Hematologic Markers and Prostate Cancer Risk: A Prospective Analysis in UK Biobank.
Risk factors for prostate cancer are not well understood. Red blood cell, platelet, and white blood cell indices may be markers of a range of exposures that might be related to prostate cancer risk. Therefore, we examined the associations of hematologic parameters with prostate cancer risk. Complete blood count data from 209,686 male UK Biobank participants who were free from cancer at study baseline were analyzed. Participants were followed up via data linkage. After a mean follow-up of 6.8 years, 5,723 men were diagnosed with prostate cancer and 323 men died from prostate cancer. Multivariable-adjusted Cox regression was used to estimate adjusted HRs and 95% confidence intervals (CI) for prostate cancer incidence and mortality by hematologic parameters, and corrected for regression dilution bias. Higher red blood cell (HR per 1 SD increase = 1.09, 95% CI, 1.05-1.13) and platelet counts (HR = 1.07, 1.04-1.11) were associated with an increased risk of prostate cancer. Higher mean corpuscular volume (HR = 0.90, 0.87-0.93), mean corpuscular hemoglobin (HR = 0.90, 0.87-0.93), mean corpuscular hemoglobin concentration (HR = 0.87, 0.77-0.97), and mean sphered cell volume (HR = 0.91, 0.87-0.94) were associated with a lower prostate cancer risk. Higher white blood cell (HR = 1.14, 1.05-1.24) and neutrophil count (HR = 1.27, 1.09-1.48) were associated with prostate cancer mortality. These associations of blood indices of prostate cancer risk and mortality may implicate shared common causes, including testosterone, nutrition, and inflammation/infection among several others in prostate cancer development and/or progression. These associations provide insights into prostate cancer development and progression.


Effects of feed supplementation with glycine chelate and iron sulfate on selected parameters of cell-mediated immune response in broiler chickens.
Because little is known about the impact of chelated (Fe-Gly, Fe-Gly+F) and inorganic (FeSO4, FeSO4+F) iron products on immune response parameters in broiler chickens, the objective of the study was to determine the effects of inorganic and organic forms of iron on selected parameters of the cell-mediated immune response in broiler chickens by assessing the percentage of CD3(+)CD4(+), CD3(+)CD8(+), CD25(+), and MHC Class II lymphocytes, as well as the CD4(+)/CD8(+) ratio and IL-2 concentration in the peripheral blood. The experiments were conducted using 50day-old Ross 308 roosters. The test material was peripheral blood. Flow cytometry was used to determine selected cell-mediated immune response parameters. The results obtained indicate that the use of iron chelates in the diet of broiler chickens may stimulate cellular defense mechanisms. As a result of the experiment an increase was observed in the percentage of Th1, mainly T CD4(+) and T CD8(+). It was also noted that application of chelated iron can increase production of T CD8(+) cytotoxic cells and IL-2, which promotes the body's natural response to developing inflammation. There were no changes in T CD4(+), T CD8(+), T CD25(+) or MHC II lymphocyte subpopulations in the chickens following application of the inorganic form of iron.


MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties.
Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.


Excited-State Electronic Properties in Zr-Based Metal-Organic Frameworks as a Function of a Topological Network.
Molecular assemblies in metal-organic frameworks (MOFs) are reminiscent of natural light-harvesting (LH) systems and considered as emerging materials for energy conversion. Such applications require understanding the correlation between their excited-state properties and underlying topological net. Two chemically identical but topologically different tetraphenylpyrene (1,3,6,8-tetrakis( p-benzoicacid)pyrene; H4TBAPy)-based ZrIV MOFs, NU-901 ( scu) and NU-1000 ( csq), are chosen to computationally and spectroscopically interrogate the impact of topological difference on their excited-state electronic structures. Time-dependent density functional theory-computed transition density matrices for selected model compounds reveal that the optically relevant S1, S2, and S n states are delocalized over more than four TBAPy linkers with a maximum exciton size of ∼1.7 nm (i.e., two neighboring TBAPy linkers). Computational data further suggests the evolution of polar excitons (hole and electron residing in two different linkers); their oscillator strengths vary with the extent of interchromophoric interaction depending on their topological network. Femtosecond transient absorption (fs-TA) spectroscopic data of NU-901 highlight instantaneous spectral evolution of an intense S1 → S n transition at 750 nm, which diminishes with the emergence of a broad (580-1100 nm) induced absorption originating from a fast excimer formation. Although these ultrafast spectroscopic data reveal the first direct spectral observation of fast excimer formation (τ = 2 ps) in MOFs, the fs-TA features seen in NU-901 are clearly absent in NU-1000 and the free H4TBAPy linker. Furthermore, transient and steady-state fluorescence data collected as a function of solvent dielectrics reveal that the emissive states in both MOF samples are electronically nonpolar; however, low-lying polar excited states may get involved in the excited-state decay processes in polar solvents. The present work shows that the topological arrangement of the linkers critically controls the excited-state electronic structures.


A media advocacy intervention linking health disparities and food insecurity.
Media advocacy is a well-established strategy for transmitting health messages to the public. This paper discusses a media advocacy intervention that raised issues about how the public interprets messages about the negative effects of poverty on population health. In conjunction with the publication of a manuscript illustrating how income-related food insecurity leads to disparities related to the consumption of a popular food product across Canada (namely, Kraft Dinner®), we launched a media intervention intended to appeal to radio, television, print and Internet journalists. All the media coverage conveyed our intended message that food insecurity is a serious population health problem, confirming that message framing, personal narratives and visual imagery are important in persuading media outlets to carry stories about poverty as a determinant of population health. Among politicians and members of the public (through on-line discussions), the coverage provoked on-message as well as off-message reactions. Population health researchers and health promotion practitioners should anticipate mixed reactions to media advocacy interventions, particularly in light of new Internet technologies. Opposition to media stories regarding the socio-economic determinants of population health can provide new insights into how we might overcome challenges in translating evidence into preventive interventions.


Comparison of Models for Forecasting of Stewart's Disease of Corn in Iowa.
Three forecasting models for Stewart's disease (Pantoea stewartii subsp. stewartii) of corn (Zea mays) were examined for their ability to accurately predict the prevalence of Stewart's disease in Iowa at the county level. The Stevens Model, which is used as a predictor of the early wilt phase of Stewart's disease, the Stevens-Boewe Model, which predicts the late leaf blight phase of Stewart's disease, and the Iowa State Model that is used to predict the prevalence of Stewart's disease, all use mean air temperatures for December, January, and February for a preplant prediction of Stewart's disease risk in a subsequent season. Models were fitted using weighted binary logistic regression with Stewart's disease prevalence data and air temperature data for 1972 to 2003. For each model, the years 1972 to 1999 (n = 786 county-years) were used for model development to obtain parameter coefficients. All three models indicated an increased likelihood for Stewart's disease occurring in growing seasons preceded by warmer winters. Using internal bootstrap validation, the Stevens Model had a maximum error between predicted and calibrated probabilities of 10%, whereas the Stevens-Boewe and Iowa State models had maximum errors of 1% or less. External validation for each model, using air temperature and seed corn inspection data between 2000 and 2003 (n = 154 county-years), indicated that overall accuracy to predict Stewart's disease at the county level was between 62 and 66%. However, both the Stevens and Stevens-Boewe models were overly optimistic in predicting that Stewart's disease would not occur within specific counties, as the sensitivity for these two models was quite low (18 and 43%, respectively). The Iowa State Model was substantially more sensitive (67%). The results of this study suggest that the Iowa State Model has increased predictive ability beyond statewide predictions for estimating the risk of Stewart's disease at the county level in Iowa.


Formaldehyde as a possible mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to yield non-alkylating species in vitro.
N-Nitramines are biologically active compounds of environmental significance. In this study the suggested bioactivation of N- nitrodimethylamine via oxidation at the methyl-group was confirmed, as was indicated by formaldehyde liberation. N- Nitrodimethylamine and formaldehyde as well as the suggested metabolites, N- nitrohydroxymethylmethylamine and N- nitromethylamine were tested for mutagenicity in histidine auxotrophic Salmonella typhimurium strains in a variety of conditions. N- Nitrodimethylamine was mutagenic only in S. typhimurium TA 100 after pre-incubation with bacteria and a complete metabolizing mixture containing 9000 g liver supernatant and NADPH-regenerating cofactors. N- Nitrohydroxymethylmethylamine and formaldehyde were approximately equally mutagenic without the metabolizing mixture in TA 100 and TA 98, but not in TA 1535. The addition of the 9000 g supernatant of homogenized liver increased the yield of his+ revertants induced by the two compounds. N- Nitromethylamine was not mutagenic with or without the metabolic activation system. The results suggest that formaldehyde is possibly the mutagenically active intermediate formed during in vitro metabolism of N- nitrodimethylamine . Furthermore the participation of formaldehyde as the mutagenic intermediate of other non-alkylating N-nitro and N-nitroso compounds is demonstrated.


Hepatocellular Carcinoma Risk Steadily Persists over Time Despite Long-Term Antiviral Therapy for Hepatitis B: A Multicenter Study.
Long-term antiviral therapy (AVT) for chronic hepatitis B (CHB) reduces the risk of hepatocellular carcinoma (HCC). We assessed the temporal trends in the incidence of HCC over time during long-term AVT among Asian patients with CHB. Patients with CHB receiving entecavir/tenofovir (ETV/TDF) as a first-line antiviral were recruited from four academic hospitals in the Republic of Korea. We compared the incidence of HCC during and after the first 5 years of ETV/TDF treatment. Among 3,156 patients, the median age was 49.6 years and males predominated (62.4%). During the follow-up, 9.0% developed HCC. The annual incidence of HCC per 100 person-years during the first 5 years (n = 1,671) and after the first 5 years (n = 1,485) was statistically similar (1.93% vs. 2.27%, P = 0.347). When the study population was stratified according to HCC prediction model, that is, modified PAGE-B score, the annual incidence of HCC was 0.11% versus 0.39% in the low-risk group (<8 points), 1.26% versus 1.82% in the intermediate-risk group (9-12 points), and 4.63% versus 5.24% in the high-risk group (≥13 points; all P > 0.05). A Poisson regression analysis indicated that the duration of AVT did not significantly affect the overall trend of the incidence of HCC (adjusted annual incidence rate ratio = 0.85; 95% confidence interval, 0.66-1.11; P = 0.232). Despite long-term AVT, the risk of HCC steadily persists over time among patients with CHB in the Republic of Korea, in whom HBV genotype C2 predominates. Careful HCC surveillance is still essential.


The maternal brain: Region-specific patterns of brain aging are traceable decades after childbirth.
Pregnancy involves maternal brain adaptations, but little is known about how parity influences women's brain aging trajectories later in life. In this study, we replicated previous findings showing less apparent brain aging in women with a history of childbirths, and identified regional brain aging patterns linked to parity in 19,787 middle- and older-aged women. Using novel applications of brain-age prediction methods, we found that a higher number of previous childbirths were linked to less apparent brain aging in striatal and limbic regions. The strongest effect was found in the accumbens-a key region in the mesolimbic reward system, which plays an important role in maternal behavior. While only prospective longitudinal studies would be conclusive, our findings indicate that subcortical brain modulations during pregnancy and postpartum may be traceable decades after childbirth.


Malagasy Dracaena Vand. ex L. (Ruscaceae): an investigation of discrepancies between morphological features and spatial genetic structure at a small evolutionary scale.
Malagasy Dracaena (Ruscaceae) are divided into four species and 14 varieties, all of them showing a high level of morphological diversity and a putatively artefactual circumscription. In order to reveal relationships between those entangled entities, a span of Malagasy Dracaena were sampled and analyzed using cpDNA sequences and AFLP. The cpDNA analyses resolved three biogeographic clades that are mostly inconsistent with morphology, since similar phenotypes are found across the three clades. Bayesian inference clustering analyses based on the AFLP were not in accordance with the cpDNA analysis. This result might be explained by (1) a recent origin of the Malagasy species of Dracaena with an incomplete sorting of chloroplast lineages; (2) a high amount of hybridizations; (3) a complex migration pattern. Interestingly, when the AFLP are analyzed using the parsimony criterion, a trend towards a directional evolution of inflorescence types and ecological features was observed. This might be considered either as phenotypic plasticity and/or as the result of fast evolution in flower characters according to habitat preferences. Overall, our results point to the difficulty of defining evolutionarily significant units in Malagasy Dracaena, emphasizing the complex speciation processes taking place in tropical regions.


Blood pressure after renal transplantation.
Hypertension is extremely common in renal allograft recipients, mainly as the result of impaired renal function and cyclosporin A therapy. Blood pressure is a powerful independent predictor of longterm graft outcome. This adverse effect is presumably mediated by both hemodynamic and non-hemodynamic factors. There is also evidence for activation of the renin angiotensin system in the renal allograft. Antihypertensive treatment is of known benefit on graft outcome in experimental models, but this has so far not been documented in clinical trials. Proteinuria is another independent predictor of longterm graft outcome. There is recent documentation of a specific antiproteinuric effect of ACE inhibitors on proteinuria which is of interest since proteinuria is an independent predictor of longterm graft outcome.


Inhibition of heterologous strains of HIV by antisense RNA.
Antisense RNA can inhibit the expression of messenger RNAs (mRNAs) to which they are complementary by a variety of mechanisms and might provide the basis for antiviral therapies of high selectivity. In a previous study of six retrovirally expressed antisense RNAs targeted to HIV-1IIIB, we found that two significantly reduced HIV-1IIIB replication. Here we test the degree to which this inhibitory effect tolerates the natural variation found in the nucleotide sequence of different strains of HIV-1. We show that the longer of the two inhibitory antisense RNAs (600 bases) inhibits replication of HIV strains RF, MN and SF2 to at least as great an extent as it does the homologous strain. In contrast, the shorter (71 bases) does not inhibit replication of the heterologous strains. An examination of the predicted positions of the mismatches in the duplexes formed between the IIIB antisense RNAs and the mRNAs of heterologous strains suggests that one requirement of an inhibitory antisense RNA is that it can form a perfect duplex with its target mRNA of at least some 51-64 base-pairs. Although the observations presented here are not definitive proof of this, they are reminiscent of the structural requirements deduced for the double-stranded RNA-mediated induction of interferon and the activation of interferon-induced 2', 5'-oligo(A) synthetase and protein kinase. We tested the ability of antisense RNA to inhibit HIV replication in Jurkat, CEM, U937 and HeLa-T4 cells. The level of inhibition of HIV-1IIIB replication varied according to the cell line in which it was expressed, but in all cases was significant.


Risks of Lynch syndrome cancers for MSH6 mutation carriers.
Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.


Modeling the distribution of migratory bird stopovers to inform landscape-scale siting of wind development.
Conservation of migratory birds requires understanding the distribution of and potential threats to their migratory habitats. However, although migratory birds are protected under international treaties, few maps have been available to represent migration at a landscape scale useful to target conservation efforts or inform the siting of wind energy developments that may affect migratory birds. To fill this gap, we developed models that predict where four groups of birds concentrate or stopover during their migration through the state of Wyoming, USA: raptors, wetland, riparian and sparse grassland birds. The models were based on existing literature and expert knowledge concerning bird migration behavior and ecology and validated using expert ratings and known occurrences. There was significant agreement between migratory occurrence data and migration models for all groups except raptors, and all models ranked well with experts. We measured the overlap between the migration concentration models and a predictive model of wind energy development to assess the potential exposure of migratory birds to wind development and illustrate the utility of migratory concentration models for landscape-scale planning. Wind development potential is high across 15% of Wyoming, and 73% of this high potential area intersects important migration concentration areas. From 5.2% to 18.8% of each group's important migration areas was represented within this high wind potential area, with the highest exposures for sparse grassland birds and the lowest for riparian birds. Our approach could be replicated elsewhere to fill critical data gaps and better inform conservation priorities and landscape-scale planning for migratory birds.


STK39, But Not BST1, HLA-DQB1, and SPPL2B Polymorphism, Is Associated With Han-Chinese Parkinson's Disease in Taiwan.
Neuroinflammation is emerging as an important pathway involved in Parkinson's disease (PD) pathogenesis. Herein, we investigated the effect of 4 top PD-associated genetic variants in Caucasians listed on the top risk loci identified by meta-analysis of genome wide-association studies in PDGene database (http://www.pdgene.org/top_results), including serine threonine kinase 39 (STK39) rs1955337, bone marrow stromal cell antigen 1 (BST1) rs11724635, major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) rs9275326, and signal peptide peptidase-like 2B (SPPL2B) rs62120679, by genotyping 596 Han-Chinese patients with PD and 597 age-matched control subjects. Compared with subjects with STK39 rs1955337 GG genotype, those with TT genotype had a 1.64-fold increased risk of PD (95% confidence interval: 1.13-2.39, P = 0.010). The recessive model also demonstrated an increased PD risk in TT genotype (odds ratio: 1.59, 95% confidence interval: 1.12-2.27) compared with the other genotypes (GT + GG). PD patients demonstrate a similar genotypic and allelic frequency in BST1 rs11724635, HLA-DQB1 rs9275326, and SPPL2B rs62120679 compared with controls. These findings suggested that the STK39 rs1955337 TT genotype is a risk factor for Han-Chinese patients with PD in Taiwan. The ethnic discrepancies of the other 3 genetic variants may indicate a distinct genetic background of neuroinflammation between PD patients in Han-Chinese and Caucasians.


Physical activity patterns among Latinos in the United States: putting the pieces together.
Estimates of participation in physical activity among Latinos are inconsistent across studies. To obtain better estimates and examine possible reasons for inconsistencies, we assessed 1) patterns of participation in various categories of physical activity among Latino adults, 2) changes in their activity patterns with acculturation, and 3) variations in their activity patterns by region of origin. Using data from four national surveillance systems (the National Health and Nutrition Examination Survey, 1999-2002; the Behavioral Risk Factor Surveillance System, 2003; the National Household Travel Survey, 2001; and the National Health Interview Survey Cancer Supplement, 2000), we estimated the percentage of Latinos who participated at least once per week in leisure-time, household, occupational, or transportation-related physical activity, as well as in an active pattern of usual daily activity. We reported prevalences by acculturation measures and region of origin. The percentage of Latinos who participated in the various types of physical activity ranged from 28.7% for having an active level of usual daily activity (usually walking most of the day and usually carrying or lifting objects) to 42.8% for participating in leisure-time physical activity at least once per week. The percentage who participated in leisure-time and household activities increased with acculturation, whereas the percentage who participated in occupational and transportation-related activities decreased with acculturation. Participation in an active level of usual daily activity did not change significantly. The prevalence of participation in transportation-related physical activity and of an active level of usual daily activity among Latino immigrants varied by region of origin. Physical activity patterns among Latinos vary with acculturation and region of origin. To assess physical activity levels in Latino communities, researchers should measure all types of physical activity and the effects of acculturation on each type of activity.


Do birds and beetles show similar responses to urbanization?
To date, the vast majority of studies in urban areas have been carried out on birds, yet it is not known whether the responses of birds to urbanization are congruent with those of other taxa. In this paper, we compared the responses of breeding birds and carabid beetles to urbanization, specifically asking whether the emerging generalizations of the effects of extreme levels of urbanization on birds (declines in total species richness and the richness of specialist species, increases in total abundance and the abundances of native generalist and introduced species, and community simplification, including increasing similarity) could also be applied to ground beetles. We also directly tested for congruence between birds and ground beetles using correlations between variables describing bird and beetle community structure and correlations between bird and beetle distance matrices describing community dissimilarity between pairs of sampling locations. Breeding bird and carabid beetle community data were collected in Ottawa, Ontario, and Gatineau, Quebec, Canada, in two groups of sites: developed sites representing the predictor variable within-site housing density, and forested sites adjacent to development representing the predictor variable neighboring housing density (each site was 0.25 km2). Breeding birds and carabid beetles do not respond similarly to increasing within-site housing density but do exhibit some similar responses to increasing neighboring housing density. Birds displayed strong declines in diversity, compositional changes, and community simplification in response to increasing within-site housing density. Forest and introduced species of birds and beetles responded similarly to increasing housing density within a site, but responses of overall diversity and open-habitat species richness and patterns of community simplification differed between birds and beetles. Increasing neighboring housing density resulted in increases in the abundances of introduced birds and introduced beetles and similar patterns of community simplification in both taxa. To better understand and mitigate the effects of urbanization on biodiversity, we suggest that, in addition to the responses of birds, future research should focus on the responses of other taxa in the urban matrix.


Neuroimaging studies of mental rotation: a meta-analysis and review.
Abstract Mental rotation is a hypothesized imagery process that has inspired controversy regarding the substrate of human spatial reasoning. Two central questions about mental rotation remain: Does mental rotation depend on analog spatial representations, and does mental rotation depend on motor simulation? A review and meta-analysis of neuroimaging studies help answer these questions. Mental rotation is accompanied by increased activity in the intraparietal sulcus and adjacent regions. These areas contain spatially mapped representations, and activity in these areas is modulated by parametric manipulations of mental rotation tasks, supporting the view that mental rotation depends on analog representations. Mental rotation also is accompanied by activity in the medial superior precentral cortex, particularly under conditions that favor motor simulation, supporting the view that mental rotation depends on motor simulation in some situations. The relationship between mental rotation and motor simulation can be understood in terms of how these two processes update spatial reference frames.


Recognition of wake-sleep stage 1 multichannel eeg patterns using spectral entropy features for drowsiness detection.
Electroencephalographic (EEG) activity recorded during the entire sleep cycle reflects various complex processes associated with brain and exhibits a high degree of irregularity through various stages of sleep. The identification of transition from wakefulness to stage1 sleep is a challenging area of research for the biomedical community. In this paper, spectral entropy (SE) is used as a complexity measure to quantify irregularities in awake and stage1 sleep of 8-channel sleep EEG data from the polysomnographic recordings of ten healthy subjects. The SE measures of awake and stage1 sleep EEG data are estimated for each second and applied to a multilayer perceptron feed forward neural network (MLP-FF). The network is trained using back propagation algorithm for recognizing these two patterns. Initially, the MLP network is trained and tested for randomly chosen subject-wise combined datasets I and II and then for the combined large dataset III. In all cases, 60 % of the entire dataset is used for training while 20 % is used for testing and 20 % for validation. Results indicate that the MLP neural network learns with maximum testing accuracy of 95.9 % for dataset II. In the case of combined large dataset, the network performs with a maximum accuracy of 99.2 % with 100 hidden neurons. Results show that in channels O1, O2, F3 and F4 (A1, A2 as reference), the mean of the spectral entropy value is higher in awake state than in stage1 sleep indicating that the EEG becomes more regular and rhythmic as the subject attains stage1 sleep from wakefulness. However, in C3 and C4 the mean values of SE values are not very much discriminative of both groups. This may prove to be a very effective indicator for scoring the first two stages of sleep EEG and may be used to detect the transition from wakefulness to stage1 sleep.


Use of herbal dietary supplement si-wu-tang and health-related quality of life in postpartum women: a population-based correlational study.
Objective. The aim of the study was to explore the association between women's use of herbal dietary supplement Si-Wu-Tang during the postpartum period and their health-related quality of life. Methods. This is a population-based correlational study. We used multistage, stratified, systematic sampling to recruit 24,200 pairs of postpartum women and newborns from the Taiwan National Birth Registry in 2005. A structured questionnaire was successfully administered to 87.8% of the sampled population. Trained interviewers performed home interviews 6 months after the women's deliveries between June 2005 and July 2006. The Medical Outcomes Study 36-item Short-Form (SF-36) was used to measure the quality of life of the women along with the frequency of Si-Wu-Tang use. Results. Si-Wu-Tang use after delivery improved women's score for bodily pain and also improved their score for mental health when used more than 10 times. In addition, there were increases in general health and vitality scores in the group who continuously used Si-Wu-Tang more than 10 times after using Sheng-Hua-Tang. Conclusion. Use of Si-Wu-Tang after delivery may be associated with women's health-related quality of life especially for those who previously used Sheng-Hua-Tang. These results are exploratory and need to be replicated.


Extended Cost-Effectiveness Analysis for Health Policy Assessment: A Tutorial.
Health policy instruments such as the public financing of health technologies (e.g., new drugs, vaccines) entail consequences in multiple domains. Fundamentally, public health policies aim at increasing the uptake of effective and efficient interventions and at subsequently leading to better health benefits (e.g., premature mortality and morbidity averted). In addition, public health policies can provide non-health benefits in addition to the sole well-being of populations and beyond the health sector. For instance, public policies such as social and health insurance programs can prevent illness-related impoverishment and procure financial risk protection. Furthermore, public policies can improve the distribution of health in the population and promote the equalization of health among individuals. Extended cost-effectiveness analysis was developed to address health policy assessment, specifically to evaluate the health and financial consequences of public policies in four domains: (1) the health gains; (2) the financial risk protection benefits; (3) the total costs to the policy makers; and (4) the distributional benefits. Here, we present a tutorial that describes both the intent of extended cost-effectiveness analysis and its keys to allow easy implementation for health policy assessment.


Sld7, an Sld3-associated protein required for efficient chromosomal DNA replication in budding yeast.
Genetic screening of yeast for sld (synthetic lethality with dpb11) mutations has identified replication proteins, including Sld2, -3, and -5, and clarified the molecular mechanisms underlying eukaryotic chromosomal DNA replication. Here, we report a new replication protein, Sld7, identified by rescreening of sld mutations. Throughout the cell cycle, Sld7 forms a complex with Sld3, which associates with replication origins in a complex with Cdc45, binds to Dpb11 when phosphorylated by cyclin-dependent kinase, and dissociates from origins once DNA replication starts. However, Sld7 does not move with the replication fork. Sld7 binds to the nonessential N-terminal portion of Sld3 and reduces its affinity for Cdc45, a component of the replication fork. Although Sld7 is not essential for cell growth, its absence reduces the level of cellular Sld3, delays the dissociation from origins of GINS, a component of the replication fork, and slows S-phase progression. These results suggest that Sld7 is required for the proper function of Sld3 at the initiation of DNA replication.


Pathological findings in organs and tissues of patients with COVID-19: A systematic review.
Coronavirus disease (COVID-19) is the pandemic caused by SARS-CoV-2 that has caused more than 2.2 million deaths worldwide. We summarize the reported pathologic findings on biopsy and autopsy in patients with severe/fatal COVID-19 and documented the presence and/or effect of SARS-CoV-2 in all organs. A systematic search of the PubMed, Embase, MedRxiv, Lilacs and Epistemonikos databases from January to August 2020 for all case reports and case series that reported histopathologic findings of COVID-19 infection at autopsy or tissue biopsy was performed. 603 COVID-19 cases from 75 of 451 screened studies met inclusion criteria. The most common pathologic findings were lungs: diffuse alveolar damage (DAD) (92%) and superimposed acute bronchopneumonia (27%); liver: hepatitis (21%), heart: myocarditis (11.4%). Vasculitis was common only in skin biopsies (25%). Microthrombi were described in the placenta (57.9%), lung (38%), kidney (20%), Central Nervous System (CNS) (18%), and gastrointestinal (GI) tract (2%). Injury of endothelial cells was common in the lung (18%) and heart (4%). Hemodynamic changes such as necrosis due to hypoxia/hypoperfusion, edema and congestion were common in kidney (53%), liver (48%), CNS (31%) and GI tract (18%). SARS-CoV-2 viral particles were demonstrated within organ-specific cells in the trachea, lung, liver, large intestine, kidney, CNS either by electron microscopy, immunofluorescence, or immunohistochemistry. Additional tissues were positive by Polymerase Chain Reaction (PCR) tests only. The included studies were from numerous countries, some were not peer reviewed, and some studies were performed by subspecialists, resulting in variable and inconsistent reporting or over statement of the reported findings. The main pathologic findings of severe/fatal COVID-19 infection are DAD, changes related to coagulopathy and/or hemodynamic compromise. In addition, according to the observed organ damage myocarditis may be associated with sequelae.


Epidemiology of fractures in 15,000 adults: the influence of age and gender.
We report a prospective study of the incidence of fractures in the adult population of Edinburgh, related to age and gender. Over a two-year period, 15,293 adults, 7428 males and 7865 females, sustained a fracture, and 5208 (34.0%) required admission. Between 15 and 49 years of age, males were 2.9 times more likely to sustain a fracture than females (95% CI 2.7 to 3.1). Over the age of 60 years, females were 2.3 times more likely to sustain a fracture than males (95% CI 2.1 to 2.4). There were three main peaks of fracture distribution: the first was in young adult males, the second was in elderly patients of both genders, mainly in metaphyseal bone such as the proximal femur, although diaphyseal fractures also showed an increase in incidence. The third increase in the incidence of fractures, especially of the wrist, was seen to start at 40 years of age in women. Our study has also shown that 'osteoporotic' fractures became evident in women earlier than expected, and that they were not entirely a postmenopausal phenomenon.


Hybrid microfluidics combined with active and passive approaches for continuous cell separation.
Microfluidics, which is classified as either active or passive, is capable of separating cells of interest from a complex and heterogeneous sample. Active methods utilise external fields such as electric, magnetic, acoustic, and optical to drive cells for separation, while passive methods utilise channel structures, intrinsic hydrodynamic forces, and steric hindrances to manipulate cells. However, when processing complex biological samples such as whole blood with rare cells, separation with a single module microfluidic device is difficult. Hybrid microfluidics is an emerging technique, which utilises active and passive methods whilst fulfilling higher requirements for stable performance, versatility, and convenience, including (i) the ability to process multi-target cells, (ii) enhanced ability for multiplexed separation, (iii) higher sensitivity, and (iv) tunability for a wider operational range. This review introduces the fundamental physics and typical formats for subclasses of hybrid microfluidic devices based on their different physical fields; presents current examples of cell sorting to highlight the advantage and usefulness of hybrid microfluidics on biomedicine, and then discusses the challenges and perspective of future development and the promising direction of research in this field.


Impact of subsidence on clinical outcomes and radiographic fusion rates in anterior cervical discectomy and fusion: a systematic review.
Systematic review. To provide a systematic review of published literature on the impact of subsidence on clinical outcomes and radiographic fusion rates after anterior cervical discectomy and fusion with plates or without plates. Subsidence of interbody implants is common after anterior cervical spine fusions. The impact of subsidence on fusion rates and clinical outcomes is unknown. Systematic literature review on published articles on anterior cervical discectomy and fusion, which objectively measured graft subsidence, radiographic fusion rates, and clinical outcomes between April 1966 and December 2010. A total of 35 articles that measured subsidence and provided fusion rates and/or clinical outcomes were selected for inclusion. The mean subsidence rate ranged from 19.3% to 42.5%. The rate of subsidence based on the type of implant ranged from 22.8% to 35.9%. The incidence of subsidence was not impacted by the type of implant (P=0.98). The overall fusion rate of the combined studies was 92.8% and was not impacted by subsidence irrespective of subsidence definition or the measurement technique used (P=0.19). Clinical outcomes were evaluated in 27 of 35 studies with all studies reporting an improvement in patient outcomes postoperatively. Subsidence irrespective of the measurement technique or definition does not appear to have an impact on successful fusion and/or clinical outcomes. A validated definition and standard measurement technique for subsidence is needed to determine the actual incidence of subsidence and its impact on radiographic and clinical outcomes.


Guidance for DNA methylation studies: statistical insights from the Illumina EPIC array.
There has been a steady increase in the number of studies aiming to identify DNA methylation differences associated with complex phenotypes. Many of the challenges of epigenetic epidemiology regarding study design and interpretation have been discussed in detail, however there are analytical concerns that are outstanding and require further exploration. In this study we seek to address three analytical issues. First, we quantify the multiple testing burden and propose a standard statistical significance threshold for identifying DNA methylation sites that are associated with an outcome. Second, we establish whether linear regression, the chosen statistical tool for the majority of studies, is appropriate and whether it is biased by the underlying distribution of DNA methylation data. Finally, we assess the sample size required for adequately powered DNA methylation association studies. We quantified DNA methylation in the Understanding Society cohort (n = 1175), a large population based study, using the Illumina EPIC array to assess the statistical properties of DNA methylation association analyses. By simulating null DNA methylation studies, we generated the distribution of p-values expected by chance and calculated the 5% family-wise error for EPIC array studies to be 9 × 10- 8. Next, we tested whether the assumptions of linear regression are violated by DNA methylation data and found that the majority of sites do not satisfy the assumption of normal residuals. Nevertheless, we found no evidence that this bias influences analyses by increasing the likelihood of affected sites to be false positives. Finally, we performed power calculations for EPIC based DNA methylation studies, demonstrating that existing studies with data on ~ 1000 samples are adequately powered to detect small differences at the majority of sites. We propose that a significance threshold of P < 9 × 10- 8 adequately controls the false positive rate for EPIC array DNA methylation studies. Moreover, our results indicate that linear regression is a valid statistical methodology for DNA methylation studies, despite the fact that the data do not always satisfy the assumptions of this test. These findings have implications for epidemiological-based studies of DNA methylation and provide a framework for the interpretation of findings from current and future studies.


Comparative effectiveness and cost-benefit analysis of local application of vancomycin powder in posterior spinal fusion for spine trauma: clinical article.
Surgical site infection (SSI) is a morbid complication with high cost in spine surgery. In this era of health care reforms, adjuvant therapies that not only improve quality but also decrease cost are considered of highest value. The authors introduced local application of vancomycin powder into their practice of posterior spinal fusion for spine trauma and undertook this study to determine the value and cost benefit of using vancomycin powder in surgical sites to prevent postoperative infections. A retrospective review of 110 patients with traumatic spine injuries treated with instrumented posterior spine fusions over a 2-year period at a single institution was performed. One group (control group) received standard systemic prophylaxis only, whereas another (treatment group) received 1 g of locally applied vancomycin powder (spread over the surgical wound) in addition to systemic prophylaxis. Data were collected on patient demographic characteristics, clinical variables, surgical variables, and 90-day morbidity. Incidence of infection was the primary outcome evaluated, and billing records were reviewed to determine total infection-related medical cost (cost of reoperation/wound debridement, medications, and diagnostic tests). The payer's cost was estimated to be 70% of the total billing cost. A total of 110 patients were included in the study. The control (n = 54) and treatment groups (n = 56) were similar at baseline. Use of vancomycin powder led to significant reduction in infection rate (13% infection rate in the control group vs 0% in the treatment group, p = 0.02). There were no adverse effects noted from the use of vancomycin powder. The total mean cost of treating postoperative infection per patient was $33,705. Use of vancomycin powder led to a cost savings of $438,165 per 100 posterior spinal fusions performed for traumatic injuries. The use of adjuvant vancomycin powder was associated with a significant reduction in the incidence of postoperative infection as well as infection-related medical cost. These findings suggest that use of adjuvant vancomycin powder in high-risk patients undergoing spinal fusion is a cost-saving option for preventing postoperative infections, as it can lead to cost-savings of $438,165 per 100 spinal fusions performed.


Self-reported vs measured body mass indices in migraineurs.
To compare and contrast body mass indices calculated based on self-reported height and weight as compared with measured height and weight in migraine patients. Obesity is a risk factor for multiple neurological disorders including stroke, dementia, and migraine chronification. In addition, several cytokines and adipocytokines associated with migraine are modulated by body mass. The body mass index (BMI) is a commonly used anthropometric measure to estimate total body fat and is often calculated based on patient's self-reported height and weight. This was a retrospective study evaluating consecutive migraine patients presenting to a headache clinic.Demographic characteristics and self-reported height and weight were obtained from a standardized questionnaire that each new patient completes upon presentation to the clinic. In addition, as depression has been shown to be associated with both migraine and obesity, information in regards to major depression utilizing the Patient Healthcare Questionnaire-9 was extracted as well. Following completion of the questionnaire, body mass indices are routinely measured, with height measured to the nearest 0.5 inch utilizing a mounted stadiometer, and weight measured with a standard scale to the nearest 0.5 lb. After this information was extracted from the charts, BMI was then calculated for both self-reported and measured body mass indices.Using the measured body mass indices as a standard, this was then compared and contrasted to the patient's self-reported body mass indices. A total of 110 patients were included in the study. Patients were predominantly female (91%) with a mean age of 38.6 +/- 11.6 years. Of the total patients included, no significant difference in self-reported height (mean 64.7 +/- 3.1 inches) as compared with measured height (mean 64.5 +/- 3.4 inches) was seen, P = .463. However, self-reported weight (169 +/- 41.3) was underestimated as compared with the measured weight (173.5 +/- 43.2), P = .001. And, the self-reported BMI (28.4 +/- 6.8) was significantly less than the measured BMI (29.4 +/- 7.5), P < .001. In our study, the self-reported mean weight and BMI for migraineurs was significantly less than the measured mean weight and BMI, and was of greater magnitude in the obese migraineurs. This suggests that conclusions drawn from studies evaluating obesity utilizing self-reported BMI in migraineurs may undercall the effect of total body obesity.


