International Medical Graduates in the US Physician Workforce and Graduate Medical Education: Current and Historical Trends.
Data show that international medical graduates (IMGs), both US and foreign born, are more likely to enter primary care specialties and practice in underserved areas. Comprehensive assessments of representation trends for IMGs in the US physician workforce are limited. We reported current and historical representation trends for IMGs in the graduate medical education (GME) training pool and US practicing physician workforce. We compared representation for the total GME and active practicing physician pools with the 20 largest residency specialties. A 2-sided test was used for comparison, with P < .001 considered significant. To assess significant increases in IMG GME trainee representation for the total pool and each of the specialties from 1990-2015, the slope was estimated using simple linear regression. IMGs showed significantly greater representation among active practicing physicians in 4 specialties: internal medicine (39%), neurology (31%), psychiatry (30%), and pediatrics (25%). IMGs in GME showed significantly greater representation in 5 specialties: pathology (39%), internal medicine (39%), neurology (36%), family medicine (32%), and psychiatry (31%; all P < .001). Over the past quarter century, IMG representation in GME has increased by 0.2% per year in the total GME pool, and 1.1% per year for family medicine, 0.5% for obstetrics and gynecology and general surgery, and 0.3% for internal medicine. IMGs make up nearly a quarter of the total GME pool and practicing physician workforce, with a disproportionate share, and larger increases over our study period in certain specialties.


Updated clinical classification of pulmonary hypertension.
In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4.


Seasonal infectious disease epidemiology.
Seasonal change in the incidence of infectious diseases is a common phenomenon in both temperate and tropical climates. However, the mechanisms responsible for seasonal disease incidence, and the epidemiological consequences of seasonality, are poorly understood with rare exception. Standard epidemiological theory and concepts such as the basic reproductive number R0 no longer apply, and the implications for interventions that themselves may be periodic, such as pulse vaccination, have not been formally examined. This paper examines the causes and consequences of seasonality, and in so doing derives several new results concerning vaccination strategy and the interpretation of disease outbreak data. It begins with a brief review of published scientific studies in support of different causes of seasonality in infectious diseases of humans, identifying four principal mechanisms and their association with different routes of transmission. It then describes the consequences of seasonality for R0, disease outbreaks, endemic dynamics and persistence. Finally, a mathematical analysis of routine and pulse vaccination programmes for seasonal infections is presented. The synthesis of seasonal infectious disease epidemiology attempted by this paper highlights the need for further empirical and theoretical work.


Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice.
Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXR(-)(/)(-)) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFNγ is one of the most upregulated pro-inflammatory cytokines in FXR(-)(/)(-) livers, we generated IFNγ(-)(/)(-)FXR(-)(/)(-) double knockout mice to determine IFNγ's roles in hepatocarcinogenesis. IFNγ(-)(/)(-) mice were crossed with an FXR(-)(/)(-) C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods. IFNγ deletion accelerated spontaneous hepatocarcinogenesis in FXR(-)(/)(-) mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFNγ deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNγ(-)(/)(-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFNγ(-)(/)(-) and IFNγ(-)(/)(-)FXR(-)(/)(-) mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNγ(-)(/)(-) and IFNγ(-)(/)(-)FXR(-)(/)(-) mice. In addition, IFNγ inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression. Increased IFNγ expression in FXR(-)(/)(-) livers represents a protective response of the liver against chronic injury and tumorigenesis. IFNγ suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation.


Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization.
Disorders of vascular structure and function play a central role in a wide variety of CNS diseases. Mutations in the Frizzled-4 (Fz4) receptor, Lrp5 coreceptor, or Norrin ligand cause retinal hypovascularization, but the mechanisms by which Norrin/Fz4/Lrp signaling controls vascular development have not been defined. Using mouse genetic and cell culture models, we show that loss of Fz4 signaling in endothelial cells causes defective vascular growth, which leads to chronic but reversible silencing of retinal neurons. Loss of Fz4 in all endothelial cells disrupts the blood brain barrier in the cerebellum, whereas excessive Fz4 signaling disrupts embryonic angiogenesis. Sox17, a transcription factor that is upregulated by Norrin/Fz4/Lrp signaling, plays a central role in inducing the angiogenic program controlled by Norrin/Fz4/Lrp. These experiments establish a cellular basis for retinal hypovascularization diseases due to insufficient Frizzled signaling, and they suggest a broader role for Frizzled signaling in vascular growth, remodeling, maintenance, and disease.


Human affection exchange: XIII. Affectionate communication accelerates neuroendocrine stress recovery.
Contemporary theory in interpersonal communication and health psychology supports the prediction that engaging in affectionate behavior within established relationships has a direct effect on the alleviation of stress symptoms following exposure to an acute stressor. Participants in this study were exposed to a series of standard laboratory stressors and were subsequently assigned either to an experimental group or to 1 of 2 control groups. Those in the experimental group were instructed to write a letter to a loved one in which they expressed their feelings of affection for that person. Those in 1 control group thought about a loved one but did not engage in any communicative behavior, and those in the other control group simply sat quietly. All 3 conditions were compared with respect to their levels of salivary free cortisol, an adrenal steroid hormone that is instrumental in the body's neuroendocrine stress response. Results indicated that, compared to the control groups, those in the experimental group experienced accelerated cortisol recovery following exposure to the acute stressors.


Predicting stock market movements using network science: an information theoretic approach.
A stock market is considered as one of the highly complex systems, which consists of many components whose prices move up and down without having a clear pattern. The complex nature of a stock market challenges us on making a reliable prediction of its future movements. In this paper, we aim at building a new method to forecast the future movements of Standard & Poor's 500 Index (S&P 500) by constructing time-series complex networks of S&P 500 underlying companies by connecting them with links whose weights are given by the mutual information of 60-min price movements of the pairs of the companies with the consecutive 5340 min price records. We showed that the changes in the strength distributions of the networks provide an important information on the network's future movements. We built several metrics using the strength distributions and network measurements such as centrality, and we combined the best two predictors by performing a linear combination. We found that the combined predictor and the changes in S&P 500 show a quadratic relationship, and it allows us to predict the amplitude of the one step future change in S&P 500. The result showed significant fluctuations in S&P 500 Index when the combined predictor was high. In terms of making the actual index predictions, we built ARIMA models with and without inclusion of network measurements, and compared the predictive power of them. We found that adding the network measurements into the ARIMA models improves the model accuracy. These findings are useful for financial market policy makers as an indicator based on which they can interfere with the markets before the markets make a drastic change, and for quantitative investors to improve their forecasting models.


Analysis of kidney function and biopsy results in liver failure patients with renal dysfunction: a new look to combined liver kidney allocation in the post-MELD era.
Renal dysfunction in the context of liver failure negatively impacts orthotopic liver transplantation (OLT) outcomes. Appropriate allocation of combined liver and kidney transplants (CLKT) is crucial with the current organ shortage and lack of standard selection criteria. We propose a practical workup algorithm for CLKT by using three variables: duration of renal insufficiency and glomerular filtration rate measured by the iodine-125 iothalamate (Glofil) test and renal biopsy findings. The study was divided into two phases. In the first phase, we retrospectively reviewed the clinical and laboratory database of all liver transplant patients (n=196) performed in our institution. In the second phase, we prospectively implemented the algorithm on 20 selected patients with liver failure and renal dysfunction (chronic kidney disease stage 3 and acute kidney injury) worked up for OLT. Based on the workup algorithm, we recommended OLT for 12 patients and CLKT for eight patients. We were able to avoid CLKT for six patients without causing adverse renal outcomes among 11 patients transplanted by using this algorithm. The average 12-month renal outcomes of these transplanted patients seem to be favorable with the mean serum creatinine 1.3 mg/dL in OLT group and 1.1 mg/dL in CLKT group. The workup algorithm, which primarily uses duration of renal failure, glofil measurement, and renal biopsy findings, offers a practical approach to this complicated decision-making process regarding appropriate allocation of organs for CLKT.


Body fat distribution and male/female differences in lipids and lipoproteins.
The role of body fat distribution, as assessed by the ratio of waist-to-hip circumferences (WHR), in statistically explaining differences in levels of lipoproteins between men and women was studied using data collected in 1985-1986 from employed adults (mean age, 40 years). As compared with the 415 women, the 709 men had higher mean levels of triglycerides (+38 mg/dl) and apolipoprotein B (+11 mg/dl) as well as lower mean levels of high density lipoprotein (HDL) cholesterol (-15 mg/dl) and apolipoprotein A-I (-19 mg/dl). Additionally, men were more overweight, consumed more alcohol, and exercised more frequently than women but were less likely to smoke cigarettes. Controlling for these characteristics, however, did not alter the differences in lipoprotein levels between men and women. In contrast, adjustment for WHR (which was greater among men) reduced the sex differences in levels of apolipoprotein B (by 98%), triglycerides (by 94%), HDL cholesterol (by 33%), and apolipoprotein A-I (by 21%). Similar results were obtained using analysis of covariance, stratification, or matching; at comparable levels of WHR, differences in lipid and lipoprotein levels between men and women were greatly reduced. Although these results are based on cross-sectional analyses of employed adults and need to be replicated in other populations, the findings emphasize the relative importance of body fat distribution. Whereas generalized obesity and body fat distribution are associated with lipid levels, fat distribution (or a characteristic influencing fat patterning) can be an important determinant of sex differences in levels of triglycerides, HDL cholesterol, and apolipoproteins B and A-I.


Identification of Key Genes and Pathways Associated with RUNX1 Mutations in Acute Myeloid Leukemia Using Bioinformatics Analysis.
BACKGROUND RUNXl plays a key regulatory role in the process of hematopoiesis and is a common target for multiple chromosomal translocations in human acute leukemia. Mutations of RUNX1 gene can lead to acute leukemia and affect the prognosis of AML patients. We aimed to identify pivotal genes and pathways involved in RUNX1-mutated patients of with acute myeloid leukemia (AML) and to explore possible molecular markers for novel therapeutic targets of the disease. MATERIAL AND METHODS The RNA sequencing datasets of 151 cases of AML were obtained from the Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified using edgeR of the R platform. PPI (protein-protein interaction) network clustering modules were analyzed with ClusterONE, and the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses for modules were performed. RESULTS A total of 379 genes were identified as DEGs. The KEGG enrichment analysis of DEGs showed significantly enriched pathways in cancer, extracellular matrix (ECM)-receptor interaction pathway, and cyclic adenosine monophosphate (cAMP) signaling pathway. The top 10 genes ranked by degree were PRKACG, ANKRD7, RNFL7, ROPN11, TEX14, PRMT8, OTOA, CFAP99, NRXN1, and DMRT1, which were identified as hub genes from the protein-protein interaction network (PPI). Statistical analysis revealed that RUNX1-mutated patients with AML had a shorter median survival time (MST) with poor clinical outcome and an increased risk of death when compared with those without RUNX1 mutations. CONCLUSIONS DEGs and pathways identified in the present study will help understand the molecular mechanisms underlying RUNX1 mutations in AML and develop effective therapeutic strategies for RUNX1-mutation AML.


Magnesium in Migraine Prophylaxis-Is There an Evidence-Based Rationale? A Systematic Review.
The primary objective was to systematically evaluate the existing evidence base on magnesium in migraine prophylaxis. The search for clinical trials published from 1990 to 2016 was separately conducted by AvL and FR using standard search terms as well as MeSh terms on PubMed and EMBASE. Randomized, double-blind, placebo-controlled trials investigating prophylactic magnesium administration in migraineurs aged 18-65 were considered eligible. In a mutual effort, the studies found were sorted and analyzed under consideration of the guidelines for controlled trials for drugs in migraine by the International Headache Society and using predefined eligibility criteria. The resulting clinical trials were jointly analyzed by FR and AvL applying the evidence classification scheme by the American Academy of Neurology and the Cochrane bias tool to assess the evidence-base. In accordance with the guidelines for controlled trials, the number of migraine days and number of migraine attacks were chosen as primary efficacy parameters. The present review was not registered. Out of 204 search results, five clinical trials fulfilling the selection procedure were found. One out of two Class I evidence trials showed a significant reduction of the number of migraine attacks compared with placebo, while two out of three Class III trials evinced a statistically significant reduction of the primary efficacy parameters compared with placebo. This systematic review provides Grade C (possibly effective) evidence for prevention of migraine with magnesium. Prophylactic treatment of migraine by means of high levels of magnesium dicitrate (600 mg) seems to be a safe and cost efficient strategy in clinical use.


Disaster-related prenatal maternal stress explains increasing amounts of variance in body composition through childhood and adolescence: Project Ice Storm.
The increasing prevalence of childhood obesity worldwide has become a public health issue. While many factors are involved in the development of obesity, stress during pregnancy has been linked to adiposity. However, research involving stressors that are independent of pregnant women's socioeconomic and psychological characteristics is rare. The present study made use of a natural disaster (1998 Quebec ice storm) to determine which aspect of the women's disaster experience (objective hardship, subjective stress, and/or cognitive appraisal) were associated with body mass index levels and/or waist to height ratio across childhood and adolescence. Measure of objective hardship, subjective stress, and cognitive appraisal were obtained following the 1998 Quebec ice storm. We measured height, weight, and waist circumference in children at ages 5½, 8½, 11½, 13½, and 15½. Our results show that higher prenatal maternal stress was associated with higher body mass index levels and central adiposity in children of ages 5½, 8½, 13½, and 15½. The effects of prenatal maternal stress on anthropometric measurements tend to increase as the children grew older. The findings of this study highlight the long-lasting effect of prenatal stress on body composition, and are compatible with the current theory of fetal programming. Hopefully, our increased knowledge of the effects of prenatal stress on the fetus will lead to improved awareness and the creation of early intervention programs, ultimately improving women's and children's health in the future.


Toward more focused multimodal and multidisciplinary approaches for pain management in Parkinson's disease.
In Parkinson's disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients' health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.


Effect of mechanical chest percussion on intracranial pressure: a pilot study.
Treatment of brain injury is often focused on minimizing intracranial pressure, which, when elevated, can lead to secondary brain injury. Chest percussion is a common practice used to treat and prevent pneumonia. Conflicting and limited anecdotal evidence indicates that physical stimulation increases intracranial pressure and should be avoided in patients at risk of intracranial hypertension. To explore the safety of performing chest percussion for patients at high risk for intracranial hypertension. A total of 28 patients with at least 1 documented episode of intracranial hypertension who were having intracranial pressure monitored were studied in a prospective randomized control trial. Patients were randomly assigned to either the control group (no chest percussion) or the intervention group (10 minutes of chest percussion at noon). Intracranial pressure was recorded once a minute before, during, and after the intervention. Mean intracranial pressures for the control group before, during, and after the study period (14.4, 15.0, and 15.9 mm Hg, respectively) did not differ significantly from pressures in the intervention group (13.6, 13.7, and 14.2 mm Hg, respectively). Mechanical chest percussion may be a safe intervention for nurses to use on neurologically injured patients who are at risk for intracranial hypertension.


Phylogenetic analysis of nonthermophilic members of the kingdom crenarchaeota and their diversity and abundance in soils
Within the last several years, molecular techniques have uncovered numerous 16S rRNA gene (rDNA) sequences which represent a unique and globally distributed lineage of the kingdom Crenarchaeota that is phylogenetically distinct from currently characterized crenarchaeotal species. rDNA sequences of members of this novel crenarchaeotal group have been recovered from low- to moderate-temperature environments (-1.5 to 32 degreesC), in contrast to the high-temperature environments (temperature, >80 degreesC) required for growth of the currently recognized crenarchaeotal species. We determined the diversity and abundance of the nonthermophilic members of the Crenarchaeota in soil samples taken from cultivated and uncultivated fields located at the Kellogg Biological Station's Long-Term Ecological Research site (Hickory Corners, Mich.). Clones were generated from 16S rDNA that was amplified by using broad-specificity archaeal PCR primers. Twelve crenarchaeotal sequences were identified, and the phylogenetic relationships between these sequences and previously described crenarchaeotal 16S rDNA sequences were determined. Phylogenetic analyses included nonthermophilic crenarchaeotal sequences found in public databases and revealed that the nonthermophilic Crenarchaeota group is composed of at least four distinct phylogenetic clusters. A 16S rRNA-targeted oligonucleotide probe specific for all known nonthermophilic crenarchaeotal sequences was designed and used to determine their abundance in soil samples. The nonthermophilic Crenarchaeota accounted for as much as 1.42% +/- 0.42% of the 16S rRNA in the soils analyzed.


Antioxidant and antimicrobial properties of phenolic rich fraction of Seabuckthorn (Hippophae rhamnoides L.) leaves in vitro.
Phenolic rich fraction (PRF) from Seabuckthorn leaves was prepared by sequential fractionation. Total phenolic content of PRF estimated as gallic acid equivalent was found to be 319.33±7.02 mg/g of PRF. Its major constituents gallic acid, rutin, quercetin-3-galactoside, quercetin-3-glucoside, myricetin, quercetin, kaempferol and isorhamnetin, were found in the range of 1.551-196.89 mg/g of PRF as determined by RP-HPLC. Antioxidant activity of PRF evaluated using 2,2-diphenyl-2-picrylhydrazyl, superoxide and nitric oxide scavenging assays. Reducing power of PRF increased with increasing amount of PRF; the equation of reducing power (y) and amount of PRF (x) was y=8.004x (r(2)=0.99), indicating that reducing ability correlated well with amount of PRF. Antibacterial activity of PRF, tested against certain medically important bacterial species showed growth inhibiting effect against Escherichia coli, Salmonella typhi, Shigella dysenteriae, Streptococcus pneumoniae and Staphylococcus aureus. In conclusion, PRF has potent antioxidant and broad spectrum antibacterial properties.


A systematic review examining the effectiveness of blending technology with team-based learning.
Technological advancements are rapidly changing nursing education in higher education settings. Nursing academics are enthusiastically blending technology with active learning approaches such as Team Based Learning (TBL). While the educational outcomes of TBL are well documented, the value of blending technology with TBL (blended-TBL) remains unclear. This paper presents a systematic review examining the effectiveness of blended-TBL in higher education health disciplines. This paper aimed to identify how technology has been incorporated into TBL in higher education health disciplines. It also sought to evaluate the educational outcomes of blended-TBL in terms of student learning and preference. A review of TBL research in Medline, CINAHL, ERIC and Embase databases was undertaken including the search terms, team based learning, nursing, health science, medical, pharmaceutical, allied health education and allied health education. Papers were appraised using the Critical Appraisal Skills Program (CASP). The final review included 9 papers involving 2094 student participants. A variety of technologies were blended with TBL including interactive eLearning and social media. There is limited evidence that blended-TBL improved student learning outcomes or student preference. Enthusiasm to blend technology with TBL may not be as well founded as initially thought. However, few studies explicitly examined the value of incorporating technology into TBL. There is a clear need for research that can discern the impact of technology into TBL on student preference and learning outcomes, with a particular focus on barriers to student participation with online learning components.


Sexually transmitted acute infection with a clustered genotype 4 hepatitis C virus in HIV-1-infected men and inefficacy of early antiviral therapy.
Recent studies have suggested an increased risk of acute hepatitis C (HCV) infection in homosexual HIV-infected men and that early treatment with standard or pegylated interferon-alfa, alone or associated with ribavirin, significantly reduces the risk of chronic evolution in HIV-infected patients. A retrospective analysis of 12 HIV-infected patients who were consecutively diagnosed as developing acute HCV infection, defined by both seroconversion of anti-HCV antibodies and detection of serum HCV RNA in those with previous negative results. Ten of these patients received early antiviral treatment with standard or pegylated interferon-alfa, alone or associated with ribavirin. The only risk factor in these patients was unprotected sexual intercourse with men. Acute HCV infection was asymptomatic in 10 patients, and the HCV genotype was 4d in 10 patients. The 10 genotype 4d viruses formed a monophylogenetic group and clustered separately from other local sequences of HCV genotype 4d, suggesting a common source of infection. None of the 10 patients who were treated early with antiviral therapy had a sustained virological response, as defined by undetectable HCV RNA 6 months after therapy. There is a risk of sexual transmission of HCV in HIV-infected men who have sex with men; the cluster of HCV genotype 4d suggested a common source of infection and a failure in prevention counselling. Early treatment with standard interferon-alfa failed to prevent chronic evolution of HCV infection in this particular group of HIV-infected patients who had acquired this peculiar cluster of genotype 4 strains.


Carbon and Sulfur Cycling below the Chemocline in a Meromictic Lake and the Identification of a Novel Taxonomic Lineage in the FCB Superphylum, Candidatus Aegiribacteria.
Mahoney Lake in British Columbia is an extreme meromictic system with unusually high levels of sulfate and sulfide present in the water column. As is common in strongly stratified lakes, Mahoney Lake hosts a dense, sulfide-oxidizing phototrophic microbial community where light reaches the chemocline. Below this "plate," the euxinic hypolimnion is anoxic, eutrophic, saline, and rich in sulfide, polysulfides, elemental sulfur, and other sulfur intermediates. While much is known regarding microbial communities in sunlit portions of euxinic systems, the composition and genetic potential of organisms living at aphotic depths have rarely been studied. Metagenomic sequencing of samples from the hypolimnion and the underlying sediments of Mahoney Lake indicate that multiple taxa contribute to sulfate reduction below the chemocline and that the hypolimnion and sediments each support distinct populations of sulfate reducing bacteria (SRB) that differ from the SRB populations observed in the chemocline. After assembling and binning the metagenomic datasets, we recovered near-complete genomes of dominant populations including two Deltaproteobacteria. One of the deltaproteobacterial genomes encoded a 16S rRNA sequence that was most closely related to the sulfur-disproportionating genus Dissulfuribacter and the other encoded a 16S rRNA sequence that was most closely related to the fatty acid- and aromatic acid-degrading genus Syntrophus. We also recovered two near-complete genomes of Firmicutes species. Analysis of concatenated ribosomal protein trees suggests these genomes are most closely related to extremely alkaliphilic genera Alkaliphilus and Dethiobacter. Our metagenomic data indicate that these Firmicutes contribute to carbon cycling below the chemocline. Lastly, we recovered a nearly complete genome from the sediment metagenome which represents a new genus within the FCB (Fibrobacteres, Chlorobi, Bacteroidetes) superphylum. Consistent with the geochemical data, we found little or no evidence for organisms capable of sulfide oxidation in the aphotic zone below the chemocline. Instead, comparison of functional genes below the chemocline are consistent with recovery of multiple populations capable of reducing oxidized sulfur. Our data support previous observations that at least some of the sulfide necessary to support the dense population of phototrophs in the chemocline is supplied from sulfate reduction in the hypolimnion and sediments. These studies provide key insights regarding the taxonomic and functional diversity within a euxinic environment and highlight the complexity of biogeochemical carbon and sulfur cycling necessary to maintain euxinia.


Multicohort study of change in job strain, poor mental health and incident cardiometabolic disease.
Several recent large-scale studies have indicated a prospective association between job strain and coronary heart disease, stroke and diabetes. Job strain is also associated with poorer mental health, a risk factor for cardiometabolic disease. This study investigates the prospective relationships between change in job strain, poor mental health and cardiometabolic disease, and whether poor mental health is a potential mediator of the relationship between job strain and cardiometabolic disease. We used data from five cohort studies from Australia, Finland, Sweden and UK, including 47 757 men and women. Data on job strain across two measurements 1-5 years apart (time 1 (T1)-time 2 (T2)) were used to define increase or decrease in job strain. Poor mental health (symptoms in the top 25% of the distribution of the scales) at T2 was considered a potential mediator in relation to incident cardiometabolic disease, including cardiovascular disease and diabetes, following T2 for a mean of 5-18 years. An increase in job strain was associated with poor mental health (HR 1.56, 95% CI 1.38 to 1.76), and a decrease in job strain was associated with lower risk in women (HR 0.70, 95% CI 0.60-0.84). However, no clear association was observed between poor mental health and incident cardiometabolic disease (HR 1.08, 95% CI 0.96-1.23), nor between increase (HR 1.01, 95% CI 0.90-1.14) and decrease (HR 1.08, 95% CI 0.96-1.22) in job strain and cardiometabolic disease. The results did not support that change in job strain is a risk factor for cardiometabolic disease and yielded no support for poor mental health as a mediator.


Loss of enzyme activity during turnover of the Bacillus cereus beta-lactamase catalysed hydrolysis of beta-lactams due to loss of zinc ion.
Metallo-beta-lactamases are zinc-ion-dependent and are known to exist either as mononuclear or as dinuclear enzymes. The kinetics and mechanism of hydrolysis of the native zinc Bacillus cereus metallo-beta-lactamase (BcII) have been investigated under pre-steady-state conditions at different pHs and zinc-ion concentrations. Biphasic kinetics are observed for the hydrolysis of cefuroxime and benzylpenicillin with submicromolar concentrations of enzyme and zinc. The initial burst of product formation far exceeds the concentration of enzyme and the subsequent slower rate of hydrolysis is attributed to a branched kinetic pathway. The pH and metal-ion dependence of the microscopic rate constants of this branching were determined, from which it is concluded that two enzyme species with different metal-to-enzyme stoichiometries are formed during catalytic turnover. The dizinc enzyme is responsible for the fast route but during the catalytic cycle it slowly loses the less tightly bound zinc ion via the branching route to give an inactive monozinc enzyme; the latter is only catalytic following the uptake of a second zinc ion. The rate constant for product formation from the dinuclear enzyme and the branching rate constant show a sigmoidal dependence on pH indicative of important ionizing groups with pK(a)s of 9.0+/-0.1 and 8.2+/-0.1, respectively. The rate constant for the regeneration of enzyme activity depends on zinc-ion concentration. This unusual behaviour is attributed to an intrinsic property of metallo hydrolytic enzymes that depend on a metal bound water both as a ligand for the second metal ion and as the nucleophile which is consumed during hydrolysis of the substrate and so has to be replaced to maintain the catalytic cycle.


Did an ancient chlamydial endosymbiosis facilitate the establishment of primary plastids?
Ancient endosymbioses are responsible for the origins of mitochondria and plastids, and they contribute to the divergence of several major eukaryotic groups. Although chlamydiae, a group of obligate intracellular bacteria, are not found in plants, an unexpected number of chlamydial genes are most similar to plant homologs, which, interestingly, often contain a plastid-targeting signal. This observation has prompted several hypotheses, including gene transfer between chlamydiae and plant-related groups and an ancestral relationship between chlamydiae and cyanobacteria. We conducted phylogenomic analyses of the red alga Cyanidioschyzon merolae to identify genes specifically related to chlamydial homologs. We show that at least 21 genes were transferred between chlamydiae and primary photosynthetic eukaryotes, with the donor most similar to the environmental Protochlamydia. Such an unusually high number of transferred genes suggests an ancient chlamydial endosymbiosis with the ancestral primary photosynthetic eukaryote. We hypothesize that three organisms were involved in establishing the primary photosynthetic lineage: the eukaryotic host cell, the cyanobacterial endosymbiont that provided photosynthetic capability, and a chlamydial endosymbiont or parasite that facilitated the establishment of the cyanobacterial endosymbiont. Our findings provide a glimpse into the complex interactions that were necessary to establish the primary endosymbiotic relationship between plastid and host cytoplasms, and thereby explain the rarity with which long-term successful endosymbiotic relationships between heterotrophs and photoautotrophs were established. Our data also provide strong and independent support for a common origin of all primary photosynthetic eukaryotes and of the plastids they harbor.


Oxidative stress, protein damage and repair in bacteria.
Oxidative damage can have a devastating effect on the structure and activity of proteins, and may even lead to cell death. The sulfur-containing amino acids cysteine and methionine are particularly susceptible to reactive oxygen species (ROS) and reactive chlorine species (RCS), which can damage proteins. In this Review, we discuss our current understanding of the reducing systems that enable bacteria to repair oxidatively damaged cysteine and methionine residues in the cytoplasm and in the bacterial cell envelope. We highlight the importance of these repair systems in bacterial physiology and virulence, and we discuss several examples of proteins that become activated by oxidation and help bacteria to respond to oxidative stress.


