Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (gt;99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMOdependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness

Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: an overview

Public Health and primary carePrevention and community carePrevention, Population and Disease management (PrePoD

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

The effects of vitamin D-2 or D-3 supplementation on glycaemic control and related metabolic parameters in people at risk of type 2 diabetes: protocol of a randomised double-blind placebo-controlled trial

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.London – Block grant from Tower Hamlets Primary Care NHS Trust and East London CLRN. Cambridge – From the operational budget of Medical Research Council Epidemiology Unit (MC_UP_A100_1003)

Comparative study of bone mineral density, calcium, and vitamin D status in the Gujarati and white populations of Leicester

Objectives: To evaluate differences in bone mineral density (BMD), calcium, and vitamin D status between the Gujarati (South Asian) and white populations resident in Leicester and to determine whether this was linked to lifestyle factors. Design: An observational cross sectional study of randomly selected Gujarati and white volunteers aged from 20–40 years. Setting: City of Leicester. Participants: Subjects were randomly selected by age (20–40 years) and ethnicity. A total of 262 individuals volunteered to participate, of which 201 (51 white females, 71 Gujarati females, 37 white males, 42 Gujarati males) were eligible for the study. Main outcome measures: Results of questionnaire, BMD at the hip and lumbar spine, and measurement of serum calcium, albumin, alkaline phosphatase, and 25-hydroxyvitamin D. Results: Male and female white subjects were significantly taller and heavier than their Gujarati counterparts. There was a statistically significant difference in BMD both at the spine (p<0.001) and hip (p<0.001) between the white and Gujarati females with the Gujaratis having a lower BMD. There was a trend for Gujarati males to have a lower BMD at the hip and spine than their white counterparts but these figures did not reach statistical significance. The intensity of cigarette smoking and the amount of alcohol consumption were both higher in the white male and female subjects. Sunlight exposure (>4 hours per day) was significantly higher in white subjects compared with Gujaratis. There were no significant differences in the mean level of serum calcium or alkaline phosphatase between the Gujaratis and whites. A significantly higher proportion (p<0.001) of the Gujarati men and women had a vitamin D level that was not measurable (that is, below the lower limit of the laboratory range of normal). Of those who had a measurable level (that is, in the normal range) mean levels of vitamin D were lower (p<0.05) in the Gujarati men and women. Conclusion: The present study is the first of its kind to note a low BMD in Gujarati subjects of South Asian origin compared with their white counterparts, living in Leicester. This study also confirms the presence of low serum vitamin D levels in Gujaratis. There is a need for more research in South Asians with regard to the collection of normal BMD values. This could provide a more meaningful reference range for identifying South Asians at risk of osteoporotic fractures and may have public health implications of relevance to this ethnic group