Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene.

CONTEXT: Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone. CASE DESCRIPTION: We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss. CONCLUSIONS: Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin.This work was supported by Grant BMBF 01GI1120A from the Federal Ministry of Education and Research. Support was also provided by the Wellcome Trust (082390/Z/07/Z), the Medical Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre, the European Research Council, and the Bernard Wolfe Health Neuroscience Fund (all to I.S.F.). J.-B.F. was supported by the International Graduate School in Molecular Medicine Ulm.This is the final version of the article. It first appeared from the Endocrine Society via http://dx.doi.org/10.1210/jc.2015-226

The phosphoproteome of choroid plexus epithelial cells following infection with Neisseria meningitidis

The Gram-negative bacterium Neisseria meningitidis, which causes meningitis in humans, has been demonstrated to manipulate or alter host signalling pathways during infection of the central nervous system (CNS). However, these complex signalling networks are not completely understood. We investigate the phosphoproteome of an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB) based on human epithelial choroid plexus (CP) papilloma (HIBCPP) cells during infection with the N. meningitidis serogroup B strain MC58 in presence and absence of the bacterial capsule. Interestingly, our data demonstrates a stronger impact on the phosphoproteome of the cells by the capsule-deficient mutant of MC58. Using enrichment analyses, potential pathways, molecular processes, biological processes, cellular components and kinases were determined to be regulated as a consequence of N. meningitidis infection of the BCSFB. Our data highlight a variety of protein regulations that are altered during infection of CP epithelial cells with N. meningitidis, with the regulation of several pathways and molecular events only being detected after infection with the capsule-deficient mutant. Mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD038560

Biodiversity, mental health and well-being: psychological mechanisms and moderators of a complex relationship (BIOWELL)

Human activities and their consequences, such as environmental pollution, the exploitation of resources or deforestation, are major causes of biodiversity loss. However, humans depend on a biologically diverse and healthy environment in many ways, as it provides access to clean water, air and food. The loss of biodiversity is an ecological crisis that threatens human health, and ultimately their very existence. At the same time, there is an unwavering interest in the positive effects of "nature" on mental health. Although these examples point to a connection between biodiversity and health, little is known about the causal effects of different facets of biodiversity on mental health. Exploring these relationships and the underlying psychological mechanisms is a major goal of this project. We will build on the expertise of an interdisciplinary team involving scholars from psychology, biodiversity research, human geography, and behavioural economics and combine this expertise with a variety of methods, with a focus on quantitative research, experimental and intervention designs, and investigate participants from different age groups to understand the causal effects of different environments with varying degrees of biological diversity on mental health, and to identify the physical, social, and psychological boundary conditions of these causal effects

Digital single-operator pancreatoscopy for the treatment of symptomatic pancreatic duct stones: a prospective multicenter cohort trial

BACKGROUND  Digital single-operator pancreatoscopy (DSOP)-guided lithotripsy is a novel treatment modality for pancreatic endotherapy, with demonstrated technical success in retrospective series of between 88 % and 100 %. The aim of this prospective multicenter trial was to systematically evaluate DSOP in patients with chronic pancreatitis and symptomatic pancreatic duct stones. METHODS  Patients with symptomatic chronic pancreatitis and three or fewer stones ≥ 5mm in the main pancreatic duct (MPD) of the pancreatic head or body were included. The primary end point was complete stone clearance (CSC) in three or fewer treatment sessions with DSOP. Current guidelines recommend extracorporeal shock wave lithotripsy (ESWL) for MPD stones > 5 mm. A performance goal was developed to show that the CSC rate of MPD stones using DSOP was above what has been previously reported for ESWL. Secondary end points were pain relief measured with the Izbicki pain score (IPS), number of interventions, and serious adverse events (SAEs). RESULTS  40 chronic pancreatitis patients were included. CSC was achieved in 90 % of patients (36/40) on intention-to-treat analysis, after a mean (SD) of 1.36 (0.64) interventions (53 procedures in total). The mean (SD) baseline IPS decreased from 55.3 (46.2) to 10.9 (18.3). Overall pain relief was achieved in 82.4 % (28/34) after 6 months of follow-up, with complete pain relief in 61.8 % (21/34) and partial pain relief in 20.6 % (7/34). SAEs occurred in 12.5 % of patients (5/40), with all treated conservatively. CONCLUSION  DSOP-guided endotherapy is effective and safe for the treatment of symptomatic MPD stones in highly selected patients with chronic pancreatitis. It significantly reduces pain and could be considered as an alternative to standard ERCP techniques for MPD stone treatment in these patients

Participant engagement with a UK community-based preschool childhood obesity prevention programme: : a focused ethnography study

Background Children’s centres in the UK provide a setting for public health programmes; offering support to families living in the most disadvantaged areas where obesity prevalence is at its highest. Health, Exercise and Nutrition in the Really Young (HENRY) is an eight-week obesity prevention programme currently delivered in children’s centres across the UK. However, low participant engagement in some local authorities threatens its potential reach and impact. This study aimed to explore the factors influencing participant engagement with HENRY to describe where local intervention may support engagement efforts. Method A focused ethnography study was undertaken in five children’s centres delivering HENRY across the UK. One hundred and ninety hours of field observations, 22 interviews with staff (commissioners, HENRY co-ordinators, managers and facilitators) and six focus groups (36 parents), took place over five consecutive days in each centre. The Consolidated Framework for Implementation Research (CFIR) was used to guide the observations and analysis of the data. Results Three overarching themes described the factors influencing participant engagement with HENRY: local authority decision making around children’s centre programmes; children’s centre implementation of HENRY; and the participant experience of HENRY. The results indicate that factors influencing participant engagement with public health programmes begin at the commissioning body level, influencing children’s centre implementation and subsequently the experience of participants. Local authority funding priorities and constraints influence availability of places and who these places are offered to, with funding often targeted towards those deemed most at need. This was perceived to have a detrimental effect on participant experience of the programme. Conclusion In summary, participant engagement is affected by multiple factors, working at different levels of the children’s centre and local authority hierarchy, most of which are at play even before participants decide whether or not they choose to enrol and maintain attendance. For programmes to achieve their optimal reach and impact, factors at the commissioning and local implementation level need to be addressed prior to addressing participant facing issues

Fertility preservation for female patients with childhood, adolescent, and young adult cancer:recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.info:eu-repo/semantics/publishe

Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

A case of phace syndrome and acquired hypopituitarism?

<p>Abstract</p> <p>Background</p> <p>PHACE is a neurocutaneous syndrome associated with: Posterior fossa brain malformations, large “segmental” facial hemangiomas, arterial cerebrovascular-, cardiovascular-, and eye anomalies.</p> <p>Case vignette</p> <p>We are reporting a girl with PHACE syndrome. The patient had a congenital right-sided facial hemangioma with plaque-morphology. At age 11 years and 2 months she presented with short stature, markedly decreased growth velocity and signs and symptoms suggestive of hypothyroidism. Magnetic Resonance Imaging (MRI) of the brain revealed complex structural and cerebrovascular arterial anomalies, including an empty sella. Testing of pituitary function revealed multiple pituitary dysfunctions, including absolute growth hormone deficiency, hypogonadotropic hypogonadism, central hypothyroidism, and secondary adrenal insufficiency.</p> <p>Conclusions</p> <p>This case suggests the necessity to screen all patients with PHACE syndrome and intracranial malformations for pituitary dysfunction at regular intervals.</p