixing, we set out to analyze the relative impact from precautionary behaviors on outbreaks of pandemic influenza in Europe and Asia. We extended an existing simulator environment with behavioral parameters from a population survey to model different behaviors. We found that precautionary behaviors even among a minority of the population can have a decisive effect on the probability of the outbreak to propagate. The results also display that assumptions strongly influences the outcome. Depending on the interpretation of how many "children" are kept from "school", R(0) changes from a range where outbreak progression is possible to a range where it is improbable in both European (R(0)=1.77/1.23) and Asian (R(0)=1.70/1.05) conditions. We conclude that unprompted distancing can have a decisive effect on pandemic propagation. An important response strategy can be to promote voluntary precautionary behavior shown to reduce disease transmission.


Independent recombination events between the duplicated human alpha globin genes; implications for their concerted evolution.
We have examined the molecular structure of the human alpha globin gene complex from individuals with a common form of alpha thalassaemia in which one of the duplicated pair of alpha genes (alpha alpha) has been deleted (-alpha 3-7). Restriction mapping and DNA sequence analysis of the mutants indicate that different -alpha 3.7 chromosomes are the result of at least three independent events. In each case the genetic crossover has occurred within a region of complete homology between the alpha 1 and alpha 2 genes. Since the -alpha chromosomes may reflect the processes of crossover fixation and gene conversion between the two genes, their structures may provide some insight into the mechanism by which the concerted evolution of the human alpha globin genes occurs.


Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance.
The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2-4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically 'steer' the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic-resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy.


Muscle activation patterns in patients with recurrent shoulder instability.
The aim of this study is to present muscle patterns observed with the direction of instability in a series of patients presenting with recurrent shoulder instability. A retrospective review was carried out on shoulder instability cases referred for fine wire dynamic electromyography (DEMG) studies at a specialist upper limb centre between 1981 and 2003. An experienced consultant clinical neurophysiologist performed dual needle insertion into four muscles (pectoralis major (PM), latissimus dorsi (LD), anterior deltoid (AD) and infraspinatus (IS)) in shoulders that were suspected to have increased or suppressed activation of muscles that could be contributing to the instability. Raw EMG signals were obtained while subjects performed simple uniplanar movements of the shoulder. The presence or absence of muscle activation was noted and compared to clinical diagnosis and direction of instability. A total of 140 (26.6%) shoulders were referred for fine wire EMG, and 131 studies were completed. Of the shoulders tested, 122 shoulders (93%) were identified as having abnormal patterns and nine had normal patterns. PM was found to be more active in 60% of shoulders presenting with anterior instability. LD was found to be more active in 81% of shoulders with anterior instability and 80% with posterior instability. AD was found to be more active in 22% of shoulders with anterior instability and 18% with posterior instability. IS was found to be inappropriately inactive in only 3% of shoulders with anterior instability but in 25% with posterior instability. Clinical assessment identified 93% of cases suspected to have muscle patterning, but the specificity of the clinical assessment was only correct in 11% of cases. The DEMG results suggest that increased activation of LD may play a role in both anterior and posterior shoulder instability; increased activation of PM may play a role in anterior instability.


Combined use of RNAi and quantitative proteomics to study gene function in Drosophila.
RNA interference is a powerful way to study gene function and is frequently combined with microarray analysis. Here we introduce a similar technology at the protein level by simultaneously applying Stable Isotope Labeling by Amino acids in Cell culture (SILAC) and RNA interference (RNAi) to Drosophila SL2 cells. After knockdown of ISWI, an ATP-hydrolyzing motor of different chromatin remodeling complexes, we obtained a quantitative proteome of more than 4,000 proteins. ISWI itself was reduced 10-fold as quantified by SILAC. Several hundred proteins were significantly regulated and clustered into distinct functional categories. Acf-1, a direct interaction partner of ISWI, is severely depleted at the protein, but not the transcript, level; this most likely results from reduced protein stability. We found little overall correlation between changes in the transcriptome and proteome with many protein changes unaccompanied by message changes. However, correlation was high for those mRNAs that changed significantly by microarray.


Direct integrin binding to insulin-like growth factor-2 through the C-domain is required for insulin-like growth factor receptor type 1 (IGF1R) signaling.
We have reported that integrins crosstalk with growth factors through direct binding to growth factors (e.g., fibroblast growth factor-1, insulin-like growth factor 1 (IGF1), neuregulin-1, fractalkine) and subsequent ternary complex formation with cognate receptor [e.g., integrin/IGF1/IGF1 receptor (IGF1R)]. IGF1 and IGF2 are overexpressed in cancer and major therapeutic targets. We previously reported that IGF1 binds to integrins ανβ3 and α6β4, and the R36E/R37E mutant in the C-domain of IGF1 is defective integrin binding and signaling functions of IGF1, and acts as an antagonist of IGF1R. We studied if integrins play a role in the signaling functions of IGF2, another member of the IGF family. Here we describe that IGF2 specifically binds to integrins ανβ3 and α6β4, and induced proliferation of CHO cells (IGF1R+) that express ανβ3 or α6β4 (β3- or α6β4-CHO cells). Arg residues to Glu at positions 24, 34, 37 and/or 38 in or close to the C-domain of IGF2 play a critical role in binding to integrins and signaling functions. The R24E/R37E/R38E, R34E/R37E/R38E, and R24E/R34E/R37E/R38E mutants were defective in integrin binding and IGF2 signaling. These mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R. These results suggest that IGF2 also requires integrin binding for signaling functions, and the IGF2 mutants that cannot bind to integrins act as antagonists of IGF1R. The present study defines the role of the C-domain in integrin binding and signaling.