Probenecid enhances central nervous system uptake of 2',3'-dideoxyinosine by inhibiting cerebrospinal fluid efflux.
The effects of probenecid on the pharmacokinetics of 2',3'-dideoxyinosine (ddl) and on the distribution of ddl to cerebrospinal fluid (CSF) and brain tissue were determined in rats during and after a 2-hr i.v. infusion of ddl, 125 mg/kg/hr. Probenecid-treated rats received a loading dose of probenecid followed by an i.v. infusion of probenecid initiated 1 hr before and continued during and for 2 hr after termination of the ddl infusion. Plasma concentrations of probenecid averaged 221 +/- 34 micrograms/ml upon termination of the ddl infusion and 258 +/- 34 micrograms/ml (mean +/- S.D., n = 4) 1 hr later. In the probenecid-treated animals, ddl concentrations were higher in plasma (1.5-fold), brain (1.5-fold) and CSF (5.4-fold) at the termination of the ddl infusion and postinfusion concentrations declined more slowly compared to controls. Postinfusion, the CSF/plasma and brain/plasma ratios steadily increased to a greater extent in the probenecid-treated rats compared to control animals. The time course of plasma, CSF and brain tissue concentrations were analyzed by nonlinear least-squares regression using two different compartmental models, one which neglected the direct exchange of drug between the CSF and brain parenchyma, whereas the other allowed for such exchange to occur and neglected direct vascular transfer of drug to brain tissue. Allowing exchange between the CSF and brain tissue gave slightly improved fitting of the data from both probenecid-treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways.
The gp130-dependent cytokines, which signal through at least two intracellular pathways, regulate osteoclast and osteoblast formation. To define their roles in regulating bone mass, we analyzed mice in which gp130 signaling via either the signal transducer and activator of transcription (STAT) 1/3 (gp130(DeltaSTAT/DeltaSTAT)) or SHP2/ras/MAPK (gp130(Y757F/Y757F)) pathway was attenuated. In gp130(DeltaSTAT/DeltaSTAT) mice, trabecular bone volume (BV/TV) and turnover were normal, but bone length was reduced by premature growth plate closure, indicating an essential role for gp130-STAT1/3 signaling in chondrocyte differentiation. In contrast, while bone size was normal in gp130(Y757F/Y757F) mice, BV/TV was reduced due to high bone turnover, indicated by high osteoclast surface/bone surface (OcS/BS) and osteoblast surface/bone surface (ObS/BS). Furthermore, generation of functional osteoclasts from bone marrow of gp130(Y757F/Y757F) mice was elevated, revealing that while gp130 family cytokines stimulate osteoclastogenesis through the osteoblast lineage, gp130, via SHP2/Ras/MAPK, inhibits osteoclastogenesis in a cell lineage-autonomous manner. Genetic ablation of IL-6 in gp130(Y757F/Y757F) mice exacerbated this osteopenia by reducing ObS/BS without affecting OcS/BS. Thus, while IL-6 is critical for high bone formation in gp130(Y757F/Y757F) mice, it is not involved in the increased osteoclastogenesis. In conclusion, gp130 is essential for normal bone growth and trabecular bone mass, with balanced regulation depending on selective activation of STAT1/3 and SHP2/ras/MAPK, respectively. Furthermore, the latter pathway can directly inhibit osteoclastogenesis in vivo.


Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats.
Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 muA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.


Anthralin modulates the expression pattern of cytokeratins and antimicrobial peptides by psoriatic keratinocytes.
Psoriasis is an inflammatory skin disease with aberrant keratinocyte proliferation, presumably as a result of immune cell activation. Th17 cytokines like IL-17A and IL-22 are critically implicated in epidermal thickening, altered keratinocyte differentiation and production of innate factors such as antimicrobial peptides. Psoriasis treatment options include modern targeted therapies using anti-cytokine antibodies and traditional non-targeted treatments like anthralin (dithranol). While the mode of action of anti-cytokine antibodies is defined, the effects of topical anthralin on psoriatic skin are not fully understood. This study aims to unravel the direct effects of anthralin on keratinocyte proliferation, differentiation and production of psoriasis-associated factors. We tested the effects of anthralin on cell proliferation, cytokeratin expression and changes in the expression of antimicrobial peptides using primary keratinocytes and 3D psoriasis tissue models with and without stimulation of the psoriasis-promoting cytokines IL-17A and IL-22. Moreover, we compared the findings derived from monolayer and multilayer cultures to data derived from lesional skin of patients with psoriasis before and under treatment with anthralin. Our study shows that anthralin directly induces cell apoptosis in vitro in monolayer cultures but not in 3D psoriasis tissue models treated with IL-17A and IL-22. Yet, keratinocyte proliferation as determined by Ki-67 staining is impaired by anthralin in vivo. In lesional skin but not in 3D psoriasis tissue models anthralin rapidly normalizes cytokeratin (CK)16 expression. Furthermore, anthralin directly inhibits DEFB4 expression in vitro and in vivo, while other antimicrobial peptides and cytokines studied like IL-6 and IL-8 are regulated differently in vitro and in vivo. Our results show that anthralin directly regulates DEFB4A expression. However, its beneficial effects on psoriasis cannot be explained by direct effects on keratinocyte differentiation or cytokine expression.


Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination.
alphaB-crystallin (CRYAB) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue. This crystallin has anti-apoptotic and neuroprotective functions. CRYAB is the major target of CD4+ T-cell immunity to the myelin sheath from multiple sclerosis brain. The pathophysiological implications of this immune response were investigated here. We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system (CNS). Cryab-/- mice showed worse experimental autoimmune encephalomyelitis (EAE) at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wild-type counterparts. Furthermore, Cryab-/- astrocytes showed more cleaved caspase-3 and more TUNEL staining, indicating an anti-apoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE. Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease.


Astragaloside IV Protects Ethanol-Induced Gastric Mucosal Injury by Preventing Mitochondrial Oxidative Stress and the Activation of Mitochondrial Pathway Apoptosis in Rats.
Alcohol consumption affects gastric mucosa by multiple and complex mechanisms depending either by direct contact of ethanol or by indirect biological damage induced by its metabolite acetaldehyde. The present study aims at further investigating the mechanism of ethanol-induced gastric mucosa injury and the protective effect of astragaloside IV (AS-IV) in an aspect of mitochondrial oxidative stress and mitochondrial pathway of apoptosis. Using an array of experimental approaches, we have shown that the development of mitochondrial oxidative stress and associated apoptosis play crucial roles in the pathogenesis of gastric injury induced by ethanol. AS-IV inhibits mitochondrial oxidative stress by scavenging accumulation of malondialdehyde and decreasing the consumption of glutathione. AS-IV also prevents ethanol-induced apoptosis by modulating the activity of caspase-3 and caspase-9, the expression of Bax/Bcl-2, and the release of cytochrome C and apoptosis inducing factor. Moreover, AS-IV reduces ethanol-mediated activation of caspase-8 and breakage of Bid. This study thus indicates that AS-IV prevented ethanol-induced gastric damage by blocking activation of mitochondrial oxidative stress and mitochondrial pathway of apoptosis induced by ethanol in the gastric mucosa.


Extracellular enzyme production and cheating in Pseudomonas fluorescens depend on diffusion rates.
Bacteria produce extracellular enzymes to obtain resources from complex chemical substrates, but this strategy is vulnerable to cheating by cells that take up reaction products without paying the cost of enzyme production. We hypothesized that cheating would suppress enzyme production in co-cultures of cheater and producer bacteria, particularly under well-mixed conditions. To test this hypothesis, we monitored protease expression and frequencies of Pseudomonas fluorescens producer and cheater genotypes over time in mixed liquid cultures and on agar plates. In mixed culture inoculated with equal frequencies of cheaters and producers, enzyme concentration declined to zero after 20 days, consistent with our hypothesis. We observed a similar decline in cultures inoculated with producers only, suggesting that cheater mutants arose de novo and swept the population. DNA sequencing showed that genetic changes most likely occurred outside the protease operon. In one experimental replicate, the population regained the ability to produce protease, likely due to further genetic changes or population dynamics. Under spatially structured conditions on agar plates, cheaters did not sweep the population. Instead, we observed a significant increase in the variation of enzyme activity levels expressed by clones isolated from the population. Together these results suggest that restricted diffusion favors a diversity of enzyme production strategies. In contrast, well-mixed conditions favor population sweeps by cheater strains, consistent with theoretical predictions. Cheater and producer strategies likely coexist in natural environments with the frequency of cheating increasing with diffusion rate.


The orientation of DNA within 80-Angstrom chromatin fibers.
Squashing salivary glands of Chironomus thummi larvae, Amblystoma tigrinum erythrocytes, or Spirostromum frequently results in stretched chromatin having highly oriented DNA as determined by polarized fluorescence microscopy of acridine orange-stained preparations. The examination of such material from C. thummi in the electron microscope indicates that the individual chromatin fibers have an average thickness of 80 A as is usually found in embedded and sectioned material. It is thus concluded that the DNA lies nearly parallel to the axis of these chromatin fibers. Detailed calculations of the polarization expected from various models of DNA packing are contained in an appendix.


DNA polymerase alpha from normal rat liver is different than DNA polymerases alpha from Morris hepatoma strains.
To investigate whether DNA replication in rat hepatoma cells is altered compared with that in normal rat liver, the main replicative enzyme, i.e. the DNA polymerase alpha complex, was partially purified from a slow-growing (TC5123) and a fast-growing (MH3924) Morris hepatoma cell strain as well as from normal rat liver. The purified DNA polymerase alpha complexes contained RNA primase. DNA polymerase alpha activities of these complexes were characterized with regard to both their molecular properties and their dNTP and DNA binding sites. The latter were probed with competitive inhibitors of dNTP binding, resulting in Ki values, and with DNA templates, yielding Km values. The sedimentation coefficients of native DNA polymerases alpha from Morris hepatoma cells were found to be lower than that of polymerase alpha from normal rat liver. Consequently, when following the procedure of Siegel and Monty for determination of molecular mass considerably smaller molecular masses were calculated for polymerases of hepatoma strains (TC5123, 127 kDa; MH3924, 138 kDa; rat liver, 168 kDa). Similar differences were found when the dNTP binding site was probed with inhibitors. Ki values obtained with butylphenyl-dGTP were higher for polymerases of the hepatoma strains than for that of normal rat liver. However, Ki values measured with aphidicolin and butylanilino-dATP were lower for DNA polymerase alpha from the fast-growing hepatoma cell strain than for that from normal rat liver, indicating a reduced affinity of the dNTP binding sites for dATP and dCTP. This reduced affinity could be responsible for lowered specificity of nucleotide selection in the base-pairing process which in turn may cause an enhanced error rate in DNA replication in malignant cells. Furthermore, when the DNA binding site was characterized by Michaelis-Menten constants using gapped DNA as a template, Km values were similar for all three DNA polymerases. In contrast, the Km value measured with single-stranded DNA as a template was found to be lower for DNA polymerase alpha from the fast-growing hepatoma MH3924 than for that from normal rat liver. Thus, the DNA-polymerizing complex from MH3924 combines both higher binding strength to single-stranded DNA templates and decreased nucleotide selection, properties which may enhance replication velocity and may lower fidelity.


The epidemiology of powdery mildew on concord grapes.
ABSTRACT Vitis labruscana 'Concord' is a grape cultivar widely grown in the United States for processing into juice and other grape products. Concord grapes are sporadically but sometimes severely damaged by the grape powdery mildew pathogen, Uncinula necator. Although the foliage is often reported to be moderately resistant to powdery mildew, severe fruit infection occurs in some years. We observed the seasonal development of powdery mildew on leaves, rachises, and berries of unsprayed Concord grapevines. Inoculations of flower and fruit clusters revealed a brief period of berry susceptibility and a protracted period of rachis susceptibility. The rachis remained highly susceptible to infection, and the severity of rachis infection increased throughout the growing season until the rachis formed a periderm shortly before harvest. In contrast, berries were nearly immune to infection within 2 weeks after fruit set. Rachis and berry infections were detected before the disease was observed on foliage, and the incidence of rachis and berry infection often exceeded disease incidence observed on foliage until after fruit acquired substantial ontogenic resistance. Excellent control of fruit infection, and adequate control of leaf infection, was achieved by two fungicide applications targeted at the peak period of fruit susceptibility. Although Concord is thought to be moderately resistant to powdery mildew, the rachis is highly susceptible, and may be the avenue by which prebloom infections make their way onto the developing fruit. Late-season infection of the rachis neither spread to the fruit, nor did it cause fruit to drop prematurely, and may be of little economic consequence on fruit destined for processing. Although fruit of V. vinifera cultivars have been reported to remain susceptible to infection until berry sugar levels reach 8 to 15%, Concord fruit become nearly immune to infection nearly 6 weeks before this stage of development. Because powdery mildew does not become conspicuous on foliage until late summer, it is generally regarded as a late-season problem on Concord grapes, and previous management programs have reflected this belief. However, the greatest contribution to control of fruit infection is due to fungicides applied during the peak period of fruit susceptibility, from bloom until shortly after fruit set, long before the disease is observed on foliage.


Community Influences on Female Genital Mutilation/Cutting in Kenya: Norms, Opportunities, and Ethnic Diversity.
Female genital mutilation/cutting (FGMC) is a human rights violation with adverse health consequences. Although prevalence is declining, the practice persists in many countries, and the individual and contextual risk factors associated with FGMC remain poorly understood. We propose an integrated theory about contextual factors and test it using multilevel discrete-time hazard models in a nationally representative sample of 7,535 women with daughters who participated in the 2014 Kenya Demographic and Health Survey. A daughter's adjusted hazard of FGMC was lower if she had an uncut mother who disfavored FGMC, lived in a community that was more opposed to FGMC, and lived in a more ethnically diverse community. Unexpectedly, a daughter's adjusted FGMC hazard was higher if she lived in a community with more extrafamilial opportunities for women. Other measures of women's opportunities warrant consideration, and interventions to shift FGMC norms in more ethnically diverse communities show promise to accelerate abandonment.


Management of brainstem cavernous malformations.
The risk of hemorrhage from brainstem cavernous malformations (BSCMs) ranges between 2.33 % and 4.1 % per patient-year across natural history studies and between 2.68 % and 6.8 % per patient-year across surgical series. The recurrent hemorrhage rate from BSCMs ranges between 5 % and 60 % per patient-year. Asymptomatic BSCMs tend to have a benign course, whereas symptomatic lesions often have a more aggressive course and carry an increasing risk of hemorrhage with subsequent bleeds. Hemorrhagic presentation, female gender, family history, and associating venous anomalies have been correlated with an increased risk of hemorrhage from BSCMs. MRI is the diagnostic imaging method of choice for the detection of CMs. Preoperative T1-weighted MRI can help assess the proximity of the lesion to the pial or ependymal surface of the brainstem and is thus essential to operative planning. Fluid attenuated inversion recovery (FLAIR) sequences can detect inflammatory activity and perilesional gliosis and may therefore correlate with an increased biological activity in the CM. This might help predict the aggressiveness of these lesions and their clinical activity. Due to the potential risks of surgery, conservative management with close follow-up should be the primary treatment option for patients with BSCMs. At least two clinically significant hemorrhagic episodes and an anatomical pial representation of the lesion are required before considering surgical intervention as an option because of the potential irreversible neurological damage to the patient. Life-threatening bleeds and rapidly progressive neurological deterioration are also potential indications for surgery. Complete removal of BSCMs when feasible is crucial to the prevention of future hemorrhage from BSCMs. An intraoperative ultrasound and a post-operative MRI can be used to rule out any unnoticed residual lesion. Minimizing the risk of surgery can be achieved by undergoing a case-based selection of the optimal surgical approach that allows for easy access to the lesion with minimal manipulation of normal neural tissues. Preserving any associated venous anomaly during surgery is crucial in order to avoid any undesirable hemorrhagic infarction. Advanced imaging techniques, such as diffusion tensor imaging integrated with intra-operative neuronavigation MRI, can be used to determine the anatomical relation between BSCM and the surrounding eloquent structures. Radiosurgery is not considered an effective treatment option for BSCMs. It is reserved only for extremely biologically aggressive lesions that cannot be accessed surgically.


Spatial warping by oriented line detectors can counteract neural delays.
The slow speed of neural transmission necessitates that cortical visual information from dynamic scenes will lag reality. The "perceiving the present" (PTP) hypothesis suggests that the visual system can mitigate the effect of such delays by spatially warping scenes to look as they will in ~100 ms from now (Changizi, 2001). We here show that the Hering illusion, in which straight lines appear bowed, can be induced by a background of optic flow, consistent with the PTP hypothesis. However, importantly, the bowing direction is the same whether the flow is inward or outward. This suggests that if the warping is meant to counteract latencies, it is accomplished by a simple strategy that is insensitive to motion direction, and that works only under typical (forward-moving) circumstances. We also find that the illusion strengthens with longer pulses of optic flow, demonstrating motion integration over ~80 ms. The illusion is identical whether optic flow precedes or follows the flashing of bars, exposing the spatial warping to be equally postdictive and predictive, i.e., peri-dictive. Additionally, the illusion is diminished by cues which suggest the bars are independent of the background movement. Collectively, our findings are consistent with a role for networks of visual orientation-tuned neurons (e.g., simple cells in primary visual cortex) in spatial warping. We conclude that under the common condition of forward ego-motion, spatial warping counteracts the disadvantage of neural latencies. It is not possible to prove that this is the purpose of spatial warping, but our findings at minimum place constraints on the PTP hypothesis, demonstrating that any spatial warping for the purpose of counteracting neural delays is not a precise, on-the-fly computation, but instead a heuristic achieved by a simple mechanism that succeeds under normal circumstances.


Identification of high-affinity calmodulin-binding proteins in rat liver.
The Ca2+-dependent binding of [125I]calmodulin (CaM) to hepatic proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was utilized to identify CaM binding or "acceptor" proteins or CAPs. Two proteins of apparent molecular weight of 60,000 (CAP-60) and 45,000 (CAP-45) comprised greater than 80% of the Ca2+-dependent CaM binding in rat liver cytosol. CAP-60 and CAP-45 were partially purified by a variety of chromatographic steps, including affinity chromatography on CaM Sepharose. CAP-60 possessed a native molecular size of 400,000, indicating it to be the CaM-binding "subunit" of a larger oligomeric complex. In contrast, CAP-45 was monomeric as judged by gel filtration. Neither CAP-60 nor CAP-45 possessed chromatographic properties consistent with known CaM-dependent enzymes reported in the literature. Two-dimensional peptide mapping provided convincing evidence that CAP-60 and CAP-45 were unrelated to other well-characterized CAPs, namely Ca2+ (CaM)-dependent protein kinase II, calcineurin, or the CaM-dependent cyclic nucleotide phosphodiesterase. The relative abundance and high affinity for CaM could suggest that these novel target proteins, CAP-60 and CAP-45, represent a dominant pathway for CaM action in the mammalian liver.


Prestroke physical activity is associated with good functional outcome and arterial recanalization after stroke due to a large vessel occlusion.
Although multiple studies and meta-analyses have consistently suggested that regular physical activity (PhA) is associated with a decreased stroke risk and recurrence, there is limited data on the possible preconditioning effect of prestroke PhA on stroke severity and prognosis. We aimed to study the association of prestroke PhA with different outcome variables in patients with acute ischemic stroke due to an anterior large vessel occlusion. The Prestroke Physical Activity and Functional Recovery in Patients with Ischemic Stroke and Arterial Occlusion trial is an observational and longitudinal study that included consecutive patients with acute ischemic stroke admitted to a single tertiary stroke center. Main inclusion criteria were: anterior circulation ischemic stroke within 12 h from symptom onset; presence of a confirmed anterior large vessel occlusion, and functional independence previous to stroke. Prestroke PhA was evaluated with the International Physical Activity Questionnaire and categorized into mild, moderate and high levels by means of metabolic equivalent (MET) minutes per week thresholds. The primary outcome measure was good functional outcome at 3 months (modified Rankin scale ≤2). Secondary outcomes were severity of stroke at admission, complete early recanalization, early dramatic neurological improvement and final infarct volume. During the study period, 159 patients fulfilled the above criteria. The mean age was 68 years, 62% were men and the baseline NIHSS score was 17. Patients with high levels of prestroke PhA were younger, had more frequently distal occlusions and had lower levels of blood glucose and fibrinogen at admission. After multivariate analysis, a high level of prestroke PhA was associated with a good functional outcome at 3 months. Regarding secondary outcome variables and after adjustment for relevant factors, a high level of prestroke PhA was independently associated with milder stroke severity at admission, early dramatic improvement, early arterial recanalization after intravenous thrombolysis and lower final infarct volume. The beneficial association of prestroke PhA with stroke outcomes was already present with a cutoff point of 1,000 MET min/week, a level of PhA easily achieved by walking 1 h/day during 5 days or by doing a vigorous aerobic activity 1 h/day twice a week. Prestroke PhA is independently associated with favorable stroke outcomes after a large vessel occlusion. Future research on the underlying mechanisms is needed to understand this neuroprotective effect of PhA.


Simultaneous representation of a spectrum of dynamically changing value estimates during decision making.
Decisions are based on value expectations derived from experience. We show that dorsal anterior cingulate cortex and three other brain regions hold multiple representations of choice value based on different timescales of experience organized in terms of systematic gradients across the cortex. Some parts of each area represent value estimates based on recent reward experience while others represent value estimates based on experience over the longer term. The value estimates within these areas interact with one another according to their temporal scaling. Some aspects of the representations change dynamically as the environment changes. The spectrum of value estimates may act as a flexible selection mechanism for combining experience-derived value information with other aspects of value to allow flexible and adaptive decisions in changing environments.


Validation of a short form Wisconsin Upper Respiratory Symptom Survey (WURSS-21).
The Wisconsin Upper Respiratory Symptom Survey (WURSS) is an illness-specific health-related quality-of-life questionnaire outcomes instrument. Research questions were: 1) How well does the WURSS-21 assess the symptoms and functional impairments associated with common cold? 2) How well can this instrument measure change over time (responsiveness)? 3) What is the minimal important difference (MID) that can be detected by the WURSS-21? 4) What are the descriptive statistics for area under the time severity curve (AUC)? 5) What sample sizes would trials require to detect MID or AUC criteria? 6) What does factor analysis tell us about the underlying dimensional structure of the common cold? 7) How reliable are items, domains, and summary scores represented in WURSS? 8) For each of these considerations, how well does the WURSS-21 compare to the WURSS-44, Jackson, and SF-8? People with Jackson-defined colds were recruited from the community in and around Madison, Wisconsin. Participants were enrolled within 48 hours of first cold symptom and monitored for up to 14 days of illness. Half the sample filled out the WURSS-21 in the morning and the WURSS-44 in the evening, with the other half reversing the daily order. External comparators were the SF-8, a 24-hour recall general health measure yielding separate physical and mental health scores, and the eight-item Jackson cold index, which assesses symptoms, but not functional impairment or quality of life. In all, 230 participants were monitored for 2,457 person-days. Participants were aged 14 to 83 years (mean 34.1, SD 13.6), majority female (66.5%), mostly white (86.0%), and represented substantive education and income diversity. WURSS-21 items demonstrated similar performance when embedded within the WURSS-44 or in the stand-alone WURSS-21. Minimal important difference (MID) and Guyatt's responsiveness index were 10.3, 0.71 for the WURSS-21 and 18.5, 0.75 for the WURSS-44. Factorial analysis suggested an eight dimension structure for the WURSS-44 and a three dimension structure for the WURSS-21, with composite reliability coefficients ranging from 0.87 to 0.97, and Cronbach's alpha ranging from 0.76 to 0.96. Both WURSS versions correlated significantly with the Jackson scale (W-21 R=0.85; W-44 R=0.88), with the SF-8 physical health (W-21 R=-0.79; W-44 R=-0.80) and SF-8 mental health (W-21 R=-0.55; W-44 R=-0.60). The WURSS-44 and WURSS-21 perform well as illness-specific quality-of-life evaluative outcome instruments. Construct validity is supported by the data presented here. While the WURSS-44 covers more symptoms, the WURSS-21 exhibits similar performance in terms of reliability, responsiveness, importance-to-patients, and convergence with other measures.


Impacts of Recurrent Hitchhiking on Divergence and Demographic Inference in Drosophila.
In species with large population sizes such as Drosophila, natural selection may have substantial effects on genetic diversity and divergence. However, the implications of this widespread nonneutrality for standard population genetic assumptions and practices remain poorly resolved. Here, we assess the consequences of recurrent hitchhiking (RHH), in which selective sweeps occur at a given rate randomly across the genome. We use forward simulations to examine two published RHH models for D. melanogaster, reflecting relatively common/weak and rare/strong selection. We find that unlike the rare/strong RHH model, the common/weak model entails a slight degree of Hill-Robertson interference in high recombination regions. We also find that the common/weak RHH model is more consistent with our genome-wide estimate of the proportion of substitutions fixed by natural selection between D. melanogaster and D. simulans (19%). Finally, we examine how these models of RHH might bias demographic inference. We find that these RHH scenarios can bias demographic parameter estimation, but such biases are weaker for parameters relating recently diverged populations, and for the common/weak RHH model in general. Thus, even for species with important genome-wide impacts of selective sweeps, neutralist demographic inference can have some utility in understanding the histories of recently diverged populations.


Assessing the Veterans Health Administration's response to intimate partner violence among women: protocol for a randomized hybrid type 2 implementation-effectiveness trial.
Intimate partner violence (IPV) against women in the United States (US) remains a complex public health crisis. Women who experience IPV are among the most vulnerable patients seen in primary care. Screening increases the detection of IPV and, when paired with appropriate response interventions, can mitigate the health effects of IPV. The Department of Veterans Affairs (VA) has encouraged evidence-based IPV screening programs since 2014, yet adoption is modest and questions remain regarding the optimal ways to implement these practices, which are not yet available within the majority of VA primary care clinics. This paper describes the planned evaluation of VA's nationwide implementation of IPV screening programs in primary care clinics through a randomized implementation-effectiveness hybrid type 2 trial. With the support of our VA operational partners, we propose a stepped wedge design to compare the impact of two implementation strategies of differing intensities (toolkit + implementation as usual vs. toolkit + implementation facilitation) and investigate the clinical effectiveness of IPV screening programs. Using balanced randomization, 16-20 VA Medical Centers will be assigned to receive implementation facilitation in one of three waves, with implementation support lasting 6 months. Implementation facilitation in this effort consists of the coordinated efforts of the two types of facilitators, external and internal. Implementation facilitation is compared to dissemination of a toolkit plus implementation as usual. We propose a mixed methods approach to collect quantitative (clinical records data) and qualitative (key informant interviews) implementation outcomes, as well as quantitative (clinical records data) clinical effectiveness outcomes. We will supplement these data collection methods with provider surveys to assess discrete implementation strategies used before, during, and following implementation facilitation. The integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework will guide the qualitative data collection and analysis. Summative data will be analyzed using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. This research will advance national VHA efforts by identifying the practices and strategies useful for enhancing the implementation of IPV screening programs, thereby ultimately improving services for and health of women seen in primary care. NCT04106193. Registered on 23 September 2019.


The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
In a previous paper, we reviewed the range of therapies available for the treatment of super-refractory status epilepticus. Here we report a review of the outcome of therapies in refractory and super-refractory status epilepticus. Patients (n = 1168) are reported who had therapy with: thiopental, pentobarbital, midazolam, propofol, ketamine, inhalational anaesthetics (isoflurane, desflurane), antiepileptic drugs (topiramate, lacosamide, pregabalin, levetiracetam), hypothermia, magnesium, pyridoxine, immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve stimulation and deep brain stimulation. The outcome parameters reported include control of status epilepticus, relapse on withdrawal, breakthrough seizures and mortality. Where reported (596 cases), the long-term outcome was found to be death (35%), severe neurological deficit (13%), mild neurological deficit (13%), undefined deficit (4%) and recovery to baseline (35%). The quality of reported outcome data is generally poor and the number of cases reported for all non-anaesthetic therapies is low. Outcome assessment is complicated by changes in co-medication, delay in response and publication bias. Given these deficits, only broad recommendations can be made regarding optimal therapy. An approach to therapy, divided into first-line, second-line and third-line therapy, is suggested on the basis of this outcome evaluation. The importance of treatments directed at the cause of the status epilepticus, and of supportive ITU care is also emphasized.


Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II.
The relation between chromatin structure and transcriptional activity was examined by in vitro transcription analysis of chromatin reconstituted in the absence or presence of histone H1. To maintain well-defined template DNA, purified components were used in the reconstitution of chromatin. Reconstitution of nucleosomal cores to an average density of 1 nucleosome per 200 base pairs of DNA resulted in a mild reduction of basal RNA polymerase II transcription to 25 to 50 percent of that obtained with naked DNA templates. This nucleosome-mediated repression was due to nucleosomal cores located at the RNA start site and could not be counteracted by the sequence-specific transcription activators Sp1 and GAL4-VP16. When H1 was incorporated into the chromatin at 0.5 to 1.0 molecule per nucleosome (200 base pairs of DNA), RNA synthesis was reduced to 1 to 4 percent of that observed with chromatin containing only nucleosomal cores, and this H1-mediated repression could be counteracted by the addition of Sp1 or GAL4-VP16 (antirepression). With naked DNA templates, transcription was increased by a factor of 3 and 8 by Sp1 and GAL4-VP-16, respectively (true activation). With H1-repressed chromatin templates, however, the magnitude of transcriptional activation mediated by Sp1 and GAL4-VP16 was 90 and more than 200 times higher, respectively, because of the combined effects of true activation and antirepression. The data provide direct biochemical evidence that support and clarify previously proposed models in which there is depletion or reconfiguration of nucleosomal cores and histone H1 at the promoter regions of active genes.