Analysis of 1 year virtual histology changes in coronary plaque located behind the struts of the everolimus eluting bioresorbable vascular scaffold.
Serial intravascular ultrasound virtual histology (IVUS-VH) after implantation of metallic stents has been unable to show any changes in the composition of the scaffolded plaque overtime. The everolimus-eluting ABSORB scaffold potentially allows for the formation of new fibrotic tissue on the scaffolded coronary plaque during bioresorption. We examined the 12 month IVUS-VH changes in composition of the plaque behind the struts (PBS) following the implantation of the ABSORB scaffold. Using IVUS-VH and dedicated software, the composition of the PBS was analyzed in all patients from the ABSORB Cohort B2 trial, who were imaged with a commercially available IVUS-VH console (s5i system, Volcano Corporation, Rancho Cordova, CA, USA), immediately post-ABSORB implantation and at 12 month follow-up. Paired IVUS-VH data, recorded with s5i system, were available in 17 patients (18 lesions). The analysis demonstrated an increase in mean PBS area (2.39 ± 1.85 mm(2) vs. 2.76 ± 1.79 mm(2), P = 0.078) and a reduction in the mean lumen area (6.37 ± 0.90 mm(2) vs. 5.98 ± 0.97 mm(2), P = 0.006). Conversely, a significant decrease of 16 and 30% in necrotic core (NC) and dense calcium (DC) content, respectively, were evident (median % NC from 43.24 to 36.06%, P = 0.016; median % DC from 20.28 to 11.36%, P = 0.002). Serial IVUS-VH analyses of plaque located behind the ABSORB struts at 12-month demonstrated an increase in plaque area with a decrease in its NC and DC content. Larger studies are required to investigate the clinical impact of these findings.


The behavioral and clinical effects of therapeutic lifestyle change on middle-aged adults.
Chronic diseases such as cancer, cardiovascular disease, stroke, and diabetes are responsible for most deaths in the United States. Lifestyle factors--poor nutrition, sedentary living, and tobacco use--appear to play a prominent role in the development of many chronic diseases. This study determined the behavioral and clinical impact of a therapeutic lifestyle-modification intervention on a group of community volunteers. Participants included 348 volunteers aged 24 to 81 years from the Rockford, Ill, metropolitan area who participated in a randomized clinical trial. The intervention group attended a 40-hour educational course delivered as lectures during a 4-week period. Participants learned the importance of making better lifestyle choices and how to make improvements in nutrition and physical activity. Changes in nutrition, physical activity behavior, and several chronic disease risk factors were assessed at baseline and 6 months. Intervention participants showed significant 6-month improvement in all nutrition and physical activity measures except calories from protein and whole-grain servings and all clinical measures except blood glucose, total cholesterol, triglycerides, and high-sensitivity C-reactive protein. Total cholesterol and low-density lipoprotein cholesterol were worse after 6 months in both groups but only significantly worse in the control group. The control group experienced small but significant improvements in systolic and diastolic blood pressure and high-density lipoproteins. Change-score comparisons between the intervention and control groups were significant for all nutrition and physical activity variables except total steps per week and daily sodium intake and were also significant for the clinical measures of weight, body fat, and body mass index. This therapeutic lifestyle-modification program can significantly improve nutrition and physical activity behavior and can reduce many of the risk factors associated with common chronic diseases.


High Fructose Corn Syrup-Moderate Fat Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling.
The neurobiological mechanisms that mediate psychiatric comorbidities associated with metabolic disorders such as obesity, metabolic syndrome and diabetes remain obscure. High fructose corn syrup (HFCS) is widely used in beverages and is often included in food products with moderate or high fat content that have been linked to many serious health issues including diabetes and obesity. However, the impact of such foods on the brain has not been fully characterized. Here, we evaluated the effects of long-term consumption of a HFCS-Moderate Fat diet (HFCS-MFD) on behavior, neuronal signal transduction, gut microbiota, and serum metabolomic profile in mice to better understand how its consumption and resulting obesity and metabolic alterations relate to behavioral dysfunction. Mice fed HFCS-MFD for 16 weeks displayed enhanced anxiogenesis, increased behavioral despair, and impaired social interactions. Furthermore, the HFCS-MFD induced gut microbiota dysbiosis and lowered serum levels of serotonin and its tryptophan-based precursors. Importantly, the HFCS-MFD altered neuronal signaling in the ventral striatum including reduced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), increased expression of ΔFosB, increased Cdk5-dependent phosphorylation of DARPP-32, and reduced PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor. These findings suggest that HFCS-MFD-induced changes in the gut microbiota and neuroactive metabolites may contribute to maladaptive alterations in ventral striatal function that underlie neurobehavioral impairment. While future studies are essential to further evaluate the interplay between these factors in obesity and metabolic syndrome-associated behavioral comorbidities, these data underscore the important role of peripheral-CNS interactions in diet-induced behavioral and brain function. This study also highlights the clinical need to address neurobehavioral comorbidities associated with obesity and metabolic syndrome.


Acemannan, an extracted product from Aloe vera, stimulates dental pulp cell proliferation, differentiation, mineralization, and dentin formation.
This study investigated the effect of acemannan (Aloe vera gel polysaccharide) on dentin formation. Primary human dental pulp cells were treated with acemannan. New DNA synthesis, bone morphogenetic protein-2, alkaline phosphatase activity, dentin sialoprotein expression, and mineralization were determined by [(3)H]-thymidine incorporation, enzyme-linked immunosorbent assay, biochemical assay, western blotting, and Alizarin Red staining, respectively. Then the upper first molars of 24 male Sprague Dawley rats were intentionally exposed and capped with either acemannan or calcium hydroxide. At day 28, the teeth were histopathologically examined and evaluated for the degree of inflammation, dentin bridge formation, and pulp tissue organization. The results revealed that acemannan significantly increased pulp cell proliferation, bone morphogenetic protein-2, alkaline phosphatase activity, dentin sialoprotein expression, and mineralization, compared with the untreated group. The acemannan-treated group also exhibited a complete homogeneous calcified dentin bridge and good pulp tissue organization, whereas neither was detected in the calcium hydroxide-treated and sham groups. In the acemannan-treated group, either mild or no inflammation was found, whereas the other groups had various degrees of inflammation. The data suggest that acemannan promotes dentin formation by stimulating primary human dental pulp cell proliferation, differentiation, extracellular matrix formation, and mineralization. Acemannan also has pulpal biocompatibility and promotes soft tissue organization.


Prediction of functional sites by analysis of sequence and structure conservation.
We present a method for prediction of functional sites in a set of aligned protein sequences. The method selects sites which are both well conserved and clustered together in space, as inferred from the 3D structures of proteins included in the alignment. We tested the method using 86 alignments from the NCBI CDD database, where the sites of experimentally determined ligand and/or macromolecular interactions are annotated. In agreement with earlier investigations, we found that functional site predictions are most successful when overall background sequence conservation is low, such that sites under evolutionary constraint become apparent. In addition, we found that averaging of conservation values across spatially clustered sites improves predictions under certain conditions: that is, when overall conservation is relatively high and when the site in question involves a large macromolecular binding interface. Under these conditions it is better to look for clusters of conserved sites than to look for particular conserved sites.


Neuropeptide receptor transcript expression levels and magnitude of ionic current responses show cell type-specific differences in a small motor circuit.
We studied the relationship between neuropeptide receptor transcript expression and current responses in the stomatogastric ganglion (STG) of the crab, Cancer borealis. We identified a transcript with high sequence similarity to crustacean cardioactive peptide (CCAP) receptors in insects and mammalian neuropeptide S receptors. This transcript was expressed throughout the nervous system, consistent with the role of CCAP in a range of different behaviors. In the STG, single-cell qPCR showed expression in only a subset of neurons. This subset had previously been shown to respond to CCAP with the activation of a modulator-activated inward current (IMI), with one exception. In the one cell type that showed expression but no IMI responses, we found CCAP modulation of synaptic currents. Expression levels within STG neuron types were fairly variable, but significantly different between some neuron types. We tested the magnitude and concentration dependence of IMI responses to CCAP application in two identified neurons, the lateral pyloric (LP) and the inferior cardiac (IC) neurons. LP had several-fold higher expression and showed larger current responses. It also was more sensitive to low CCAP concentrations and showed saturation at lower concentrations, as sigmoid fits showed smaller EC50 values and steeper slopes. In addition, occlusion experiments with proctolin, a different neuropeptide converging onto IMI, showed that saturating concentrations of CCAP activated all available IMI in LP, but only approximately two-thirds in IC, the neuron with lower receptor transcript expression. The implications of these findings for comodulation are discussed.


Relevance of nonsynonymous CYP2C8 polymorphisms to 13-cis retinoic acid and paclitaxel hydroxylation.
CYP2C8 has a major role in the metabolism of the anticancer agents 13-cis retinoic acid (13cisRA) and paclitaxel. There is evidence that polymorphisms in the CYP2C8 gene contribute to observed interindividual differences in paclitaxel metabolism. However, no studies have been performed to determine the relevance of CYP2C8 polymorphisms to 13cisRA metabolism. In the current study, the effect of two common nonsynonymous CYP2C8 polymorphisms, CYP2C8*3 (R139K and K399R) and *4 (I264M), on the metabolism of 13cisRA and paclitaxel was examined using an Escherichia coli expression system with coexpression of human cytochrome P450 reductase. No statistically significant differences in the level of 13cisRA 4-hydroxylase activity were associated with either CYP2C8 allelic variant compared with the wild-type CYP2C8.1 enzyme. Furthermore, no differences were observed for the CYP2C8.3 or CYP2C8.4 enzymes with respect to paclitaxel 6alpha-hydroxylase kinetics compared with wild-type CYP2C8.1. However, when the effects of the individual polymorphisms making up the CYP2C8*3 allele were considered, a significantly lower level of paclitaxel 6alpha-hydroxylase activity was associated with the K399R enzyme. A lower level of activity was also seen for the R139K enzyme, although this difference was not significant. No differences were observed with respect to 13cisRA 4-hydroxylase activity. We conclude that common CYP2C8 polymorphisms are unlikely to explain reported interindividual variation in 13cisRA or paclitaxel pharmacokinetics.


Senataxin homologue Sen1 is required for efficient termination of RNA polymerase III transcription.
R-loop disassembly by the human helicase Senataxin contributes to genome integrity and to proper transcription termination at a subset of RNA polymerase II genes. Whether Senataxin also contributes to transcription termination at other classes of genes has remained unclear. Here, we show that Sen1, one of two fission yeast homologues of Senataxin, promotes efficient termination of RNA polymerase III (RNAP3) transcription in vivo. In the absence of Sen1, RNAP3 accumulates downstream of RNAP3-transcribed genes and produces long exosome-sensitive 3'-extended transcripts. Importantly, neither of these defects was affected by the removal of R-loops. The finding that Sen1 acts as an ancillary factor for RNAP3 transcription termination in vivo challenges the pre-existing view that RNAP3 terminates transcription autonomously. We propose that Sen1 is a cofactor for transcription termination that has been co-opted by different RNA polymerases in the course of evolution.


The short-term impact of COVID-19 pandemic on spine surgeons: a cross-sectional global study.
The outbreak of COVID-19 erupted in December 2019 in Wuhan, China. In a few weeks, it progressed rapidly into a global pandemic which resulted in an overwhelming burden on health care systems, medical resources and staff. Spine surgeons as health care providers are no exception. In this study, we try to highlight the impact of the crisis on spine surgeons in terms of knowledge, attitude, practice and socioeconomic burden. This was global, multicentric cross-sectional study on 781 spine surgeons that utilized an Internet-based validated questionnaire to evaluate knowledge about COVID-19, availability of personal protective equipment, future perceptions, effect of this crisis on practice and psychological distress. Univariate and multivariate ordinal logistic regression analyses were used to evaluate the predictors for the degree of COVID-19 effect on practice. Overall, 20.2%, 52% and 27.8% of the participants were affected minimally, intermediately and hugely by COVID-19, respectively. Older ages (β = 0.33, 95% CI 0.11-0.56), orthopedic spine surgeons (β = 0.30, 95% CI 0.01-0.61) and those who work in the private sector (β = 0.05, 95% CI 0.19-0.61) were the most affected by COVID-19. Those who work in university hospitals (β = - 0.36, 95% CI 0.00 to - 0.71) were affected the least. The availability of N95 masks (47%) and disposable eye protectors or face shields (39.4%) was significantly associated with lower psychological stress (p = 0.01). Only 6.9%, 3.7% and 5% had mild, moderate and severe mental distress, respectively. While it is important to recognize the short-term impact of COVID-19 pandemic on the practice of spine surgery, predicting where we will be standing in 6-12 months remains difficult and unknown. The COVID-19 crisis will probably have an unexpected long-term impact on lives and economies.


Genome-wide survey and developmental expression mapping of zebrafish SET domain-containing genes.
SET domain-containing proteins represent an evolutionarily conserved family of epigenetic regulators, which are responsible for most histone lysine methylation. Since some of these genes have been revealed to be essential for embryonic development, we propose that the zebrafish, a vertebrate model organism possessing many advantages for developmental studies, can be utilized to study the biological functions of these genes and the related epigenetic mechanisms during early development. To this end, we have performed a genome-wide survey of zebrafish SET domain genes. 58 genes total have been identified. Although gene duplication events give rise to several lineage-specific paralogs, clear reciprocal orthologous relationship reveals high conservation between zebrafish and human SET domain genes. These data were further subject to an evolutionary analysis ranging from yeast to human, leading to the identification of putative clusters of orthologous groups (COGs) of this gene family. By means of whole-mount mRNA in situ hybridization strategy, we have also carried out a developmental expression mapping of these genes. A group of maternal SET domain genes, which are implicated in the programming of histone modification states in early development, have been identified and predicted to be responsible for all known sites of SET domain-mediated histone methylation. Furthermore, some genes show specific expression patterns in certain tissues at certain stages, suggesting the involvement of epigenetic mechanisms in the development of these systems. These results provide a global view of zebrafish SET domain histone methyltransferases in evolutionary and developmental dimensions and pave the way for using zebrafish to systematically study the roles of these genes during development.


Physicochemical and biological evaluation of a cinnamamide derivative R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608) for nervous system disorders.
A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, and additionally, thermal analysis showed that it exists in one crystalline form. The compound was evaluated in vivo in rodents as anticonvulsant, antiepileptogenic, analgesic, and neuroprotective agent. The beneficial properties of the compound were found in animal models of seizures evoked electrically (maximal electroshock test, 6-Hz) and chemically (subcutaneous pentylenetetrazole seizure test) as well as in three animal models of epileptogenesis: corneal-kindled mice, hippocampal-kindled rats, and lamotrigine-resistant amygdala-kindled rats. Quantitative pharmacological parameters calculated for the tested compound were comparable to those of currently used antiepileptic drugs. In vivo pharmacological profile of KM-608 corresponds with the activity of valproic acid.


Co-Expression Analysis of Blood Cell Genome Expression to Preliminary Investigation of Regulatory Mechanisms in Uremia.
BACKGROUND Uremia involves a series of clinical manifestations and is a common syndrome that occurs in nearly all end-stage kidney diseases. However, the exact genetic and/or molecular mechanisms that underlie uremia remain poorly understood. MATERIAL AND METHODS In this case-control study, we analyzed whole-genome microarray of 75 uremia patients and 20 healthy controls to investigate changes in gene expression and cellular mechanisms relevant to uremia. Gene co-expression network analysis was performed to construct co-expression networks using differentially expressed genes (DEGs) in uremia. We then determined hub models of co-expressed gene networks by MCODE, and we used miRNA enrichment analysis to detect key miRNAs in each hub module. RESULTS We found nine co-expressed hub modules implicated in uremia. These modules were enriched in specific biological functions, including "proteolysis", "membrane-enclosed lumen", and "apoptosis". Finally, miRNA enrichment analysis to detect key miRNAs in each hub module found 15 miRNAs that were specifically targeted to uremia-related hub modules. Of these, miRNA-21-3p and miRNA-210-3p have been identified in other studies as being important for uremia. CONCLUSIONS In summary, our study connected biological functions, genes, and miRNAs that underpin the network modules that can be used to elucidate the molecular mechanisms involved in uremia.


Cytotoxin-associated Gene-A-positive Helicobacter pylori strains infection increases the risk of recurrent atherosclerotic stroke.
CagA-positive Helicobacter pylori infection has been found to be associated with a first-ever atherosclerotic stroke. The aim of this study was to investigate whether these strains represent an independent risk factor for recurrent atherosclerotic stroke. We performed a longitudinal study of patients with a first-ever large vessels stroke and resulted positive at H. pylori serology. Patients had clinical examination 1 month after the acute event, and were subsequently visited or contacted by telephone up to 3 years at 6-month intervals. Sera obtained at the time of enrollment were frozen and analyzed for the presence of anti-CagA antibodies at the end of the study. The primary outcome event was any fatal or nonfatal stroke after the index stroke. One hundred seventy H. pylori-positive patients were included (n = 68 CagA positive and n = 102 CagA negative). No significant difference regarding age and other stroke risk factors was detected. According to Kaplan-Meier survival analysis, CagA-positive patients showed a significantly higher risk for stroke recurrence than CagA-negative ones (45.6% vs 17.6%; p < .001). Difference in the rate of recurrent stroke between the two groups persisted after Cox regression analysis taking into account possible confounding factors (hazard ratio = 3.5; 95% CI = 1.9-6.4; p < .001). Infection with H. pylori CagA-positive strains increases the risk of recurrent atherosclerotic stroke. Seropositivity determination should be performed in order to identify high-risk patients requiring a strict clinical surveillance, and the possible beneficial effect of eradication therapy should be evaluated.


Breast cancer incidence among American Indian and Alaska Native women: US, 1999-2004.
Breast cancer is a leading cause of cancer morbidity and mortality among American Indian and Alaska Native (AI/AN) women. Although published studies have suggested that breast cancer rates among AI/AN women are lower than those among other racial and ethnic populations, accurate determinations of the breast cancer burden have been hampered by misclassification of AI/AN race. Cancer incidence data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program were combined to estimate age-adjusted rates for the diagnosis years 1999 through 2004. Several steps were taken to reduce the misclassification of AI/AN race: linking cases to Indian Health Service (IHS) patient services database, restricting analyses to Contract Health Service Delivery Area counties, and stratifying results by IHS region. Breast cancer incidence rates among AI/AN women varied nearly 3-fold across IHS regions. The highest rates were in Alaska (134.8) and the Plains (Northern, 115.9; Southern, 115.7), and the lowest rates were in the Southwest (50.8). The rate in Alaska was similar to the rate among non-Hispanic white (NHW) women in Alaska. Overall, AI/AN women had lower rates of breast cancer than NHW women, but AI/AN women were more likely to be diagnosed with late-stage disease. To the authors' knowledge, this report provides the most comprehensive breast cancer incidence data for AI/AN women to date. The wide regional variation indicates an important need for etiologic and health services research, and the large percentage of AI/AN women with late-stage disease demands innovative approaches for increasing access to screening.


Comparison of Glucose Area Under the Curve Measured Using Minimally Invasive Interstitial Fluid Extraction Technology with Continuous Glucose Monitoring System in Diabetic Patients.
Continuous glucose monitoring (CGM) is reported to be a useful technique, but difficult or inconvenient for some patients and institutions. We are developing a glucose area under the curve (AUC) monitoring system without blood sampling using a minimally invasive interstitial fluid extraction technology (MIET). Here we evaluated the accuracy of interstitial fluid glucose (IG) AUC measured by MIET in patients with diabetes for an extended time interval and the potency of detecting hyperglycemia using CGM data as a reference. Thirty-eight inpatients with diabetes undergoing CGM were enrolled. MIET comprised a pretreatment step using a plastic microneedle array and glucose accumulation step with a hydrogel patch, which was placed on two sites from 9:00 AM to 5:00 PM or from 10:00 PM to 6:00 AM. IG AUC was calculated by accumulated glucose extracted by hydrogel patches using sodium ion as standard. A significant correlation was observed between the predicted AUC by MIET and CGM in daytime (r=0.76) and nighttime (r=0.82). The optimal cutoff for the IG AUC value of MIET to predict hyperglycemia over 200 mg/dL measured by CGM for 8 hours was 1,067.3 mg·hr/dL with 88.2% sensitivity and 81.5% specificity. We showed that 8-hour IG AUC levels using MIET were valuable in estimating the blood glucose AUC without blood sampling. The results also supported the concept of using this technique for evaluating glucose excursion and for screening hyperglycemia during 8 hours in patients with diabetes at any time of day.


CDC National Health Report: leading causes of morbidity and mortality and associated behavioral risk and protective factors--United States, 2005-2013.
Although substantial progress has been made in improving the health of persons in the United States, serious problems remain to be solved. Life expectancy is increasing, and the rates of the leading causes of death are improving in many cases; however, numerous indicators (i.e., measures of observed or calculated data on the status of a condition) of the health and safety of the U.S. population remain poor. This report reviews population health in the United States and provides an assessment of recent progress in meeting high-priority health objectives. The health status indicators described in this report were selected because of their direct relation to the leading causes of death and other substantial sources of morbidity and mortality and should be the focus of prevention efforts. Data are reported starting in 2005 (or the earliest available year since 2005) through the current data year. Because data sources and specific indicators vary regarding when data are available, the most recent year for which data are available might range from 2010 to 2013. Data were obtained from 17 CDC surveys or surveillance systems and three non-CDC sources to provide a view of this particular point of time in the nation's health and trends in recent years. Data from the following CDC surveillance systems and surveys were used: Behavioral Risk Factor Surveillance System (BRFSS); Emerging Infections Program/Active Bacterial Core surveillance (EIP/ABCs); Foodborne Diseases Active Surveillance Network (FoodNet); Internet Panel Surveys: Influenza Vaccination Coverage Among Health-Care Personnel and Influenza Vaccination Coverage Among Pregnant Women; National Ambulatory Medical Care Survey (NAMCS); National Health and Nutrition Examination Survey (NHANES); National Health Interview Survey (NHIS); National Healthcare Safety Network (NHSN); National HIV Surveillance System; National Hospital Discharge Survey (NHDS); National Immunization Survey (NIS); National Immunization Survey-Teen (NIS-Teen); National Notifiable Disease Surveillance System (NNDSS); Nationally Notifiable STD Surveillance; National Vital Statistics System (NVSS); and Youth Risk Behavior Surveillance System (YRBSS). Three non-CDC sources were used: the Alcohol and Tobacco Tax and Trade Bureau Monthly Statistical Releases; the National Highway Traffic Safety Administration Fatality Analysis Reporting System (FARS); and the Substance Abuse and Mental Health Services Administration's National Survey on Drug Use and Health (NSDUH). Since 2005, life expectancy at birth in the U.S. has increased by 1 year; however, the number of persons who died prematurely was relatively constant. The years of potential life lost declined for eight of the 10 leading causes of death. Age-adjusted rates declined among all leading causes except deaths attributable to Alzheimer's disease and suicide, although the numbers of deaths increased for most causes. Heart disease, stroke, and deaths attributed to motor-vehicle injuries demonstrated notable declines since 2005. Numbers and rates increased for both Alzheimer's disease and suicide. The number of deaths from drug poisoning increased by approximately 11,000, and the number of deaths among older adults caused by falls increased by approximately 7,000. Risk and protective factors for these leading causes of death also showed mixed progress. Current smoking among adults remained stable at approximately 25% while smoking among youths declined to a record low of 15.7%. Obesity rates remained level at approximately 35% for adults and approximately 17% for youths. Approximately 21% of adults met recommended levels of physical activity, consistent with results recorded in the 3 previous years. Control of blood pressure and cholesterol increased to 46.3% and 29.5%, respectively. During the 2012-13 influenza season, vaccination rates reached highs of 72.0% for health-care personnel, 56.6% for children aged <17 years, 50.5% for pregnant women, and 41.5% for persons aged >18 years. Other important measures of the health of the U.S. population also varied. Rates of foodborne illness varied from year to year, with average annual increases for Salmonella and Salmonella serotype Enteritidis. Listeria rates were stable in recent years at 0.26 cases per 100,000 population. Shiga toxin-producing E. coli (STEC) O157 increased during the past 3 years to a rate of 1.15 cases per 100,000 population, even though the annual change for the study period noted an average decline overall. Health-care-associated infections declined, on average, for central-line associated bloodstream infections (CLABSI), surgical site infections (SSI), and Methicillin-resistant Staphylococcus aureus (MRSA) infection. The percentage of persons living with HIV who know their serostatus increased to 84.2%, but trends fluctuated for the number of new HIV infections and the rate of HIV transmission among adolescents and adults. Chlamydia rates increased by an average of 3.3% per year for persons aged 15-19 years and by 4.9% per year for women aged 20-24 years. The number of new cases of hepatitis C and hepatitis C-associated deaths increased by an average of 6.4% and 6.0% per year. Indictors of maternal and child health all improved, including historically low rates of infant mortality (6.1 per 1,000 live births) and teen births (26.6 per 1,000 female population). The percentage of infants breastfed at 6 months increased to 49.4%. Among children aged 19-35 months, 70.4% received the set of universally recommended vaccines, an increase of 2.9% from the previous year. The findings in this report indicate that progress has been steady but slow for many of the priority health issues in the United States. The age-adjusted rates for most of the leading causes of death are declining, but in some cases, the number of deaths is increasing, in part reflecting the growing U.S. population. Several protective factors that have registered substantial average increases (e.g., physical activity among adults, high blood pressure control, and human papillomavirus vaccination among adolescent females) have stalled in recent years. Many protective factors, even those with impressive relative gains, still represent only a minority of the U.S. population (e.g., control of high cholesterol at 29.5%). More data are needed to properly interpret fluctuating trends, such as those observed with the number of HIV infections and HIV transmission rates. Finally, some indicators of disease that appear to be increasing, such as chlamydia and hepatitis C, reflect increased efforts to engage in targeted screening but also suggest that the actual burden of infection is much greater than the reported data alone indicate. Although not all-inclusive, this compilation highlights important health concerns, points to areas in which important success has been achieved, and highlights areas in which more effort is needed. By tracking progress, public health officials, program managers, and decision makers can better identify areas for improvement and institute policies and programs to improve health and the quality of life.


Cardiomyocyte specific adipose triglyceride lipase overexpression prevents doxorubicin induced cardiac dysfunction in female mice.
Anthracyclines such as doxorubicin are an effective class of antineoplastic agents. Despite its efficacy in the treatment of a variety of cancers, the clinical use of doxorubicin is limited by cardiac side effects. While it has been suggested that doxorubicin alters myocardial fatty acid metabolism, it is poorly understood whether this is the case and whether variations in myocardial triacylglycerol (TAG) metabolism contribute to doxorubicin induced cardiotoxicity. Since TAG catabolism in the heart is controlled by adipose triglyceride lipase (ATGL), this study examined the influence of doxorubicin on cardiac energy metabolism and TAG values as well as the consequence of forced expression of ATGL in the setting of doxorubicin induced cardiotoxicity. Wild type (WT) mice and mice with cardiomyocyte specific ATGL overexpression were divided into two groups per genotype that received a weekly intraperitoneal injection of saline or doxorubicin for 4 weeks. Four weeks of doxorubicin administration significantly impaired in vivo systolic function (11% reduction in ejection fraction, p<0.05), which was associated with increased lung wet to dry weight ratios. Furthermore, doxorubicin induced cardiac dysfunction was independent of changes in glucose and fatty acid oxidation in WT hearts. However, doxorubicin administration significantly reduced myocardial TAG content in WT mice (p<0.05). Importantly, cardiomyocyte specific ATGL overexpression and the resulting decrease in cardiac TAG accumulation attenuated the decrease in ejection fraction (p<0.05) and thus protected mice from doxorubicin induced cardiac dysfunction. Taken together, our data suggest that chronic reduction in myocardial TAG content by cardiomyocyte specific ATGL overexpression is able to prevent doxorubicin induced cardiac dysfunction.


[The social deficit in autism: focus on joint attention].
Autism is best thought of as a spectrum disorder with the dimensional components of social cognition, communication and flexibility varying between individuals meeting the criteria of autism. The core clinical feature that defines autism is a disturbance in social interaction which is not absolute and differs depending on a child's cognitive level, developmental stage, and the type of social structure in which they are observed. Social skills are under strong genetic influence with a continuous distribution of social interaction deficits in the general population with arbitrary cutoffs defining who is and is not affected with an autism spectrum disorder; this is the result of a complex interplay between numerous biological and environmental factors. Joint attention refers to the capacity of individuals to coordinate attention with a social partner in relation to some object or event and a disturbance in this early skill and in particular impairment in the ability to initiate joint attention, is a central symptom of autism. There are data to suggest that dorso-medial frontal cortex and anterior cingulate contribute to the development of an infant's ability to maintain representations of self, a social partner and an interesting object. The ability to engage frequently in social orienting behaviors and ultimately in numerous episodes of social attention coordination, or joint attention, may be a critical experience during a particular developmental window that serves to organize social neurodevelopment. A neurodevelopmental model explaining how these early deficits in social cognition may lead to autism is reviewed.


Informed consent, exploitation and whether it is possible to conduct human subjects research without either one.
Clinical research with adults who are unable to provide informed consent has the potential to improve understanding and care of a number of devastating conditions. This research also has the potential to exploit some of society's most vulnerable members. Recently, a number of task forces and individual writers have proposed guidelines to ensure that such research is both possible and ethical. Yet, there is widespread disagreement over which safeguards should be adopted. In the present paper, I consider to what extent these disagreements can be resolved by appeal to a general account of the interests of subjects who are unable to consent and the conditions that must be satisfied for research enrollment to constitute exploitation of their inability to make their own decisions.


Using avidin-mediated binding to enhance initial endothelial cell attachment and spreading.
Binding between the protein avidin and the vitamin biotin was used as an extrinsic, high affinity receptor-ligand system to augment the intrinsic integrin-dependent cellular adhesion mechanism. Glass substrates were coupled with avidin receptors through an adsorbed film of biotinylated bovine serum albumin (b-BSA). The avidin-treated slides then were seeded with biotinylated bovine aortic endothelial cells (BAEC). A 3:1 ratio of BSA:b-BSA provided the best results in terms of specific cellular attachment, growth, and spreading. Control surfaces consisted of bare glass or glass with adsorbed BSA. Attachment of unmodified BAEC to glass decreased in the presence of anti-beta 1 integrin antibody. Adhesion of biotinylated BAEC to avidin-treated slides was not affected by anti-beta 1 integrin antibody, consistent with integrin-independent avidin-mediated adhesion. The initial rate of cell spreading was greatest for avidin-biotin-mediated adhesion (80.0 +/- 25.6 microns2/h), followed by integrin-dependent cellular adhesion on plain glass (35.7 +/- 7.7 microns2/h) and, finally, by adhesion on BSA-coated protein surfaces (10.2 +/- 0.3 microns2/h). Biotinylated and unmodified BAEC, cultured for 1 h in serum-containing media, were subjected to laminar flow in a variable-height flow chamber that provided a range of shear stresses from 0.2 to 75 dynes/cm2. The critical shear stress required to detach 50% of the cells in serum-containing media increased from 4.6 +/- 0.8 dynes/cm2 for integrin-dependent adhesion to 12.6 +/- 1.2 dynes/cm2 for avidin-biotin-mediated adhesion. Avidin-mediated attachment for biotinylated BAEC increased initial cellular spreading rates and strength of attachment (i.e., at 1 h) by a factor of two and three, respectively. These results support the hypothesis that integrin-mediated cell attachment and spreading can be enhanced using high affinity integrin-independent binding.


Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules.
Proteasome-mediated proteolysis plays a crucial role in many basic cellular processes. In addition to constitutive proteasomes (CPs), which are found in all eukaryotes, jawed vertebrates also express immunoproteasomes (IPs). Evidence suggests that the key role of IPs may hinge on their impact on the repertoire of peptides associated to major histocompatibility complex (MHC) I molecules. Using a label-free quantitative proteomics approach, we identified 417 peptides presented by MHC I molecules on primary mouse dendritic cells (DCs). By comparing MHC I-associated peptides (MIPs) eluted from primary DCs and thymocytes, we found that the MIP repertoire concealed a cell type-specific signature correlating with cell function. Notably, mass spectrometry analyses of DCs expressing or not IP subunits MECL1 and LMP7 showed that IPs substantially increase the abundance and diversity of MIPs. Bioinformatic analyses provided evidence that proteasomes harboring LMP7 and MECL1 have specific cleavage preferences and recognize unstructured protein regions. Moreover, while differences in MIP repertoire cannot be attributed to potential effects of IPs on gene transcription, IP subunits deficiency altered mRNA levels of a set of genes controlling DC function. Regulated genes segregated in clusters that were enriched in chromosomes 4 and 8. Our peptidomic studies performed on untransfected primary cells provide a detailed account of the MHC I-associated immune self. This work uncovers the dramatic impact of IP subunits MECL1 and LMP7 on the MIP repertoire and their non-redundant influence on expression of immune-related genes.


Differing association of alcohol consumption with different stroke types: a systematic review and meta-analysis.
Whether light-to-moderate alcohol consumption is protective against stroke, and whether any association differs by stroke type, is controversial. We conducted a meta-analysis to summarize the evidence from prospective studies on alcohol drinking and stroke types. Studies were identified by searching PubMed to September 1, 2016, and reference lists of retrieved articles. Additional data from 73,587 Swedish adults in two prospective studies were included. Study-specific results were combined in a random-effects model. The meta-analysis included 27 prospective studies with data on ischemic stroke (25 studies), intracerebral hemorrhage (11 studies), and/or subarachnoid hemorrhage (11 studies). Light and moderate alcohol consumption was associated with a lower risk of ischemic stroke, whereas high and heavy drinking was associated with an increased risk; the overall RRs were 0.90 (95 % CI, 0.85-0.95) for less than 1 drink/day, 0.92 (95 % CI, 0.87-0.97) for 1-2 drinks/day, 1.08 (95 % CI, 1.01-1.15) for more than 2-4 drinks/day, and 1.14 (95 % CI, 1.02-1.28) for more than 4 drinks/day. Light and moderate alcohol drinking was not associated with any hemorrhagic stroke subtype. High alcohol consumption (>2-4 drinks/day) was associated with a non-significant increased risk of both hemorrhagic stroke subtypes, and the relative risk for heavy drinking (>4 drinks/day) were 1.67 (95 % CI, 1.25-2.23) for intracerebral hemorrhage and 1.82 (95 % CI, 1.18-2.82) for subarachnoid hemorrhage. Light and moderate alcohol consumption was inversely associated only with ischemic stroke, whereas heavy drinking was associated with increased risk of all stroke types with a stronger association for hemorrhagic strokes.


The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir.
Recommended treatments for newly diagnosed HIV-positive individuals now focus on the integrase strand transfer inhibitors, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). In treatment-naive individuals, cases of RAL-based and EVG-based virological failure, although rare, are associated with the occurrence of resistance mutations in integrase and/or reverse transcriptase coding sequences. In such cases, common resistance substitutions in reverse transcriptase that were associated with nucleos(t)ide reverse transcriptase inhibitors included M184I/V and K65R and these occurred together with various mutations in integrase. In some instances, these mutations in reverse transcriptase preceded the emergence of mutations in integrase. In contrast, no resistance substitutions in either integrase or reverse transcriptase have been observed to date in viruses isolated from treatment-naive individuals who experienced treatment failure with DTG-based regimens. The objective of this study was to determine the effects of the M184I/V and K65R substitutions in reverse transcriptase on the ability of HIV-1 to become resistant against RAL, EVG or DTG. We performed tissue culture selection experiments using reverse transcriptase inhibitor-resistant viruses containing resistance substitutions at positions K65R, M184I or M184V in the presence of increasing concentrations of RAL, EVG or DTG and monitored changes in integrase sequences by genotyping. Selections using EVG and RAL led to the emergence of resistance mutations in integrase. In contrast, only the wild-type virus was able to acquire resistance mutations for DTG. Resistance mutations against nucleos(t)ide reverse transcriptase inhibitors antagonized the development of HIV-1 resistance against DTG but not RAL or EVG.


The South Asian genome.
The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.


Effects of physical training and mental practice of in-clothes swimming: assessment by physiological parameters.
This study examined whether a short-term physical or mental training reduces the physiological load and perceived exertion of the in-clothes swimming. The study included 24 male inter-collegiate competitive swimmers with no previous experience of the in-clothes swimming. Prior to the training, the subjects performed 200-meter swimming with two styles of swimming, namely the crawl and elementary backstroke, and the degree of perceived exertion in the Borg scale, heart rate, and blood lactic acid level were determined. Following this baseline determination, the subjects were divided into 4 groups with 6 individuals each. These four groups were Group A "in-clothes training", Group B "image training", Group C "swimsuit training", and Group N "no training". Group A and C were lectured on the in-clothes swimming and practiced 7.5 min-long in-clothes swimming per day for a week with the two swimming styles, with Group A subjects wearing daily clothes and Group C subjects in swimsuits. Group B received 15 min of nonphysical mental practice primarily through viewing video recording of swimming performance everyday for a week. No training was given to Group N. At the completion of the training session, the subjects underwent the 2nd 200-meter swimming, and the physiological parameters were determined. The 1st in-clothes swimming load test showed that the elementary backstroke swimming resulted in significantly lower values of heart rate, blood lactic acid level, and perceived exertion than the crawl. For Group N, no difference was observed in the physiological parameters between the 1st and 2nd load test with either the elementary backstroke or crawl. Upon the 2nd in-clothes load test with the elementary backstroke, all three parameters were lower for Group A, B, and C than those seen for the 1st load test, and these differences were statistically significant, except for blood lactic acid in Group A. The 2nd in-clothes load test with the crawl showed that both heart rate and blood lactic acid were lower than those of the 1st load test for all three groups, with the differences in heart rate and blood lactic acid in Group A and that in blood lactic acid in Group B reaching the statistic significance. With respect to perceived exertion, the Borg score determined after the in-clothes load test with the crawl was significantly reduced for Group A, B, and C. The score after the in-clothes load test with the elementary backstroke was significantly reduced only for Group A. The elementary backstroke, when practiced in-clothes, imposes a relatively less physiological load. The present training methods can reduce physiological load and/or perceived exertion of the in-clothes swimming. Thus, both image training and swimsuit swimming are equally effective as a training method of the in-clothes swimming.