Magnetic resonance imaging of the condylar growth pattern and disk position after chin cup therapy: a preliminary study.
This study was conducted on lateral cephalograms and magnetic resonance images (MRIs) obtained from 20 subjects with Class III malocclusion. Only clinically temporomandibular joint (TMJ) symptom-free subjects were included in this study. In the treatment group, a chin cup with 600 g of force was applied in 13 patients (10 girls and three boys) with a mean age of nine years. The chin cup was applied in a direction from the chin toward the TMJ. The control group consisted of seven patients (six girls and one boy) with a mean age of eight year nine months. Orthodontic treatment was not applied in the control group. Records were taken at the beginning and end of chin cup therapy from all the subjects. Measurements were made on lateral cephalograms and unilateral-left sagittal-oblique TMJ MRIs. Variables obtained at the beginning and end of the study were compared by Student's t-tests and paired t-tests. Relationships between craniofacial and TMJ variables were analyzed by correlation analysis. The mandibular corpus length was increased and condylar head angle was decreased by chin cup therapy. A positive correlation existed between activation of sagittal maxillary and mandibular growth and bending of the condylar head. This study showed that the condylar growth pattern was altered by chin cup. It may be implied that the source of improvement is adaptation of the craniofacial structures to the changes of the condylar growth pattern produced by the chin cup.


Haemodynamic goal-directed therapy and postoperative infections: earlier is better. A systematic review and meta-analysis.
Infectious complications are the main causes of postoperative morbidity. The early timing of their promoting factors is the rationale for perioperative strategies attempting to reduce them. Our aim was to determine the effects of perioperative haemodynamic goal-directed therapy on postoperative infection rates. We performed a systematic review and meta-analysis. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched up to March 2011. Randomised, controlled trials of major surgery in adult patients managed with perioperative goal-directed therapy or according to routine haemodynamic practice were included. Primary outcome measure was specific type of infection. Twenty-six randomised, controlled trials with a combined total of 4,188 participants met our inclusion criteria. Perioperative goal-directed therapy significantly reduced surgical site infections (pooled OR 0.58, 95% CI 0.46 to 0.74; P < 0.0001), pneumonia (pooled OR 0.71, 95% CI 0.55 to 0.92; P = 0.009), and urinary tract infections (pooled OR 0.44, 95% CI 0.22 to 0.84; P = 0.02). A significant benefit was found regarding total infectious episodes (OR 0.40, 95% CI 0.28 to 0.58; P < 0.00001). Flow-directed haemodynamic therapy designed to optimise oxygen delivery protects surgical patients against postoperative hospital-acquired infections and must be strongly encouraged, particularly in the high-risk surgical population.


Extensive characterization of magnetic microrods observed using optical microscopy.
The usage of micro or nanorods is steadily increasing in various applications from fundamental research to industry. Therefore their geometrical, mechanical and eventually magnetic properties need to be well determined. Here, using an optical microscope equipped with magnetic tweezers, we report an experimental procedure to obtain all those information on a single magnetic rod. In particular, we measure magnetic susceptibility χ by analyzing the deformation of a rod subjected to a uniform magnetic field. To do so, we refine a theoretical model which takes into account the variation of χ with the internal field. We prove experimentally that this model yields consistent measurements, at any value of the field strength and the incidence angle. From the combination of the different measurements, we also deduce the number of iron oxide nanoparticles which are embedded within the polymer matrix of the superparamagnetic rods under study.


Fluid core size of Mars from detection of the solar tide.
The solar tidal deformation of Mars, measured by its k2 potential Love number, has been obtained from an analysis of Mars Global Surveyor radio tracking. The observed k2 of 0.153 +/- 0.017 is large enough to rule out a solid iron core and so indicates that at least the outer part of the core is liquid. The inferred core radius is between 1520 and 1840 kilometers and is independent of many interior properties, although partial melt of the mantle is one factor that could reduce core size. Ice-cap mass changes can be deduced from the seasonal variations in air pressure and the odd gravity harmonic J3, given knowledge of cap mass distribution with latitude. The south cap seasonal mass change is about 30 to 40% larger than that of the north cap.


Insights into the thermoelectric properties of SnSe from ab initio calculations.
The thermoelectric properties of SnSe are studied by first-principles methods using an original methodology. We computed first the electronic structure of the system, which justifies its macroscopic anisotropy; the inclusion of van der Waals dispersive corrections improves the agreement of the structural parameters with experiments. The Seebeck coefficient and the electrical and thermal conductivities of single crystals and polycrystals are subsequently described in good agreement with experimental data. As for the electrical conductivity, values calculated with a temperature-dependent relaxation time compare well with the available measurements, especially for single crystals; in contrast, a constant relaxation time suffices to describe the results for polycrystals. Based on the iterative solution of the Boltzmann transport equation for phonons, we discuss the behavior of the thermal conductivity of the system in terms of its phonon spectrum. Finally, the figure of merit of SnSe single crystals and polycrystals is calculated and correlated with the previous discussions about electrical and thermal conductivities. From these findings, possible strategies to increase the figure of merit in practice are suggested.


