Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms

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Sexuality talk during adolescent health maintenance visits

IMPORTANCE: Physicians may be important sources of sexuality information and preventive services, and one-on-one confidential time during health maintenance visits is recommended to allow discussions of sexual development, behavior, and risk reduction. However, little is known about the occurrence and characteristics of physician-adolescent discussions about sexuality. OBJECTIVE: To examine predictors of time spent discussing sexuality, level of adolescent participation, and physician and patient characteristics associated with sexuality discussions during health maintenance visits by early and middle adolescents. DESIGN, SETTING, AND PARTICIPANTS: Observational study of audio-recorded conversations between 253 adolescents (mean age, 14.3 years; 53% female; 40% white; 47% African American) and 49 physicians (82% pediatricians; 84% white; 65% female; mean age, 40.9 years; mean [SD] duration in practice, 11.8 [8.7] years) coded for sexuality content at 11 clinics (3 academic and 8 community-based practices) located throughout the Raleigh/Durham, North Carolina, area. MAIN OUTCOMES AND MEASURES: Total time per visit during which sexuality issues were discussed. RESULTS One hundred sixty-five (65%) of all visits had some sexual content within it. The average time of sexuality talk was 36 seconds (35% 0 seconds; 30% 1-35 seconds; and 35% ≥ 36 seconds). Ordinal logistic regression (outcome of duration: 0, 1-35, or ≥ 36 seconds), adjusted for clustering of patients within physicians, found that female patients (odds ratio [OR] = 2.58; 95% CI, 1.53-4.36), older patients (OR = 1.37; 95% CI, 1.13-1.65), conversations with explicit confidentiality discussions (OR = 4.33; 95% CI, 2.58-7.28), African American adolescents (OR = 1.58; 95% CI, 1.01-2.48), and longer overall visit (OR = 1.07; 95% CI, 1.03-1.11) were associated with more sexuality talk, and Asian physicians were associated with less sexuality talk (OR = 0.13; 95% CI, 0.08-0.20). In addition, the same significant associations between adolescent, physician, and visit characteristics were significantly associated with greater adolescent participation. CONCLUSIONS AND RELEVANCE: Our study may be the first to directly observe sexuality talk between physicians and adolescents. We found that one-third of all adolescents had annual visits without any mention of sexuality issues; when sexuality talk occurred, it was brief. Research is needed to identify successful strategies physicians can use to engage adolescents in discussions about sexuality to help promote healthy sexual development and decision making. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01040975

Neuroanatomical characterisation of the expression of the lipodystrophy and motor-neuropathy gene Bscl2 in adult mouse brain

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The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens

In this study the `Malaria Box' chemical library comprising 400 compounds with antiplasmodial activity was screened for compounds that perturb the internal pH of the malaria parasite, Plasmodium falciparum. Fifteen compounds induced an acidification of the parasite cytosol. Two of these did so by inhibiting the parasite's formate nitrite transporter (PfFNT), which mediates the H+-coupled efflux from the parasite of lactate generated by glycolysis. Both compounds were shown to inhibit lactate transport across the parasite plasma membrane, and the transport of lactate by PfFNT expressed in Xenopus laevis oocytes. PfFNT inhibition caused accumulation of lactate in parasitised erythrocytes, and swelling of both the parasite and parasitised erythrocyte. Long-term exposure of parasites to one of the inhibitors gave rise to resistant parasites with a mutant form of PfFNT that showed reduced inhibitor sensitivity. This study provides the first evidence that PfFNT is a druggable antimalarial target.Aspects of this work were supported by a Project Grant (1042272 to KK) from the Australian National Health and Medical Research Council (NHMRC). AML is the recipient of an Australian Research Council Discovery Early Career Researcher Award (DE160101035), REM was supported by a NHMRC Career Development Fellowship (1053082) and MJM is a NHMRC Principal Research Fello

Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity

Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. γ-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that γ-synuclein is nutritionally regulated in white adipose tissue whereas its loss partially protects mice from high-fat diet (HFD)–induced obesity and ameliorates some of the associated metabolic complications. Compared with HFD-fed WT mice, HFD-fed γ-synuclein–null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of γ-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. γ-Synuclein–deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that γ-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, γ-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal γ-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess

A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs.

Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin (POMC) with an allele frequency of 12%. The deletion disrupts the β-MSH and β-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation. The mutation is significantly more common in Labrador retrievers selected to become assistance dogs than pets. In conclusion, the deletion in POMC is a significant modifier of weight and appetite in Labrador retrievers and FCRs and may influence other behavioral traits.We are grateful to Rachel Moxon of Guide Dogs UK for collecting the assistance dog samples; Stephen J Sharp of the MRC Epidemiology Unit for his statistical advice; Jens Häggström, Karin Hultin Jäderlund and Berndt Klingeborn for the Swedish dog samples; Anne White for efforts to develop a canine beta MSH assay and adaptation of her original for figure 1b; and the Dogslife Consortium for samples from British Labrador retrievers (supported by an Institute Core Strategic Grant from the BBSRC to the Roslin Institute). A full list of the investigators who contributed to the Dogslife project is available from www.dogslife.ac.uk/who-runs-dogslife. AJG's academic post at the University of Liverpool is financially supported by Royal Canin. The work was primarily supported by the Wellcome Trust (Senior Investigator Award 095515/Z/11/Z and Strategic Award 100574/Z/12/Z), MRC (MRC Metabolic Diseases Unit, award 4050281695 and MRC_MC_UU_12012/5), and Dogs Trust. The authors would like to thank all the veterinary surgeons and nurses, owners and dogs who contributed samples.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.cmet.2016.04.01

Frequent mechanical stress suppresses proliferation of mesenchymal stem cells from human bone marrow without loss of multipotency

Mounting evidence indicated that human mesenchymal stem cells (hMSCs) are responsive not only to biochemical but also to physical cues, such as substrate topography and stiffness. To simulate the dynamic structures of extracellular environments of the marrow in vivo, we designed a novel surrogate substrate for marrow derived hMSCs based on physically cross-linked hydrogels whose elasticity can be adopted dynamically by chemical stimuli. Under frequent mechanical stress, hMSCs grown on our hydrogel substrates maintain the expression of STRO-1 over 20 d, irrespective of the substrate elasticity. On exposure to the corresponding induction media, these cultured hMSCs can undergo adipogenesis and osteogenesis without requiring cell transfer onto other substrates. Moreover, we demonstrated that our surrogate substrate suppresses the proliferation of hMSCs by up to 90% without any loss of multiple lineage potential by changing the substrate elasticity every 2nd days. Such “dynamic in vitro niche” can be used not only for a better understanding of the role of dynamic mechanical stresses on the fate of hMSCs but also for the synchronized differentiation of adult stem cells to a specific lineage

Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome

Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair (MMR) gene mutation (Lynch syndrome)

Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome

Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes