Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa.

Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago

Incommensurable worldviews? Is public use of complementary and alternative medicines incompatible with support for science and conventional medicine?

Proponents of controversial Complementary and Alternative Medicines, such as homeopathy, argue that these treatments can be used with great effect in addition to, and sometimes instead of, ?conventional? medicine. In doing so, they accept the idea that the scientific approach to the evaluation of treatment does not undermine use of and support for some of the more controversial CAM treatments. For those adhering to the scientific canon, however, such efficacy claims lack the requisite evidential basis from randomised controlled trials. It is not clear, however, whether such opposition characterises the views of the general public. In this paper we use data from the 2009 Wellcome Monitor survey to investigate public use of and beliefs about the efficacy of a prominent and controversial CAM within the United Kingdom, homeopathy. We proceed by using Latent Class Analysis to assess whether it is possible to identify a sub-group of the population who are at ease in combining support for science and conventional medicine with use of CAM treatments, and belief in the efficacy of homeopathy. Our results suggest that over 40% of the British public maintain positive evaluations of both homeopathy and conventional medicine simultaneously. Explanatory analyses reveal that simultaneous support for a controversial CAM treatment and conventional medicine is, in part, explained by a lack of scientific knowledge as well as concerns about the regulation of medical research

Association of Health Literacy with Complementary and Alternative Medicine Use: A Cross-Sectional Study in Adult Primary Care Patients

<p>Abstract</p> <p>Background</p> <p>In the United States, it is estimated that 40% of adults utilize complementary and alternative medicine (CAM) therapies. Recently, national surveys report that over 90 million adults have inadequate health literacy. To date, no study has assessed health literacy and its effect on CAM use. The primary objective of this study was to assess the relationship between health literacy and CAM use independent of educational attainment. Second objective was to evaluate the differential effect of health literacy on CAM use by race.</p> <p>Methods</p> <p>351 patients were recruited from an outpatient primary care clinic. Validated surveys assessed CAM use (I-CAM-Q), health literacy (REALM-R), and demographic information. We compared demographics by health literacy (adequate vs. inadequate) and overall and individual CAM categories by health literacy using chi square statistics. We found a race by health literacy interaction and ran sequential logistic regression models stratified by race to test the association between health literacy and overall CAM use (Model 1), Model 1 + education (Model 2), and Model 2 + other demographic characteristics (Model 3). We reported the adjusted effect of health literacy on CAM use for both whites and African Americans separately.</p> <p>Results</p> <p>75% of the participants had adequate literacy and 80% used CAM. CAM use differed by CAM category. Among whites, adequate health literacy was significantly associated with increased CAM use in both unadjusted (Model 1, OR 7.68; p = 0.001) and models adjusted for education (Model 2, OR 7.70; p = 0.002) and other sociodemographics (Model 3, OR 9.42; p = 0.01). Among African Americans, adequate health literacy was not associated with CAM use in any of the models.</p> <p>Conclusions</p> <p>We found a race by literacy interaction suggesting that the relationship between health literacy and CAM use differed significantly by race. Adequate health literacy among whites is associated with increased CAM use, but not associated with CAM use in African Americans.</p

Low potency toxins reveal dense interaction networks in metabolism

Background The chemicals of metabolism are constructed of a small set of atoms and bonds. This may be because chemical structures outside the chemical space in which life operates are incompatible with biochemistry, or because mechanisms to make or utilize such excluded structures has not evolved. In this paper I address the extent to which biochemistry is restricted to a small fraction of the chemical space of possible chemicals, a restricted subset that I call Biochemical Space. I explore evidence that this restriction is at least in part due to selection again specific structures, and suggest a mechanism by which this occurs. Results Chemicals that contain structures that our outside Biochemical Space (UnBiological groups) are more likely to be toxic to a wide range of organisms, even though they have no specifically toxic groups and no obvious mechanism of toxicity. This correlation of UnBiological with toxicity is stronger for low potency (millimolar) toxins. I relate this to the observation that most chemicals interact with many biological structures at low millimolar toxicity. I hypothesise that life has to select its components not only to have a specific set of functions but also to avoid interactions with all the other components of life that might degrade their function. Conclusions The chemistry of life has to form a dense, self-consistent network of chemical structures, and cannot easily be arbitrarily extended. The toxicity of arbitrary chemicals is a reflection of the disruption to that network occasioned by trying to insert a chemical into it without also selecting all the other components to tolerate that chemical. This suggests new ways to test for the toxicity of chemicals, and that engineering organisms to make high concentrations of materials such as chemical precursors or fuels may require more substantial engineering than just of the synthetic pathways involved

Exclusive Leptoproduction of rho^0 Mesons from Hydrogen at Intermediate Virtual Photon Energies

Measurements of the cross section for exclusive virtual-photoproduction of rho^0 mesons from hydrogen are reported. The data were collected by the HERMES experiment using 27.5 GeV positrons incident on a hydrogen gas target in the HERA storage ring. The invariant mass W of the photon-nucleon system ranges from 4.0 to 6.0 GeV, while the negative squared four-momentum Q^2 of the virtual photon varies from 0.7 to 5.0 GeV^2. The present data together with most of the previous data at W > 4 GeV are well described by a model that infers the W-dependence of the cross section from the dependence on the Bjorken scaling variable x of the unpolarized structure function for deep-inelastic scattering. In addition, a model calculation based on Off-Forward Parton Distributions gives a fairly good account of the longitudinal component of the rho^0 production cross section for Q^2 > 2 GeV^2.Comment: 10 pages, 6 embedded figures, LaTeX for SVJour(epj) document class. Revisions: curves added to Fig. 1, several clarifications added to tex

Comparison of primary care models in the prevention of cardiovascular disease - a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Primary care providers play an important role in preventing and managing cardiovascular disease. This study compared the quality of preventive cardiovascular care delivery amongst different primary care models.</p> <p>Methods</p> <p>This is a secondary analysis of a larger randomized control trial, known as the Improved Delivery of Cardiovascular Care (IDOCC) through Outreach Facilitation. Using baseline data collected through IDOCC, we conducted a cross-sectional study of 82 primary care practices from three delivery models in Eastern Ontario, Canada: 43 fee-for-service, 27 blended-capitation and 12 community health centres with salary-based physicians. Medical chart audits from 4,808 patients with or at high risk of developing cardiovascular disease were used to examine each practice's adherence to ten evidence-based processes of care for diabetes, chronic kidney disease, dyslipidemia, hypertension, weight management, and smoking cessation care. Generalized estimating equation models adjusting for age, sex, rurality, number of cardiovascular-related comorbidities, and year of data collection were used to compare guideline adherence amongst the three models.</p> <p>Results</p> <p>The percentage of patients with diabetes that received two hemoglobin A1c tests during the study year was significantly higher in community health centres (69%) than in fee-for-service (45%) practices (Adjusted Odds Ratio (AOR) = 2.4 [95% CI 1.4-4.2], p = 0.001). Blended capitation practices had a significantly higher percentage of patients who had their waistlines monitored than in fee-for-service practices (19% vs. 5%, AOR = 3.7 [1.8-7.8], p = 0.0006), and who were recommended a smoking cessation drug when compared to community health centres (33% vs. 16%, AOR = 2.4 [1.3-4.6], p = 0.007). Overall, quality of diabetes care was higher in community health centres, while smoking cessation care and weight management was higher in the blended-capitation models. Fee-for-service practices had the greatest gaps in care, most noticeably in diabetes care and weight management.</p> <p>Conclusions</p> <p>This study adds to the evidence suggesting that primary care delivery model impacts quality of care. These findings support current Ontario reforms to move away from the traditional fee-for-service practice.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00574808">NCT00574808</a></p

Toxoplasma Effector MAF1 Mediates Recruitment of Host Mitochondria and Impacts the Host Response

Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II×III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA-) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA- strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria. © 2014 Pernas et al

Double Negative (CD3+4−8−) TCRαβ Splenic Cells from Young NOD Mice Provide Long-Lasting Protection against Type 1 Diabetes

-reactive T-cells. Herein, we analyzed the function and phenotype of DNCD3 splenic cells in young NOD mice predisposed to several autoimmune disorders among which, the human-like autoimmune diabetes. with a predominant Vβ13 gene usage.T-regulatory cells. DNCD3 splenic cells could be potentially manipulated towards the development of autologous cell therapies in autoimmune diabetes

Contrasting Transcriptional Responses of a Virulent and an Attenuated Strain of Mycobacterium tuberculosis Infecting Macrophages

Along with the recent identification of single nucleotide polymorphisms in H37Ra when compared to H37Rv, our demonstration of differential expression of PhoP-regulated and ESX-1 region-related genes during macrophage infection further highlights the significance of these genes in the attenuation of H37Ra