Reduced density of calbindin-immunoreactive interneurons in the planum temporale in schizophrenia.
Reduced density of calbindin-containing interneurons in the prefrontal cortex in schizophrenia has been reported (Beasley et al 2002; Biol Psych 52:708-715). Calbindin is a calcium-binding protein (CBP) present in a subpopulation of GABAergic neurons restricted mainly to layer II of the cortex. A paraffin-embedded, 10-mum-thick section from the planum temporale (PT) of each hemisphere was prepared from 12 patients with schizophrenia and 12 controls. Calbindin-containing cells were stained using an antibody (D-28K). Counting frames were superimposed to sample within layer II of the PT. A bilateral reduction (20%) in calbindin cell density was found in patients (controlling for fixation time). Furthermore, mean calbindin cell cross-sectional area was increased in female patients and reduced in male patients. Reduced CBP expression (reducing the excitability of interneurons) or reduced number of CBP-containing cells may cause disinhibition of pyramidal cells. The majority of calbindin-containing cells in the mature brain are double-bouquet cells with vertically oriented dendrites and axon bundles. By exercising inhibitory modulation of pyramidal cells in a columnar arrangement, they make possible cohesive vertical inhibition of minicolumns. Loss of columnar inhibition may result in reduced minicolumnar segregation and altered cell size may reflect altered minicolumn size.


Effects of growth hormone overproduction on grip strength of transgenic mice.
Growth hormone (GH) is used by athletes like bodybuilders to increase muscle strength and weight gain. On the other hand, chronic hypersecretion of GH in active acromegaly may result in outwardly hypertrophied but functionally weaker muscles. As a model for studying long-term effects of GH on muscle strength, we analysed transgenic mice (TM) carrying rat phosphoenolpyruvate carboxykinase-bovine GH (PEPCKbGH) fusion genes, which are expressed in liver and kidney but not in skeletal muscle. Circulating GH levels in TM ranged between 0.5 and 3 micrograms/ml, resulting in increased (p < 0.001) body weight (wt) as well as increased (p < 0.01) weights of forelimb and hindlimb muscles. However, muscle weight/body wt ratios of TM were 16-20% smaller than in controls (p < 0.05). Forelimb grip strength of hemizygous TM (16 males, 132 +/- 45 days old, body wt = 56.8 +/- 8.3 g; 32 females, 146 +/- 38 days old, body wt = 54.9 +/- 6.1 g) and non-transgenic controls (28 males, 127 +/- 47 days old, body wt = 40.5 +/- 2.9 g; 33 females, 126 +/- 47 days old, body wt = 32.1 +/- 3.6 g) was determined using an automated grip strength meter. Data were computed by analysis of variance, taking into account effects of group, sex and age. Least-squares means estimated for the grip strength (N) of male TM (1.91) and controls (1.92) were significantly (p < 0.05) greater than those of female TM (1.78) and controls (1.61). A significant difference between groups was only seen in females (p < 0.01). Least-squares means estimated for grip strength/body wt ratios (N/10 g) of male (0.34) and female TM (0.33) were 29% and 35% lower than those of male (0.48) and female controls (0.51), respectively (p < 0.001). In summary, long-term elevated GH levels in TM increased muscle weight less efficiently than body weight, and muscle strength did not increase proportionally with muscle weight.


Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle.
Autophagy is a highly inducible intracellular degradation process. It is generally induced by nutrient starvation and suppressed by food intake. Mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is considered to be the major regulator of autophagy, but the precise mechanism of in vivo regulation remains to be fully characterized. Here, we examined the autophagy-suppressive effect of glucose, insulin, and amino acids in the liver and muscle in mice starved for 1 day. Refeeding after starvation with a standard mouse chow rapidly suppressed autophagy in both tissues, and this suppression was inhibited by rapamycin administration almost completely in the liver and partially in muscle, confirming that mTORC1 is indeed a crucial regulator in vivo. As glucose administration showed no major suppressive effect on autophagy, we examined the role of insulin and amino acids using hyperinsulinemic-euglycemic clamp and intravenous amino acid infusion techniques. Insulin administration showed a clear effect on the mTORC1-autophagy pathway in muscle, but had only a very weak effect in the liver. By contrast, amino acids were able to regulate the mTORC1-autophagy pathway in the liver, but less effectively in muscle. These results suggest that autophagy is differentially regulated by insulin and amino acids in a tissue-dependent manner.


Selective sweeps of mitochondrial DNA can drive the evolution of uniparental inheritance.
Although the uniparental (or maternal) inheritance of mitochondrial DNA (mtDNA) is widespread, the reasons for its evolution remain unclear. Two main hypotheses have been proposed: selection against individuals containing different mtDNAs (heteroplasmy) and selection against "selfish" mtDNA mutations. Recently, uniparental inheritance was shown to promote adaptive evolution in mtDNA, potentially providing a third hypothesis for its evolution. Here, we explore this hypothesis theoretically and ask if the accumulation of beneficial mutations provides a sufficient fitness advantage for uniparental inheritance to invade a population in which mtDNA is inherited biparentally. In a deterministic model, uniparental inheritance increases in frequency but cannot replace biparental inheritance if only a single beneficial mtDNA mutation sweeps through the population. When we allow successive selective sweeps of mtDNA, however, uniparental inheritance can replace biparental inheritance. Using a stochastic model, we show that a combination of selection and drift facilitates the fixation of uniparental inheritance (compared to a neutral trait) when there is only a single selective mtDNA sweep. When we consider multiple mtDNA sweeps in a stochastic model, uniparental inheritance becomes even more likely to replace biparental inheritance. Our findings thus suggest that selective sweeps of beneficial mtDNA haplotypes can drive the evolution of uniparental inheritance.


Families' values and attitudes regarding responsibility for the frail elderly: implications for aging policy.
This study examines the norms and values associated with care to disabled and frail aging parents, in particular those with regard to the sharing of responsibilities for care between families and formal services, and this within three age cohorts in Quebec, Canada. It is based on a telephone interview of 1,315 people. Factor analysis yielded four factors: (1) family responsibility; (2) uncompromising family obligations; (3) acceptance of services; (4) distrust of services. Analyses of the data indicate that all three age cohorts consider that families have responsibilities for their aging family members, at the same time that they score very high on the acceptance of service scale. This article discusses these seemingly paradoxical results and their implications for aging policy.


Genomic imprinting and the expression of affect in Angelman syndrome: what's in the smile?
Kinship theory (or the genomic conflict hypothesis) proposes that the phenotypic effects of genomic imprinting arise from conflict between paternally and maternally inherited alleles. A prediction arising for social behaviour from this theory is that imbalance in this conflict resulting from a deletion of a maternally imprinted gene, as in Angelman syndrome (AS), will result in a behavioural phenotype that should evidence behaviours that increase access to maternally provided social resources (adult contact). Observation of the social behaviour of children with AS (n = 13), caused by a deletion at 15q11-q13, and a matched comparison group (n = 10) was undertaken for four hours in a socially competitive setting and the effect of adult attention on child behaviours and the effect of child smiling on adult behaviours evaluated using group comparisons and observational lag sequential analyses. The AS group smiled more than the comparison group in all settings, which had different levels of adult attention, and more when the level of adult attention was high. Smiling by children with AS evoked higher levels of adult attention, eye contact and smiling both than by chance and in comparison to other children and this effect was sustained for 30 s to 50 s. Smiling by children with AS was frequently preceded by child initiated contact toward the adult. The results are consistent with a kinship theory explanation of the function of heightened levels of sociability and smiling in Angelman syndrome and provide support for an emotion signalling interpretation of the mechanism by which smiling accesses social resources. Further research on other behaviours characteristic of Angelman and Prader-Willi syndromes warrant examination from this perspective.


The role for protein tyrosine phosphatase nonreceptor type 2 in regulating autophagosome formation.
Genome-wide association studies have identified single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2) as a risk factor for the development of chronic inflammatory diseases, such as inflammatory bowel disease (IBD), type 1 diabetes, and rheumatoid arthritis. IBD is characterized by a breakdown of the intestinal epithelial barrier function leading to an overwhelming and uncontrolled immune response to bacterial antigens. Recent studies demonstrated that PTPN2 regulates cytokine-induced signaling pathways, epithelial barrier function, and cytokine secretion in human intestinal cells. Dysfunction of PTPN2 is also associated with impaired autophagosome formation and defective bacterial handling in intestinal cells. All of these cellular functions have been demonstrated to play a crucial role in the pathogenesis of IBD. The genetic variations within the PTPN2 gene may result in altered protein function, thereby essentially contributing to the onset and perpetuation of chronic inflammatory conditions in the intestine.


Crystal structure of the Bacillus subtilis penicillin-binding protein 4a, and its complex with a peptidoglycan mimetic peptide.
The genome of Bacillus subtilis encodes 16 penicillin-binding proteins (PBPs) involved in the synthesis and/or remodelling of the peptidoglycan during the complex life cycle of this sporulating Gram-positive rod-shaped bacterium. PBP4a (encoded by the dacC gene) is a low-molecular mass PBP clearly exhibiting in vitro DD-carboxypeptidase activity. We have solved the crystal structure of this protein alone and in complex with a peptide (D-alpha-aminopymelyl-epsilon-D-alanyl-D-alanine) that mimics the C-terminal end of the Bacillus peptidoglycan stem peptide. PBP4a is composed of three domains: the penicillin-binding domain with a fold similar to the class A beta-lactamase structure and two domains inserted between the conserved motifs 1 and 2 characteristic of the penicillin-recognizing enzymes. The soaking of PBP4a in a solution of D-alpha-aminopymelyl-epsilon-D-alanyl-D-alanine resulted in an adduct between PBP4a and a D-alpha-aminopimelyl-epsilon-D-alanine dipeptide and an unbound D-alanine, i.e. the products of acylation of PBP4a by D-alpha-aminopymelyl-epsilon-D-alanyl-D-alanine with the release of a D-alanine. The adduct also reveals a binding pocket specific to the diaminopimelic acid, the third residue of the peptidoglycan stem pentapeptide of B. subtilis. This pocket is specific for this class of PBPs.


Intracoronary magnesium and diltiazem affect to a similar extent certain hemostatic factors during acute myocardial infarction in swine.
The use of calcium antagonists and magnesium (Mg) in the treatment of acute myocardial infarction is controversial. We compared changes in hemostasis during acute myocardial infarction after either low-dose intracoronary Mg or diltiazem infusion in 20 Yorkshire swine undergoing thoracotomy and coronary artery occlusion for 50 min, followed by 3 h of reperfusion. The first group received MgSO4 (250 mg), delivered at the onset of reperfusion, the second group received diltiazem (2.5 mg) at the beginning of reperfusion. Six controls received saline. Plasma antithrombin III, protein C, total protein S, fibronectin, endothelin 1, and metabolites of thromboxane and prostacyclin were measured at baseline, twice during occlusion, and three times during reperfusion. Compared to controls, Mg and diltiazem infusion diminished endothelin 1 (32.9 vs. 34.5%) and fibronectin. (21.7 vs. 23.2%), but increased protein C (31.9 vs. 29.3%). Intracoronary Mg, like diltiazem, improved hemostasis in swine.


[Dynamic inflammatory response in a critically ill COVID-19 patient treated with corticosteroids].
To investigate the effect of corticosteroids therapy on the inflammatory response in a critically ill coronavirus disease 2019 (COVID-19) patient. A 55-year old female patient with critical ill COVID-19 was admitted in Taizhou Hospital on January 19, 2020. The patient was treated with methylprednisolone 80 mg on the 2nd day after admission. Thereafter, the dose was adjusted in a timely manner and the therapy lasted for 13 days. The peripheral lymphocyte subsets (CD3+T, CD4+ T, CD8+ T, NK cells, B cells), as well as serum levels of lymphocyte factors (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) were dynamically monitored. On D1 of admission, the numbers of peripheral blood CD3+ T, CD4+ T, CD8+ T, and NK cells were significantly lower than the normal range. With the improvement of the disease, the numbers of CD3+ T, CD8+ T and CD4 + T cells gradually recovered and showed a linear growth trend (linear fitting equation: Y=18.59X+109.4, P<0.05). On D2 of admission, the patient's IL-6 and IL-10 levels were significantly higher than normal values, IFN-γ was at a normal high value, and then rapidly decreased; IL-2, IL-4, and TNF-α were all in the normal range. On the D6 and D7, the IL-6 and IL-10 decreased to the normal range for the first time. On the D18, the sputum virus nucleic acid test was negative for the first time, and the fecal virus nucleic acid test was still positive; on the D20 the sputum and fecal virus nucleic acid test were both negative. On D34, the patient recovered and was discharged. At the discharge the muscle strength score of the patient was 44 and the daily life ability evaluation was 90. In the absence of effective antiviral drugs, early use of appropriate doses of corticosteroids in critically ill patient with COVID-19 can quickly alleviate inflammatory response and improve clinical symptoms, however, it may reduce the number of T cells, and to adjust the dose in time is necessary.


A systematic approach to improve the outcomes of type A aortic dissection.
The aims of this study are to evaluate the outcomes and trends of contemporary emergency surgery for acute type A aortic dissection on the basis of a systematic approach and to assess the impact of temporary aortic crossclamping during systemic cooling on early and late outcomes. We retrospectively reviewed 702 consecutive patients who underwent emergency surgery for acute type A aortic dissection between March 2004 and May 2015. Our clinical protocol includes rapid transfer to the operating room, quick establishment of cardiopulmonary bypass, temporary aortic crossclamping during cooling, primary entry resection, and open distal anastomosis. We analyzed the perioperative data, survival, freedom from aortic reinterventions, and impact of aortic crossclamping on early and late outcomes. The median time from hospital arrival to cardiopulmonary bypass establishment was 115 minutes and has decreased over the last decade (trend test P < .001). We perfused the femoral artery in 615 patients (87.6%), placed aortic crossclamping in 616 patients (87.7%), and performed open distal anastomosis in all patients. The operative mortality was 5.4% (38/702), and the incidence of stroke was 10.8% (76/702). The 7-year overall survival and freedom from aortic reinterventions were 80.4% and 87.5%, respectively. Compared with the nonclamping group, the crossclamping group had a shorter operation time, similar operative mortality, incidence of stroke, and freedom from aortic reinterventions. Emergency surgery for acute type A aortic dissection based on our systematic approach demonstrated excellent early and late outcomes. The temporary aortic crossclamping during cooling decreased the operation time without increasing early and late adverse events.


Effectiveness of acupuncture on chronic prostatitis-chronic pelvic pain syndrome category IIIB patients: a prospective, randomized, nonblinded, clinical trial.
To compare the acupuncture treatment and the medical treatment with antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) on pain control, urinary symptoms, and quality of life of category IIIB chronic prostatitis-chronic pelvic pain syndrome (CP-CPPS). From November 2008 to May 2009, 54 male patients with category IIIB CP-CPPS were randomly divided into 2 groups: the medical treatment group (group 1, n = 28) and the acupuncture treatment group (group 2, n = 26). Group 1 took levofloxacin 500 mg daily and ibuprofen 200 mg twice a day for 6 weeks. In the acupuncture group (group 2), bilateral BL32 (Ciliao) and BL33 (Zhongliao) acupoints were used to stimulate the sacral nerve using an electrical pulse generator, twice a week for 7 weeks. The change in National Institutes of Health Chronic Prostatitis Symptom Index scores from the baseline to the end of the treatment was observed. The mean follow-up was 28 weeks from the baseline (range, 20-43 weeks). In acupuncture group, reduction of pain, urinary symptoms, quality of life, and total National Institutes of Health Chronic Prostatitis Symptom Index score was higher compared with the medical group. However the treatment of CP-CPPS is challenging and difficult for the urologists. This clinical study showed that the acupuncture treatment is a safe and effective treatment of category IIIB CP-CPPS.


[Impact of cigarette package health warnings with pictures in Mexico: results from a survey of smokers in Guadalajara].
Evaluate the impact of the first pictorial health warning labels (HWLs) on cigarette packs in Mexico. Cross-sectional survey of a representative sample of 1 765 adult smokers from Guadalajara, Mexico, 2010. Logistic regression models were estimated to determine the association between recall of having purchased a pack with a pictorial HWL and psychosocial variables indicating their impact. 58% reported having purchased a pack with one of the pictorial HWLs, and these were considered the exposed population. Exposed smokers reported a greater frequency of thinking about smoking-related risks (34 vs. 25% p=0.003), and thinking about quitting smoking (23 vs. 14% p=0.001). Exposure to pictorial HWLs was also associated with a greater acceptability of HWLs as a means of communicating with smokers (93 vs. 87% p<0.001), as was the perception that the government communicates well about tobacco-related health risks (68 vs. 55% p<0.001). Pictorial HWLs have made smokers think more about these risks and about quitting smoking. This policy should continue to be exploited as a cost-effective educational intervention.


The scanning ion-conductance microscope.
A scanning ion-conductance microscope (SICM) has been developed that can image the topography of nonconducting surfaces that are covered with electrolytes. The probe of the SICM is an electrolyte-filled micropipette. The flow of ions through the opening of the pipette is blocked at short distances between the probe and the surface, thus, limiting the ion conductance. A feedback mechanism can be used to maintain a given conductance and in turn determine the distance to the surface. The SICM can also sample and image the local ion currents above the surfaces. To illustrate its potential for imaging ion currents through channels in membranes, a topographic image of a membrane filter with 0.80-micrometer pores and an image of the ion currents flowing through such pores are presented.


Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy.
Recombinant erythropoietin (EPO) analogs [erythropoiesis-stimulating agents (ESA)] are clinically used to treat anemia in patients with cancer receiving chemotherapy. After clinical trials reporting increased adverse events and/or reduced survival in ESA-treated patients, concerns have been raised about the potential role of ESAs in promoting tumor progression, possibly through tumor cell stimulation. However, evidence is lacking on the ability of EPO to directly affect cancer stem-like cells, which are thought to be responsible for tumor progression and relapse. We found that breast cancer stem-like cells (BCSC) isolated from patient tumors express the EPO receptor and respond to EPO treatment with increased proliferation and self-renewal. Importantly, EPO stimulation increased BCSC resistance to chemotherapeutic agents and activated cellular pathways responsible for survival and drug resistance. Specifically, the Akt and ERK pathways were activated in BCSC at early time points following EPO treatment, whereas Bcl-xL levels increased at later times. In vivo, EPO administration counteracted the effects of chemotherapeutic agents on BCSC-derived orthotopic tumor xenografts and promoted metastatic progression both in the presence and in the absence of chemotherapy treatment. Altogether, these results indicate that EPO acts directly on BCSC by activating specific survival pathways, resulting in BCSC protection from chemotherapy and enhanced tumor progression.