Reprograming of gut microbiome energy metabolism by the FUT2 Crohn's disease risk polymorphism.

Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. The H antigen is an oligosaccharide moiety that acts as both an attachment site and carbon source for intestinal bacteria. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease (CD). To characterize the effect of FUT2 polymorphism on the mucosal ecosystem, we profiled the microbiome, meta-proteome and meta-metabolome of 75 endoscopic lavage samples from the cecum and sigmoid of 39 healthy subjects (12 SeSe, 18 Sese and 9 sese). Imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism and glycan biosynthesis and metabolism-related pathways, and the depletion of amino-acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2(-/-) genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. Therefore, the colonic microbiota of non-secretors is altered at both the compositional and functional levels, affecting the host mucosal state and potentially explaining the association of FUT2 genotype and CD susceptibility

A screen of Crohn's disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells.

Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn's disease, we screened 139 predicted Crohn's disease-associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn's disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism

Religion and HIV in Tanzania: Influence of Religious Beliefs on HIV stigma, Disclosure, and Treatment Attitudes.

Religion shapes everyday beliefs and activities, but few studies have examined its associations with attitudes about HIV. This exploratory study in Tanzania probed associations between religious beliefs and HIV stigma, disclosure, and attitudes toward antiretroviral (ARV) treatment. A self-administered survey was distributed to a convenience sample of parishioners (n = 438) attending Catholic, Lutheran, and Pentecostal churches in both urban and rural areas. The survey included questions about religious beliefs, opinions about HIV, and knowledge and attitudes about ARVs. Multivariate logistic regression analysis was performed to assess how religion was associated with perceptions about HIV, HIV treatment, and people living with HIV/AIDS. Results indicate that shame-related HIV stigma is strongly associated with religious beliefs such as the belief that HIV is a punishment from God (p < 0.01) or that people living with HIV/AIDS (PLWHA) have not followed the Word of God (p < 0.001). Most participants (84.2%) said that they would disclose their HIV status to their pastor or congregation if they became infected. Although the majority of respondents (80.8%) believed that prayer could cure HIV, almost all (93.7%) said that they would begin ARV treatment if they became HIV-infected. The multivariate analysis found that respondents' hypothetical willingness to begin ARV treatme was not significantly associated with the belief that prayer could cure HIV or with other religious factors. Refusal of ARV treatment was instead correlated with lack of secondary schooling and lack of knowledge about ARVs. The decision to start ARVs hinged primarily on education-level and knowledge about ARVs rather than on religious factors. Research results highlight the influence of religious beliefs on HIV-related stigma and willingness to disclose, and should help to inform HIV-education outreach for religious groups

Awareness, use, attitude and perceived need for Complementary and Alternative Medicine (CAM) education among undergraduate pharmacy students in Sierra Leone: A descriptive cross-sectional survey

© 2014 James and Bah. Background: The widespread use of CAM around the world requires health professionals including pharmacists to have the required knowledge to better advise their patients. This has lead to an increased need for the inclusion of CAM instruction into the mainstream undergraduate Pharmacy education. This study was designed to describe pharmacy students awareness, use, attitude and perceived need for CAM education at COMAHS-USL and at the same time, determine how these descriptive outcomes are influenced by the socio-demographic variables considered in this study. Methods: A descriptive cross-sectional survey was conducted among undergraduate pharmacy students (n = 90) at the College of Medicine and Allied Health Sciences, University of Sierra Leone using a structured questionnaire. Chi square, fisher exact test, and general linear model univariate analysis were used to compare data between independent cohorts. Results: All 90 (100%) of the students were aware and have used (except Ayurveda) at least one of the listed CAM modalities. Herbal/Botanical/Supplements followed by Spirituality/Prayer were the most commonly known and used CAM modalities. Almost two thirds of students considered the CAM modalities they have used to be effective and not harmful. Overall, pharmacy students had a positive attitude towards CAM (Mean attitudinal score = 34.9 ± 4. 5 (range 19-43)) with fourth and fifth year students showing a significantly less positive attitude as compared to the first, second and third year (B = -3.203 p = 0.001, 95% confidence interval - 5.093 to -1.314). The media [53 (58.9%)] was the most frequent source of information about CAM. Nearly all students [89 (98.9%)] agreed that CAM knowledge is important to them as future pharmacist and that CAM should be included into the Pharmacy curriculum at COMAHS-USL [81 (90.0%)]. Conclusion: Pharmacy students in Sierra Leone are aware of and have used at least one of the CAM modalities and do show a positive attitude towards CAM. This was demonstrated by their overwhelming endorsement for CAM course to be part of the undergraduate pharmacy training at COMAHS-USL. This study among others will inform and guide the development and implementation of CAM instruction at COMAHS-USL

Carrier-mediated magnetoelectricity in complex oxide heterostructures

While tremendous success has been achieved to date in creating both single phase and composite magnetoelectric materials, the quintessential electric-field control of magnetism remains elusive. In this work, we demonstrate a linear magnetoelectric effect which arises from a novel carrier-mediated mechanism, and is a universal feature of the interface between a dielectric and a spin-polarized metal. Using first-principles density functional calculations, we illustrate this effect at the SrRuO$_3$/SrTiO$_3$ interface and describe its origin. To formally quantify the magnetic response of such an interface to an applied electric field, we introduce and define the concept of spin capacitance. In addition to its magnetoelectric and spin capacitive behavior, the interface displays a spatial coexistence of magnetism and dielectric polarization suggesting a route to a new type of interfacial multiferroic

Gene mobility promotes the spread of resistance in bacterial populations

Theory predicts that horizontal gene transfer (HGT) expands the selective conditions under which genes spread in bacterial populations. Whereas vertically inherited genes can only spread by positively selected clonal expansion, mobile genetic elements can drive fixation of genes by infectious HGT. We tested this using populations of Pseudomonas fluorescens and the conjugative mercury resistance (Hg R) plasmid pQBR57. HGT expanded the selective conditions allowing the spread of Hg R: Chromosomal Hg R only increased in frequency under positive selection, whereas plasmid-encoded Hg R reached fixation with or without positive selection. Tracking plasmid dynamics over time revealed that the mode of Hg R inheritance varied across mercury environments. Under mercury selection, the spread of Hg R was driven primarily by clonal expansion while in the absence of mercury Hg R dynamics were dominated by infectious transfer. Thus, HGT is most likely to drive the spread of resistance genes in environments where resistance is useless

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships

Background: Consistent compositional shifts in the gut microbiota are observed in IBD and other chronic intestinal disorders and may contribute to pathogenesis. The identities of microbial biomolecular mechanisms and metabolic products responsible for disease phenotypes remain to be determined, as do the means by which such microbial functions may be therapeutically modified. Results: The composition of the microbiota and metabolites in gut microbiome samples in 47 subjects were determined. Samples were obtained by endoscopic mucosal lavage from the cecum and sigmoid colon regions, and each sample was sequenced using the 16S rRNA gene V4 region (Illumina-HiSeq 2000 platform) and assessed by UPLC mass spectroscopy. Spearman correlations were used to identify widespread, statistically significant microbial-metabolite relationships. Metagenomes for identified microbial OTUs were imputed using PICRUSt, and KEGG metabolic pathway modules for imputed genes were assigned using HUMAnN. The resulting metabolic pathway abundances were mostly concordant with metabolite data. Analysis of the metabolome-driven distribution of OTU phylogeny and function revealed clusters of clades that were both metabolically and metagenomically similar. Conclusions: The results suggest that microbes are syntropic with mucosal metabolome composition and therefore may be the source of and/or dependent upon gut epithelial metabolites. The consistent relationship between inferred metagenomic function and assayed metabolites suggests that metagenomic composition is predictive to a reasonable degree of microbial community metabolite pools. The finding that certain metabolites strongly correlate with microbial community structure raises the possibility of targeting metabolites for monitoring and/or therapeutically manipulating microbial community function in IBD and other chronic diseases

Stable Heterogeneity for the Production of Diffusible Factors in Cell Populations

The production of diffusible molecules that promote survival and growth is common in bacterial and eukaryotic cell populations, and can be considered a form of cooperation between cells. While evolutionary game theory shows that producers and non-producers can coexist in well-mixed populations, there is no consensus on the possibility of a stable polymorphism in spatially structured populations where the effect of the diffusible molecule extends beyond one-step neighbours. I study the dynamics of biological public goods using an evolutionary game on a lattice, taking into account two assumptions that have not been considered simultaneously in existing models: that the benefit of the diffusible molecule is a non-linear function of its concentration, and that the molecule diffuses according to a decreasing gradient. Stable coexistence of producers and non-producers is observed when the benefit of the molecule is a sigmoid function of its concentration, while strictly diminishing returns lead to coexistence only for very specific parameters and linear benefits never lead to coexistence. The shape of the diffusion gradient is largely irrelevant and can be approximated by a step function. Since the effect of a biological molecule is generally a sigmoid function of its concentration (as described by the Hill equation), linear benefits or strictly diminishing returns are not an appropriate approximations for the study of biological public goods. A stable polymorphism of producers and non-producers is in line with the predictions of evolutionary game theory and likely to be common in cell populations

Cost-effectiveness analysis of 3-D computerized tomography colonography versus optical colonoscopy for imaging symptomatic gastroenterology patients.

BACKGROUND: When symptomatic gastroenterology patients have an indication for colonic imaging, clinicians have a choice between optical colonoscopy (OC) and computerized tomography colonography with three-dimensional reconstruction (3-D CTC). 3-D CTC provides a minimally invasive and rapid evaluation of the entire colon, and it can be an efficient modality for diagnosing symptoms. It allows for a more targeted use of OC, which is associated with a higher risk of major adverse events and higher procedural costs. A case can be made for 3-D CTC as a primary test for colonic imaging followed if necessary by targeted therapeutic OC; however, the relative long-term costs and benefits of introducing 3-D CTC as a first-line investigation are unknown. AIM: The aim of this study was to assess the cost effectiveness of 3-D CTC versus OC for colonic imaging of symptomatic gastroenterology patients in the UK NHS. METHODS: We used a Markov model to follow a cohort of 100,000 symptomatic gastroenterology patients, aged 50 years or older, and estimate the expected lifetime outcomes, life years (LYs) and quality-adjusted life years (QALYs), and costs (£, 2010-2011) associated with 3-D CTC and OC. Sensitivity analyses were performed to assess the robustness of the base-case cost-effectiveness results to variation in input parameters and methodological assumptions. RESULTS: 3D-CTC provided a similar number of LYs (7.737 vs 7.739) and QALYs (7.013 vs 7.018) per individual compared with OC, and it was associated with substantially lower mean costs per patient (£467 vs £583), leading to a positive incremental net benefit. After accounting for the overall uncertainty, the probability of 3-D CTC being cost effective was around 60 %, at typical willingness-to-pay values of £20,000-£30,000 per QALY gained. CONCLUSION: 3-D CTC is a cost-saving and cost-effective option for colonic imaging of symptomatic gastroenterology patients compared with OC