Placebo interventions for all clinical conditions.
Placebo interventions are often claimed to substantially improve patient-reported and observer-reported outcomes in many clinical conditions, but most reports on effects of placebos are based on studies that have not randomised patients to placebo or no treatment. Two previous versions of this review from 2001 and 2004 found that placebo interventions in general did not have clinically important effects, but that there were possible beneficial effects on patient-reported outcomes, especially pain. Since then several relevant trials have been published. Our primary aims were to assess the effect of placebo interventions in general across all clinical conditions, and to investigate the effects of placebo interventions on specific clinical conditions. Our secondary aims were to assess whether the effect of placebo treatments differed for patient-reported and observer-reported outcomes, and to explore other reasons for variations in effect. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 4, 2007), MEDLINE (1966 to March 2008), EMBASE (1980 to March 2008), PsycINFO (1887 to March 2008) and Biological Abstracts (1986 to March 2008). We contacted experts on placebo research, and read references in the included trials. We included randomised placebo trials with a no-treatment control group investigating any health problem. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Trials with binary data were summarised using relative risk (a value of less than 1 indicates a beneficial effect of placebo), and trials with continuous outcomes were summarised using standardised mean difference (a negative value indicates a beneficial effect of placebo). Outcome data were available in 202 out of 234 included trials, investigating 60 clinical conditions. We regarded the risk of bias as low in only 16 trials (8%), five of which had binary outcomes.In 44 studies with binary outcomes (6041 patients), there was moderate heterogeneity (P < 0.001; I(2) 45%) but no clear difference in effects between small and large trials (symmetrical funnel plot). The overall pooled effect of placebo was a relative risk of 0.93 (95% confidence interval (CI) 0.88 to 0.99). The pooled relative risk for patient-reported outcomes was 0.93 (95% CI 0.86 to 1.00) and for observer-reported outcomes 0.93 (95% CI 0.85 to 1.02). We found no statistically significant effect of placebo interventions in four clinical conditions that had been investigated in three trials or more: pain, nausea, smoking, and depression, but confidence intervals were wide. The effect on pain varied considerably, even among trials with low risk of bias.In 158 trials with continuous outcomes (10,525 patients), there was moderate heterogeneity (P < 0.001; I(2) 42%), and considerable variation in effects between small and large trials (asymmetrical funnel plot). It is therefore a questionable procedure to pool all the trials, and we did so mainly as a basis for exploring causes for heterogeneity. We found an overall effect of placebo treatments, standardised mean difference (SMD) -0.23 (95% CI -0.28 to -0.17). The SMD for patient-reported outcomes was -0.26 (95% CI -0.32 to -0.19), and for observer-reported outcomes, SMD -0.13 (95% CI -0.24 to -0.02). We found an effect on pain, SMD -0.28 (95% CI -0.36 to -0.19)); nausea, SMD -0.25 (-0.46 to -0.04)), asthma (-0.35 (-0.70 to -0.01)), and phobia (SMD -0.63 (95% CI -1.17 to -0.08)). The effect on pain was very variable, also among trials with low risk of bias. Four similarly-designed acupuncture trials conducted by an overlapping group of authors reported large effects (SMD -0.68 (-0.85 to -0.50)) whereas three other pain trials reported low or no effect (SMD -0.13 (-0.28 to 0.03)). The pooled effect on nausea was small, but consistent. The effects on phobia and asthma were very uncertain due to high risk of bias. There was no statistically significant effect of placebo interventions in the seven other clinical conditions investigated in three trials or more: smoking, dementia, depression, obesity, hypertension, insomnia and anxiety, but confidence intervals were wide.Meta-regression analyses showed that larger effects of placebo interventions were associated with physical placebo interventions (e.g. sham acupuncture), patient-involved outcomes (patient-reported outcomes and observer-reported outcomes involving patient cooperation), small trials, and trials with the explicit purpose of studying placebo. Larger effects of placebo were also found in trials that did not inform patients about the possible placebo intervention. We did not find that placebo interventions have important clinical effects in general. However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting. The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important. Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed.


Exploration of Lipid Metabolism in Gastric Cancer: A Novel Prognostic Genes Expression Profile.
Alterations in lipid metabolism are increasingly being recognized. However, the application of lipid metabolism in the prognosis of gastric cancer (GC) has not yet been explored. A total of 204 lipid metabolism relative genes were analyzed in the GC cohort from The Cancer Genome Atlas (TCGA), and four independent cohorts from Gene Expression Omnibus (GEO) and one cohort from Wuhan Union Hospital were applied for external validation. Differential expression and enrichment analyses were performed between GC and normal tissue. The LASSO-Cox proportional hazard regression model was applied to select prognostic genes and to construct a gene expression profile. Our research indicated that higher expression level of AKR1B1, PLD1, and UGT8 were correlated with worse prognosis of GC patients, while AGPAT3 was correlated with better prognosis. Furthermore, we developed a gene profile composed of AGPAT3, AKR1B1, PLD1, and UGT8 suggested three groups with a significant difference in overall survival (OS). The profile was successfully validated in an independent cohort and performed well in the immunohistochemical cohort. Furthermore, we found that ether lipid metabolism, glycerophospholipid metabolism, and glycerolipid metabolism were upregulated, and fatty acid β-oxidation and other lipid peroxidation processes were reduced in GC. Collectively, we found lipid metabolism is reliable and clinically applicable in predicting the prognosis of GC based on a novel gene profile.


Accuracy of 3-Tesla magnetic resonance imaging for the diagnosis of intra-articular knee injuries in children and teenagers.
Magnetic resonance imaging (MRI) is a commonly used tool for the diagnosis of intra-articular knee pathologies. Although many studies have reported the accuracy of MRI in the adult population, fewer studies have investigated these tests in younger patients. Furthermore, these studies have shown a higher variability in both the sensitivity and the specificity of MRI for these knee injuries in this age group. Advancements in MRI technology, such as the 3-Tesla (3T) MRI magnet, have shown promising results for musculoskeletal injury diagnosis in adults. This study aims to evaluate 3 T MRI for the diagnosis of intra-articular knee pathologies in a pediatric and adolescent patient population. The records of 116 patients (119 knees) under the age of 20 years who underwent 3 T MRI studies of the knee and subsequent knee arthroscopy were reviewed retrospectively. The MRI report from the musculoskeletal radiology staff, the interpretation from the staff orthopedic surgeon, and the operative note dictations were compared, with a focus on meniscus and anterior cruciate ligament (ACL) pathologies. Seventeen orthopedic staff reads were not obtainable. Arthroscopy was used as the gold standard for diagnosis. The average age at MRI exam was 16.0 years and at surgery was 16.2 years. Using the musculoskeletal radiologist interpretation, the sensitivity and the specificity of 3 T MRI were 81.0% and 90.9% for medial meniscus injuries, 68.8% and 93% for lateral meniscus injuries, and 97.9% and 98.6% for ACL injuries, respectively. The orthopedic surgeon's interpretation of 3 T MRI had a sensitivity and specificity of 75.7% and 92.4% for medial meniscus injuries, 69.8% and 98.3% for lateral meniscus injuries, and 100% and 98.6% for ACL injuries, respectively. Posterior horn tears had the greatest discrepancies. When performed on pediatric and adolescent patients, newer 3 T MRI studies have excellent accuracy for diagnosing ACL tears. These studies also show a higher accuracy for the diagnosis of medial meniscal tears than lateral meniscal tears. Diagnostic study--Level 2.


Efficacy and safety of pharmacological, physical, and psychological interventions for the management of chronic pain in children: a WHO systematic review and meta-analysis.
Chronic pain in childhood is an international public health problem. We conducted a systematic review and meta-analysis to provide a summary of the published evidence of pharmacological, physical, and psychological therapies for children with chronic pain conditions. We searched CENTRAL, MEDLINE, EMBASE, and PsycINFO from inception to April 2020; clinical trial registries; and other sources for randomised controlled trials or comparative observational trials. We extracted critical outcomes of pain intensity, quality of life, physical functioning, role functioning, emotional functioning, sleep, and adverse events. We assessed studies for risk of bias and certainty of the evidence using GRADE. We included 34 pharmacological (4091 participants), 25 physical therapy (1470 participants), and 63 psychological trials (5025 participants). Participants reported a range of chronic pain conditions. Most studies were assessed to have unclear or high risk of bias across multiple domains. Pharmacological, physical, and psychological therapies showed some benefit for reducing pain, posttreatment, but only physical and psychological therapies improved physical functioning. We found no benefit of any treatment modality for health-related quality of life, role functioning, emotional functioning, or sleep. Adverse events were poorly reported, particularly for psychological and physical interventions. The largest evidence base for the management of chronic pain in children supports the use of psychological therapies, followed by pharmacological and physical therapies. However, we rated most outcomes as low or very low certainty, meaning further evidence is likely to change our confidence in the estimates of effects. This protocol was registered on PROSPERO (CRD42020172451).


Influence of TS and ABCB1 gene polymorphisms on survival outcomes of 5‑FU-based chemotherapy in a Chinese population of advanced gastric cancer patients.
To investigate the impacts of gene variations on survival outcomes of advanced gastric cancer (AGC) patients treated with 5‑fluorouracil (5-FU)-based chemotherapy, we analyzed the associations of 2 indels of the TS gene rs34743033 (double or triple tandem repeats of a 28 bp sequence in 5'-UTR, denoted as 2R or 3R allele) and rs16430 (a 6 bp variation at 1494 bp in 3'-UTR, denoted as ins6 or del6 allele) and 2 single nucleotide polymorphisms (SNPs) of ABCB1gene rs2032582 in exon 21 and rs1045642 in exon 26, with clinical outcomes after 5‑FU treatment. Generally, indels rs34743033 and rs16430 were genotyped by PCR and polyacrylamide gel electrophoresis assay and SNPs rs2032582 and rs1045642 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 110 Chinese AGC patients post-chemotherapy. Cox regression analysis was used to analyze the risk factors affecting patient survival. As a result, rs34743033, rs1045642 and rs2032582 were shown to be significantly associated with overall survival (P < 0.05), and associations between the four polymorphisms with disease-free survival were also observed (P < 0.05). Moreover, we found that genotypes rs34743033 3R/2R, rs16430 ins6/del6, rs1045642 CC or CT, and rs2032582 GG were beneficial predictors of clinical treatment outcome in AGC patients, suggesting some clinical implications in chemotherapy of a Chinese population.


Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to Predict Progression to Clinical Macular Edema: An Attempt of Composite Grading of Macular Edema.
To characterize the relevance of macular thickness changes in the inner and outer rings in the progression of macular edema in eyes/patients with diabetes type 2. A total of 374 type 2 diabetic patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20-35) were included in a 12-month prospective observational study to identify retinopathy progression. Retinal thickness analyses were performed in 194 eyes/patients using Cirrus SD- OCT and 166 eyes/patients using Spectralis SD-OCT. The DRCR.net classification of subclinical and clinical macular edema was used. A composite grading of macular edema is proposed in this study. A total of 317 eyes/patients completed the study. SD-OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Increased thickness of the central subfield is the best predictor for the development of clinical macular edema, with 85.7% sensitivity and 71.9% specificity (OR: 2.57, 95% CI: 0.82-7.99). However, the involvement of the inner and outer rings is a cumulative predictor of progression to clinical macular edema (OR: 8.69, 95% CI: 2.85-26.52). A composite OCT grading of macular edema taking into account the retinal thickness changes in the inner and outer macular rings offers a simple way to characterize macular edema, with added clinical value.


Analysis of a circular derivative of Saccharomyces cerevisiae chromosome III: a physical map and identification and location of ARS elements.
DNA was isolated from a circular derivative of chromosome III to prepare a library of recombinant plasmids enriched in chromosome III sequences. An ordered set of recombinant plasmids and bacteriophages carrying the contiguous 210-kilobase region of chromosome III between the HML and MAT loci was identified, and a complete restriction map was prepared with BamHI and EcoRI. Using the high frequency transformation assay and extensive subcloning, 13 ARS elements were mapped in the cloned region. Comparison of the physical maps of chromosome III from three strains revealed that the chromosomes differ in the number and positions of Ty elements and also show restriction site polymorphisms. A comparison of the physical map with the genetic map shows that meiotic recombination rates vary at least tenfold along the length of the chromosome.


Exposure to aflatoxins and fumonisins and linear growth of children in rural Ethiopia: a longitudinal study.
We hypothesise that exposure to aflatoxins and fumonisins, measured in serum, alters protein synthesis, reducing serum protein and insulin-like growth factor 1 (IGF-1), increasing inflammation and infection, leading to child's linear growth failure. Children 6-35 months, stratified by baseline stunting, were subsampled from an intervention trial on quality protein maize consumption and evaluated at two time-points. Blood samples and anthropometric data were collected in the pre-harvest (August-September 2015) and post-harvest (February 2016) seasons in rural Ethiopia. 102 children (50 stunted and 52 non-stunted). Proportions of children exposed to aflatoxin G1, aflatoxin G2 and aflatoxin M1 were higher in the pre-harvest (8, 33 and 7, respectively) compared to post-harvest season (4, 28 and 4, respectively). The proportion of children exposed to any aflatoxin was higher in the pre-harvest than post-harvest season (51 % v. 41 %). Fumonisin exposure ranged from 0 % to 11 %. In joint statistical tests, aflatoxin exposure was associated with serum biomarkers of inflammation (C-reactive protein, α-1-glycoprotein) and protein status (transthyretin, lysine, tryptophan), IGF-1 and linear growth (all P < 0·01). However, exposure to specific aflatoxins was not significantly associated with any biomarkers or outcomes (all P > 0·05). Aflatoxin exposure among rural Ethiopian children was high, with large variation between seasons and individual aflatoxins. Fumonisin exposure was low. There was no clear association between aflatoxin exposure and protein status, inflammation or linear growth. A larger study may be needed to examine the potential biological interactions, and the assessment of aflatoxins in food is needed to determine sources of high exposure.


Unilateral eye closure and interhemispheric EEG asymmetry during sleep in the pigeon (Columba livia).
Aquatic mammals (i.e., Cetaceans, eared seals and manatees) and birds show interhemispheric asymmetries (IA) in slow-wave sleep-related electroencephalographic (EEG) activity, suggesting that the depth of sleep differs between hemispheres. In birds, an association between unilateral eye closure and IA has been reported in five species from three orders (i.e., Galliformes, Charadriiformes, and Anseriformes). Moreover, unilateral eye closure has been observed during behaviorally defined sleep in 29 species from 13 avian orders, suggesting that birds in general display IA during sleep. Despite the apparent prevalence of unilateral eye closure and IA in birds, previous work did not detect IA in the pigeon, thereby challenging the conclusion that this is a general feature of birds. Using digital period amplitude analysis, an objective method for quantifying EEG power (a measure of wave amplitude) across different frequencies, we demonstrate that pigeons do, in fact, display an association between unilateral eye closure and IA. For a given hemisphere, standardized 2-4 Hz EEG power was greater when the contralateral eye was closed when compared to open. We also found that pigeons used the open eye during IA to monitor their environment. In addition, individual pigeons showed a bias for keeping one eye open more than the other. The direction (left vs. right) of this bias differed across birds, and appeared to be influenced by the structure of the surrounding environment. Finally, with the addition of pigeons (order Columbiformes), IA associated with unilateral eye closure has been recorded in four avian orders, suggesting that this form of sleep is widespread in birds.


Epidemiology and symptomatology of depression in Sri Lanka: a cross-sectional population-based survey in Colombo District.
It is important to understand the nature of depression in non-Western and lower-income countries, but little such research exists. This study aimed to examine the characteristic features of depression in Sri Lanka, and to identify environmental risk factors. Depression diagnoses, symptoms and impairment were measured using the Composite International Diagnostic Interview, in a population-based sample of 6014 twins and non-twins in the Colombo region of Sri Lanka (the CoTASS sample). Socio-demographic factors and environments were assessed via questionnaires. Lifetime-ever depression was reported in 6.6% of participants, rising to 11.2% if the functional impairment criterion was excluded. The symptom profile of depression and its socio-demographic associations were very comparable to those in Western and more economically developed countries, whether functional impairment was included in the definition or not. Standard of living was independently associated with depression, especially among men at the more deprived end of the distribution. Specific associations were found with both financial wellbeing and material characteristics of the home environment. The observational associations identified are cross-sectional, so do not necessarily imply causal links. Aside from a lower prevalence, depression is very similar in this predominantly urban Sri Lankan sample to higher-income, Western countries, and may be under-identified due to a relatively low cultural appropriateness of the assessment of impairment. Under Sri Lanka's cultural and environmental context, certain aspects of the material environment are associated with depression among certain segments of society, perhaps because of their particular link to social status and social networks.


Microglial Activation Induces Generation of Oligodendrocyte Progenitor Cells from the Subventricular Zone after Focal Demyelination in the Corpus Callosum.
Neuroblasts derived from neural stem cells (NSCs) in the subventricular zone (SVZ) migrate along the rostral migratory stream into the olfactory bulb to generate interneurons under normal physiological conditions. When demyelination occurs, NSCs or neural progenitor cells (NPCs) in the SVZ provide newly formed oligodendrocytes to demyelinated lesions. The plasticity of NSC/NPC lineages may tend to oligodendrogenesis under the influence of demyelinated lesions. The mechanisms, however, still remain unknown. This study revealed that focal demyelination in the corpus callosum caused activation of the microglia, not only at the site of demyelination but also in the SVZ, and dramatically increased the generation of oligodendrocyte progenitor cells (OPCs) in the SVZ. Furthermore, the inhibition of microglial activation by minocycline treatment decreased OPC generation in the SVZ, suggesting that microglial activation in the SVZ, induced by the focal demyelination in the corpus callosum, regulates NSC/NPC lineage plasticity in situ. In contrast to the findings regarding demyelination in the corpus callosum, inducing focal demyelination in the internal capsule did not induce either microglial activation or OPC generation in the SVZ. These results suggest that the mechanism of OPC generation in the SVZ after inducing demyelinating lesions could be different across the demyelinated regions.


Cerebral subcortical small vessel disease in subjects with pathologically confirmed Alzheimer disease: a clinicopathologic study in the Oxford Project to Investigate Memory and Ageing (OPTIMA).
The understanding of how cerebrovascular disease (CVD) contributes to dementia is hampered by a lack of agreed and validated pathologic methods to accord weight to the contribution of different aspects of CVD to dementia. A previous study from the Oxford Project to Investigate Memory and Ageing (OPTIMA) validated a scheme for assessing the contribution of subcortical small vessel disease (SVD) toward dementia in the elderly by showing a significant inverse relationship between the severity of SVD and cognition in subjects without any other dementia pathology using this method. In the present paper, the method has been used to assess severity of SVD in 161 cases of neuropathologically confirmed Alzheimer disease. The results showed there was no relationship between the SVD score and cognitive scores acquired in the last 2 years of life. SVD scores were significantly related to age (P<0.0017) and were slightly but significantly higher in females than males (P<0.049). SVD scores were not related to blood pressure at entry to OPTIMA and were significantly lower when compared with the cohort of OPTIMA cases with only CVD (mean 5.06 ± 1.85 vs. 5.9 ± 2.67; P<0.0065). We conclude that when Alzheimer disease pathology is present in elderly subjects, it overwhelms the modest contribution that SVD makes to cognitive impairment.


Predicting human protein function with multi-task deep neural networks.
Machine learning methods for protein function prediction are urgently needed, especially now that a substantial fraction of known sequences remains unannotated despite the extensive use of functional assignments based on sequence similarity. One major bottleneck supervised learning faces in protein function prediction is the structured, multi-label nature of the problem, because biological roles are represented by lists of terms from hierarchically organised controlled vocabularies such as the Gene Ontology. In this work, we build on recent developments in the area of deep learning and investigate the usefulness of multi-task deep neural networks (MTDNN), which consist of upstream shared layers upon which are stacked in parallel as many independent modules (additional hidden layers with their own output units) as the number of output GO terms (the tasks). MTDNN learns individual tasks partially using shared representations and partially from task-specific characteristics. When no close homologues with experimentally validated functions can be identified, MTDNN gives more accurate predictions than baseline methods based on annotation frequencies in public databases or homology transfers. More importantly, the results show that MTDNN binary classification accuracy is higher than alternative machine learning-based methods that do not exploit commonalities and differences among prediction tasks. Interestingly, compared with a single-task predictor, the performance improvement is not linearly correlated with the number of tasks in MTDNN, but medium size models provide more improvement in our case. One of advantages of MTDNN is that given a set of features, there is no requirement for MTDNN to have a bootstrap feature selection procedure as what traditional machine learning algorithms do. Overall, the results indicate that the proposed MTDNN algorithm improves the performance of protein function prediction. On the other hand, there is still large room for deep learning techniques to further enhance prediction ability.


Comparison of the Resistance of Bond Strength of Cemented Fiberglass Posts in Different Root Thirds with and without Silanization: An Ex Vivo Study.
To compare the application of silane in the bond strength of fiberglass posts in different thirds of the cemented root with a self-adhesive system in an ex vivo study. Freshly extracted teeth were collected, which had indication of extraction for periodontal or orthodontic reasons. The study evaluated n = 42 specimens that were divided into two large groups: I (control, without silane) and II (with silane); the resistance to adhesion in the respective thirds of the root (cervical, middle, and apical) was also evaluated. The prefabricated fiberglass posts were cemented with and without silane according to the manufacturer's instructions and were cemented with a resin-based cementing agent. The adhesion strength test was evaluated by the universal testing machine. According to the results of this experimental trial, the fiberglass posts that did not receive silane had the highest adhesion strength of 26.5 ± 10.6 MPa, while silane-cemented posts only had 21.7 ± 8.1 MPa. The statistical analysis was performed using the Kruskal-Wallis test and work with a level of significance of p < 0.05. The use of silane as part of the cementing protocol in fiberglass posts does not influence the adhesion strength between the surfaces of the posts and the resin cement because there were statistically significant differences between both adhesion protocols. This study has a great impact because according to the results, clinical decisions can be made when cementing the fiberglass posts through the application of silane or not.


Modeling the effect of palate shape on the articulatory-acoustics mapping.
Articulatory variability is reduced for people with flatter palates [Bakst and Lin (2015). Proceedings of the 18th International Congress of Phonetic Sciences; Brunner, Fuchs, and Perrier (2009). J. Acoust. Soc. Am. 125(6), 3936-3949]. Brunner, Fuchs, and Perrier [(2009). J. Acoust. Soc. Am. 125(6), 3936-3949] hypothesized that this is because the mapping between articulation and acoustics depends on palate depth. Articulatory synthesis was used with three different palate shapes to generate productions of /r/. The parameter spaces of the articulatory synthesizers were searched for vocal tract configurations that result in low F3 (the hallmark acoustic cue for /r/). Palate shape influences not only the sensitivity of the articulatory-acoustic mapping, but also the effect of each individual articulatory parameter on F3.


Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20 patients.
Varicella zoster virus (VZV) is a leading cause of acute viral encephalitis but little is known about its clinical, biological and imaging features. Furthermore, the most favourable treatment regimen has not been determined. We studied a prospective cohort of 20 HIV-negative patients presenting with acute VZV encephalitis caused by primary infection or reactivation. VZV was identified in 16 of 20 cases by PCR detection of the DNA in the cerebrospinal fluid. The four remaining cases occurred during or soon after a VZV rash. The median age of the 17 adults was 76 (19-86) years; the three other patients were children (0.5-5 years). Three patients were immunocompromised. Nine adult patients presented with a rash. Eighteen patients presented with fever and an acute encephalitic syndrome: diffuse brain dysfunction, focal neurological signs, seizures and cranial nerve palsies. Three patients presented with either ventricular or subdural haemorrhage, one with myelitis, and one with asymptomatic stenosis of the middle cerebral artery. The imaging was either normal or revealed non-specific abnormalities such as cortical atrophy but no evidence of stroke. All patients were given acyclovir at various dosages and durations but the case fatality rate remained high (15%) and sequelae were frequently observed either at discharge or at follow-up 3 years later.


The effect of cluster size on the optical band gap energy of Zn-based metal-organic frameworks.
We have synthesized three Metal-Organic Frameworks (MOFs) in which Zn metal ions form the secondary building unit, and 4,4'-sulfonyldibenzoic acid (SDB) serves as the ligand: [[Zn(DMF)(SDB)](DMF), 1, [Zn(3)(DMF)(3)(SDB)(3)](DMF), 2 and [Zn(3)(OH)(2)(SDB)(2)] (DMF)(2), 3, where DMF = dimethyl formamide]. Compound contains a paddle-wheel type Zn dimer, compound contains a Zn trimer motif, and contains a one-dimensional Zn-OH-Zn chain. These building units may be considered to be Zn clusters. We have measured and theoretically calculated the band gap energy and by theoretical investigations we found that the cluster size plays an important role in the band gap energy, however additional effects are observed. The larger cluster size corresponds to a larger band gap energy, however the cavity of the trimer based compound (2) traps a solvent molecule that decreases the band gap energy.


Despite Resources From The ACA, Most States Do Little To Help Addiction Treatment Programs Implement Health Care Reform.
The Affordable Care Act (ACA) dramatically expands health insurance for addiction treatment and provides unprecedented opportunities for service growth and delivery model reform. Yet most addiction treatment programs lack the staffing and technological capabilities to respond successfully to ACA-driven system change. In light of these challenges, we conducted a national survey to examine how Single State Agencies for addiction treatment--the state governmental organizations charged with overseeing addiction treatment programs--are helping programs respond to new requirements under the ACA. We found that most Single State Agencies provide little assistance to addiction treatment programs. Most agencies are helping programs develop collaborations with other health service programs. However, fewer than half reported providing help in modernizing systems to support insurance participation, and only one in three provided assistance with enrollment outreach. In the absence of technical assistance, it is unlikely that addiction treatment programs will fully realize the ACA's promise to improve access to and quality of addiction treatment.


Early determinants of obesity.
High rates of overweight and obesity even in very young children argue the case for strategies to prevent overweight from very young ages. Historical studies, prospective birth cohorts, and more recently genetic studies all indicate that the rapid weight gain trajectory to later obesity starts in the first months of life, even from birth. Early puberty and age at menarche are consequences of rapid infant weight gain and childhood overweight, and in turn these adolescent traits are predictive for obesity, diabetes, hypertension and cardiovascular disease events in later life. Understanding of the nutritional, parental and wider determinants of rapid infant weight gain are informing the development of obesity prevention strategies starting in early life. Such strategies could be further refined by future studies that address the specific regulation of infant adiposity, and also by studies that explore whether these life-course trajectories are modifiable during adolescence.


Universal Approximation Capability of Broad Learning System and Its Structural Variations.
After a very fast and efficient discriminative broad learning system (BLS) that takes advantage of flatted structure and incremental learning has been developed, here, a mathematical proof of the universal approximation property of BLS is provided. In addition, the framework of several BLS variants with their mathematical modeling is given. The variations include cascade, recurrent, and broad-deep combination structures. From the experimental results, the BLS and its variations outperform several exist learning algorithms on regression performance over function approximation, time series prediction, and face recognition databases. In addition, experiments on the extremely challenging data set, such as MS-Celeb-1M, are given. Compared with other convolutional networks, the effectiveness and efficiency of the variants of BLS are demonstrated.


Prognostic models in myelodysplastic syndromes.
Establishing the prognosis for patients with myelodysplastic syndromes (MDS) is a key element of their care. It helps patients understand the severity of their disease and set expectations for their future. For physicians, an accurate estimate of prognosis drives decisions about the timing and choice of therapeutic options to consider. The International Prognostic Scoring System (IPSS) has been the standard tool for MDS risk stratification since it was released in 1997. It has been used to describe patients in pivotal clinical trials and is a key element of practice guidelines. Subsequent changes to the classification scheme for MDS and an underestimation of risk in some patients from the low and intermediate-1 categories have led to the development of several newer prognostic models. The most recent is the revised IPSS (IPSS-R), which addresses several of the perceived deficiencies of its predecessor. Despite their utility, none of the available prognostic systems incorporates disease-related molecular abnormalities such as somatic mutations. These lesions are present in the nearly all cases and many have been shown to improve upon existing prognostic models. However, the interpretation of somatic mutations can be challenging and it is not yet clear how best to combine them with clinical predictors of outcome. Here I review several prognostic scoring systems developed after the IPSS and describe the emerging use of molecular markers to refine risk stratification in the MDS patient population.


No effect of probiotics on respiratory allergies: a seven-year follow-up of a randomized controlled trial in infancy.
Supplementation with the probiotic Lactobacillus reuteri reduced the incidence of IgE-associated allergic disease in infancy. This treatment might therefore also reduce the risk of asthma and allergic rhinoconjunctivitis in school age. To evaluate whether perinatal and infant supplementation with L. reuteri reduced the prevalence of respiratory allergic disease in school age and to explore whether this supplementation was associated with any long-term side effects. A randomized, placebo-controlled trial with oral supplementation with L. reuteri ATCC 55730 (1 × 10(8) CFU) during the last month of gestation and through the first year of life comprising 232 families with allergic disease, of whom 184 completed a 7-yr follow-up. The primary outcomes at 7 yr of age were allergic disease and skin prick test reactivity (ClinicalTrials.gov ID NCT01285830). The prevalence of asthma (15% in the probiotic vs. 16% in placebo group), allergic rhinoconjunctivitis (27% vs. 20%), eczema (21% vs. 19%) and skin prick test reactivity (29% vs. 26%) was similar in the probiotic and placebo group. Growth indices and gastrointestinal symptoms were similar in the two groups. No severe adverse events were reported. The effect of L. reuteri on sensitization and IgE-associated eczema in infancy did not lead to a lower prevalence of respiratory allergic disease in school age. Thus, the effect of L. reuteri on the immune system seems to be transient. Administration of L. reuteri during the last weeks of gestation and in infancy was not associated with any long-term side effects.


Shift in Emergency Department Provider Attitudes Toward Patients With Sickle Cell Disease.
Patients with sickle cell disease frequently seek care in the emergency department. They have reported experiencing negative attitudes from emergency providers. This study was undertaken to evaluate change in emergency provider attitudes toward patients with sickle cell disease over a 2.5-year time period when several educational efforts were ongoing. The General Perceptions about Sickle Cell Disease Patients Scale was used to measure emergency provider attitudes at 2 emergency departments at baseline, 6 months, and 30 months into the project. Analyses of covariance were used to test for effects of site, time, and provider type, as well as their interactions, on Negative attitudes, Uneasiness With Care, and Positive Attitudes subscale scores, after controlling for years of provider experience. The number of surveys returned at the 3 time points was 216, 182, and 113, respectively. The mean Negative Attitudes subscale scores decreased significantly over time, with significantly higher mean Negative Attitudes subscale scores reported by nurses than by physicians. The mean Uneasiness With Care subscale scores did not differ significantly over time, but the mean score was significantly higher for physicians than for nurses. The mean Positive Attitudes subscale scores significantly improved over time, with physicians tending to have a higher mean Positive Attitudes subscale scores than nurses. During the observation period, there was improvement in attitudes, with a decline in mean Negative Attitudes subscale scores and increase in mean Positive Attitudes subscale scores. Physicians reported better attitudes than nurses.


Altered visual information processing systems in bipolar disorder: evidence from visual MMN and P3.
Mismatch negativity (MMN) and P3 are unique ERP components that provide objective indices of human cognitive functions such as short-term memory and prediction. Bipolar disorder (BD) is an endogenous psychiatric disorder characterized by extreme shifts in mood, energy, and ability to function socially. BD patients usually show cognitive dysfunction, and the goal of this study was to access their altered visual information processing via visual MMN (vMMN) and P3 using windmill pattern stimuli. Twenty patients with BD and 20 healthy controls matched for age, gender, and handedness participated in this study. Subjects were seated in front of a monitor and listened to a story via earphones. Two types of windmill patterns (standard and deviant) and white circle (target) stimuli were randomly presented on the monitor. All stimuli were presented in random order at 200-ms durations with an 800-ms inter-stimulus interval. Stimuli were presented at 80% (standard), 10% (deviant), and 10% (target) probabilities. The participants were instructed to attend to the story and press a button as soon as possible when the target stimuli were presented. Event-related potentials (ERPs) were recorded throughout the experiment using 128-channel EEG equipment. vMMN was obtained by subtracting standard from deviant stimuli responses, and P3 was evoked from the target stimulus. Mean reaction times for target stimuli in the BD group were significantly higher than those in the control group. Additionally, mean vMMN-amplitudes and peak P3-amplitudes were significantly lower in the BD group than in controls. Abnormal vMMN and P3 in patients indicate a deficit of visual information processing in BD, which is consistent with their increased reaction time to visual target stimuli. Both bottom-up and top-down visual information processing are likely altered in BD.


Gangliosides' protection against lysosomal pathology of synucleinopathies.
Gangliosides are abundantly expressed in the nervous system, and deregulated expression or activity of gangliosides is associated with the progression of various disorders, including lysosomal storage diseases, Guillain-Barre syndrome and Alzheimer disease. By contrast, previous studies show that GM1 ganglioside may act in a protective manner in the drug (e.g., MPTP and 6-OHDA)-induced Parkinsonian models, although the precise mechanisms have not been well addressed. In our recent publication, dementia with Lewy bodies (DLB)-linked neuroblastoma cells were treated with D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthetase. These PDMP-treated cells develop lysosomal diseases characterized by reduced lysosomal activity, enhanced lysosomal permeability and cytotoxicity. Furthermore, PDMP-mediated inhibition of autophagy-lysosomal pathway result in both accumulation of alpha-synuclein and mutant beta-synuclein. Finally, these phenotypes are reversed by ganglioside treatment. Taken together, our results suggest that endogenous gangliosides may play a protective role against the lysosomal pathology of synucleinopathies.


Money, men and markets: economic and sexual empowerment of market women in southwestern Uganda.
Market trading requires access to cash, independent decision-making, mobility and social interaction. This study sought to explore whether market work empowers women with respect to spending decisions and negotiation over sex and condom-use. A semi-structured questionnaire was administered to 212 market women; and 12 focus group discussions and 52 in-depths interviews were conducted among market women in southwestern Uganda. Market women reported high levels of independence, mobility, assertiveness and social interaction. Access to cash was not synonymous with control over it, however. Spending decisions were limited by men's ability to selectively withdraw finances for expenditures central to women's concerns including household and children's needs. Trading in markets earns women masculine labels such as kiwagi, characterized variously as independent, rebellious and insubordinate. Earning money does not change expectations of correct behaviour for wives, making it difficult for women to initiate, deny sex or ask for condoms. Independence and income from market work may make it easier for women to enter and exit new sexual relationships. However, unable to protect themselves within partnerships, HIV risk may increase as a result.


Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.
As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ), these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.


Weaving versus blending: a quantitative assessment of the information carrying capacities of two alternative methods for conveying multivariate data with color.
In many applications, it is important to understand the individual values of, and relationships between, multiple related scalar variables defined across a common domain. Several approaches have been proposed for representing data in these situations. In this paper we focus on strategies for the visualization of multivariate data that rely on color mixing. In particular, through a series of controlled observer experiments, we seek to establish a fundamental understanding of the information-carrying capacities of two alternative methods for encoding multivariate information using color: color blending and color weaving. We begin with a baseline experiment in which we assess participants' abilities to accurately read numerical data encoded in six different basic color scales defined in the L*a*b* color space. We then assess participants' abilities to read combinations of 2, 3, 4 and 6 different data values represented in a common region of the domain, encoded using either color blending or color weaving. In color blending a single mixed color is formed via linear combination of the individual values in L*a*b* space, and in color weaving the original individual colors are displayed side-by-side in a high frequency texture that fills the region. A third experiment was conducted to clarify some of the trends regarding the color contrast and its effect on the magnitude of the error that was observed in the second experiment. The results indicate that when the component colors are represented side-by-side in a high frequency texture, most participants' abilities to infer the values of individual components are significantly improved, relative to when the colors are blended. Participants' performance was significantly better with color weaving particularly when more than 2 colors were used, and even when the individual colors subtended only 3 minutes of visual angle in the texture. However, the information-carrying capacity of the color weaving approach has its limits. We found that participants' abilities to accurately interpret each of the individual components in a high frequency color texture typically falls off as the number of components increases from 4 to 6. We found no significant advantages, in either color blending or color weaving, to using color scales based on component hues thatare more widely separated in the L*a*b* color space. Furthermore, we found some indications that extra difficulties may arise when opponent hues are employed.


Why do delayed summaries improve metacomprehension accuracy?
We showed that metacomprehension accuracy improved when participants (N=87 college students) wrote summaries of texts prior to judging their comprehension; however, accuracy only improved when summaries were written after a delay, not when written immediately after reading. We evaluated two hypotheses proposed to account for this delayed-summarization effect (the accessibility hypothesis and the situation model hypothesis). The data suggest that participants based metacomprehension judgments more on the gist of texts when they generated summaries after a delay; whereas, they based judgments more on details when they generated summaries immediately after reading. Focusing on information relevant to the situation model of a text (the gist of a text) produced higher levels of metacomprehension accuracy, which is consistent with situation model hypothesis.