Acetylcholinesterase Inhibitor Pyridostigmine Bromide Attenuates Gut Pathology and Bacterial Dysbiosis in a Murine Model of Ulcerative Colitis

Abstract Background Ulcerative colitis (UC) is a Th2 infammatory bowel disease characterized by increased IL-5 and IL-13 expression, eosinophilic/neutrophilic infltration, decreased mucus production, impaired epithelial barrier, and bacterial dysbiosis of the colon. Acetylcholine and nicotine stimulate mucus production and suppress Th2 infammation through nicotinic receptors in lungs but UC is rarely observed in smokers and the mechanism of the protection is unclear. Methods In order to evaluate whether acetylcholine can ameliorate UC-associated pathologies, we employed a mouse model of dextran sodium sulfate (DSS)-induced UC-like conditions, and a group of mice were treated with Pyridostigmine bromide (PB) to increase acetylcholine availability. The efects on colonic tissue morphology, Th2 infammatory factors, MUC2 mucin, and gut microbiota were analyzed. Results DSS challenge damaged the murine colonic architecture, reduced the MUC2 mucin and the tight-junction protein ZO-1. The PB treatment signifcantly attenuated these DSS-induced responses along with the eosinophilic infltration and the pro-Th2 infammatory factors. Moreover, PB inhibited the DSS-induced loss of commensal Clostridia and Flavobacteria, and the gain of pathogenic Erysipelotrichia and Fusobacteria. Conclusions Together, these data suggest that in colons of a murine model, PB promotes MUC2 synthesis, suppresses Th2 infammation and attenuates bacterial dysbiosis therefore, PB has a therapeutic potential in UC

Prospective evaluation of voice outcome during the first two years in male patients treated by radiotherapy or laser surgery for T1a glottic carcinoma

In this prospective cohort study, we assessed voice outcome in patients before and up to 2 years after treatment for early glottic cancer either by radiotherapy or by laser surgery; 106 male patients, treated for T1aN0M0 glottic cancer either by endoscopic laser surgery (n = 67) or by radiotherapy (n = 39), participated in the study. Patients’ voices were recorded and analysed pre-treatment and 3, 6, 12 and 24 months post-treatment at their routine visit at the outpatient clinic. Average fundamental frequency (F0), percent jitter, percent shimmer and normalized noise energy (NNE) were determined. After 2 years, local control rate was 95% in the radiotherapy group and 97% in the laser surgery group. Larynx preservation rate was 95% after radiotherapy and 100% after laser surgery. Voice outcome recovers more quickly in patients treated with laser surgery in comparison to radiotherapy: 3 months after laser surgery there is no longer a difference with regard to normal voices except for the fundamental frequency, which remains higher pitched, even in the longer term. For patients treated with radiotherapy it takes longer for jitter, shimmer and NNE to become normal, where jitter remains significantly different from normal voices even after 2 years. According to these results, we believe that laser surgery is the first treatment of choice in the treatment of selected cases of T1a glottic carcinomas with good functional and oncological results

Balloon kyphoplasty in the treatment of metastatic disease of the spine: a 2-year prospective evaluation

There is currently little data on the longer term efficacy and safety of balloon kyphoplasty (BKP) in patients with metastatic vertebral compression fractures (VCFs). To prospectively assess the long-term efficacy and safety of BKP in treating thoracic and lumbar spinal metastatic fractures that result in pain or instability. Sixty-five patients (37 men, mean age: 66 years) underwent 99 BKP procedures. Patient-related outcomes of pain visual analogue scale (VAS) and Oswestry Disability Index were assessed pre- and post-operatively and after 3, 6, 12 and 24 months. Correction of vertebral height and kyphotic deformity were assessed by radiographic measurements. Mean pain VAS and Oswestry Disability Index significantly improved from pre- to post-treatment (P < 0.0001), this improvement being sustained up to 24-month follow up. A gain in height restoration and a reduction of the post-operative kyphotic angle were seen post-operatively and at 3 months although these radiographic outcomes returned to pre-operative levels at 12 months. BKP was associated with a rate of cement leakage and incidence vertebral fracture of 12 and 8%, respectively. No symptomatic cement leaks or serious adverse events were seen during the 24 months of follow up. BKP is a minimally invasive procedure that provides immediate and long-term pain relief and improvement in functional ability in selected patients with metastatic VCFs. The procedure appears to have good long-term safety

To be or not to be a pseudogene: a molecular epidemiological approach to the mclx genes and its impact in tuberculosis

Tuberculosis presents a myriad of symptoms, progression routes and propagation patterns not yet fully understood. Whereas for a long time research has focused solely on the patient immunity and overall susceptibility, it is nowadays widely accepted that the genetic diversity of its causative agent, Mycobacterium tuberculosis, plays a key role in this dynamic. This study focuses on a particular family of genes, the mclxs (Mycobacterium cyclase/LuxR-like genes), which codify for a particular and nearly mycobacterial-exclusive combination of protein domains. mclxs genes were found to be pseudogenized by frameshift-causing insertion(s)/deletion(s) in a considerable number of M. tuberculosis complex strains and clinical isolates. To discern the functional implications of the pseudogenization, we have analysed the pattern of frameshift-causing mutations in a group of M. tuberculosis isolates while taking into account their microbial-, patient- and disease-related traits. Our logistic regression-based analyses have revealed disparate effects associated with the transcriptional inactivation of two mclx genes. In fact, mclx2 (Rv1358) pseudogenization appears to be primarily driven by the microbial phylogenetic background, being mainly related to the Euro-American (EAm) lineage; on the other hand, mclx3 (Rv2488c) presents a higher tendency for pseudogenization among isolates from patients born on the Western Pacific area, and from isolates causing extra-pulmonary infections. These results contribute to the overall knowledge on the biology of M. tuberculosis infection, whereas at the same time launch the necessary basis for the functional assessment of these so far overlooked genes.This work was supported by Fundacao para a Ciencia e Tecnologia (FCT), Portugal, and cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estrategico Nacional (QREN), through the Fundo Europeu de Desenvolvimento Regional (FEDER), and from Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). H.N.-G. received a personal FCT Grant (SFRH/BD/33902/2209). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Zinc status and its association with the health of adolescents: a review of studies in India

Background: Zinc is important in adolescence because of its role in growth and sexual maturation. Adolescents from developing countries such as India may be at high risk of zinc deficiency because of unwholesome food habits and poor bioavailability of zinc from plant-based diets. Objectives: (1) to study zinc status and its association with profile of other micronutrients, (2) to construct a simple tool in the form of Adolescent Micronutrient Quality Index (AMQI) to assess quality of diets of the girls and (3) to examine the effect of zinc supplement on health of adolescent girls. Methods: Girls (10&#x2013;16 years) from two secondary schools of Pune, Maharashtra state, in Western India were enrolled in a cross-sectional study (n = 630). Data were collected on dietary intake, cognitive performance, taste acuity, haemoglobin, erythrocyte zinc and plasma levels of zinc, vitamin C, &#x03B2;-carotene and retinol. AMQI was developed using age&#x2013;sex-specific Indian dietary guidelines and healthy foods and habits described in the recent US dietary guidelines. Zinc-rich recipes were developed considering habitual diets of the girls and vegetarian sources of zinc. An intervention trial (n = 180) was conducted to assess the effect of zinc-rich dietary supplements and ayurvedic zinc (Jasad) supplementation. Results: Prevalence of micronutrient deficiencies was high in these girls. Poor cognitive performance was seen in half of the girls, and salt taste perception was affected in 45%. AMQI was correlated with nutrient intakes and blood micronutrient levels (p &#60; 0.01), indicating the potential of AMQI to measure micronutrient quality of diets of adolescent girls. Results of the intervention trial indicated that supplementation of zinc-rich recipes vis-a-vis ayurvedic Jasad zinc has the potential to improve plasma zinc status, cognitive performance and taste acuity in adolescent girls. Conclusion: Review of the studies on Indian adolescent girls demonstrates the necessity of adopting zinc and micronutrient-rich diets for positive health building in adolescents

Brane-World Gravity

The observable universe could be a 1+3-surface (the "brane") embedded in a 1+3+\textit{d}-dimensional spacetime (the "bulk"), with Standard Model particles and fields trapped on the brane while gravity is free to access the bulk. At least one of the \textit{d} extra spatial dimensions could be very large relative to the Planck scale, which lowers the fundamental gravity scale, possibly even down to the electroweak ($\sim$ TeV) level. This revolutionary picture arises in the framework of recent developments in M theory. The 1+10-dimensional M theory encompasses the known 1+9-dimensional superstring theories, and is widely considered to be a promising potential route to quantum gravity. At low energies, gravity is localized at the brane and general relativity is recovered, but at high energies gravity "leaks" into the bulk, behaving in a truly higher-dimensional way. This introduces significant changes to gravitational dynamics and perturbations, with interesting and potentially testable implications for high-energy astrophysics, black holes, and cosmology. Brane-world models offer a phenomenological way to test some of the novel predictions and corrections to general relativity that are implied by M theory. This review analyzes the geometry, dynamics and perturbations of simple brane-world models for cosmology and astrophysics, mainly focusing on warped 5-dimensional brane-worlds based on the Randall--Sundrum models. We also cover the simplest brane-world models in which 4-dimensional gravity on the brane is modified at \emph{low} energies -- the 5-dimensional Dvali--Gabadadze--Porrati models. Then we discuss co-dimension two branes in 6-dimensional models.Comment: A major update of Living Reviews in Relativity 7:7 (2004) "Brane-World Gravity", 119 pages, 28 figures, the update contains new material on RS perturbations, including full numerical solutions of gravitational waves and scalar perturbations, on DGP models, and also on 6D models. A published version in Living Reviews in Relativit

Bin mapping of tomato diversity array (DArT) markers to genomic regions of Solanum lycopersicum × Solanum pennellii introgression lines

Marker-trait association studies in tomato have progressed rapidly due to the availability of several populations developed between wild species and domesticated tomato. However, in the absence of whole genome sequences for each wild species, molecular marker methods for whole genome comparisons and fine mapping are required. We describe the development and validation of a diversity arrays technology (DArT) platform for tomato using an introgression line (IL) population consisting of wild Solanumpennellii introgressed into Solanumlycopersicum (cv. M82). A tomato diversity array consisting of 6,912 clones from domesticated tomato and twelve wild tomato/Solanaceous species was constructed. We successfully bin-mapped 990 polymorphic DArT markers together with 108 RFLP markers across the IL population, increasing the number of markers available for each S.pennellii introgression by tenfold on average. A subset of DArT markers from ILs previously associated with increased levels of lycopene and carotene were sequenced, and 44% matched protein coding genes. The bin-map position and order of sequenced DArT markers correlated well with their physical position on scaffolds of the draft tomato genome sequence (SL2.40). The utility of sequenced DArT markers was illustrated by converting several markers in both the S.pennellii and S.lycopersicum phases to cleaved amplified polymorphic sequence (CAPS) markers. Genotype scores from the CAPS markers confirmed the genotype scores from the DArT hybridizations used to construct the bin map. The tomato diversity array provides additional “sequence-characterized” markers for fine mapping of QTLs in S.pennellii ILs and wild tomato species

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation