Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation

BACKGROUND: The heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome. // METHODS: Exome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study. // FINDINGS: We report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast. // INTERPRETATION: Our data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. // FUND: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study

Anti-infectives in Drug Delivery-Overcoming the Gram-Negative Bacterial Cell Envelope.

Infectious diseases are becoming a major menace to the state of health worldwide, with difficulties in effective treatment especially of nosocomial infections caused by Gram-negative bacteria being increasingly reported. Inadequate permeation of anti-infectives into or across the Gram-negative bacterial cell envelope, due to its intrinsic barrier function as well as barrier enhancement mediated by resistance mechanisms, can be identified as one of the major reasons for insufficient therapeutic effects. Several in vitro, in silico, and in cellulo models are currently employed to increase the knowledge of anti-infective transport processes into or across the bacterial cell envelope; however, all such models exhibit drawbacks or have limitations with respect to the information they are able to provide. Thus, new approaches which allow for more comprehensive characterization of anti-infective permeation processes (and as such, would be usable as screening methods in early drug discovery and development) are desperately needed. Furthermore, delivery methods or technologies capable of enhancing anti-infective permeation into or across the bacterial cell envelope are required. In this respect, particle-based carrier systems have already been shown to provide the opportunity to overcome compound-related difficulties and allow for targeted delivery. In addition, formulations combining efflux pump inhibitors or antimicrobial peptides with anti-infectives show promise in the restoration of antibiotic activity in resistant bacterial strains. Despite considerable progress in this field however, the design of carriers to specifically enhance transport across the bacterial envelope or to target difficult-to-treat (e.g., intracellular) infections remains an urgently needed area of improvement. What follows is a summary and evaluation of the state of the art of both bacterial permeation models and advanced anti-infective formulation strategies, together with an outlook for future directions in these fields

Shorter Mandibular Length is Associated with a Greater Fall in AHI with Weight Loss.

RATIONALE: Obesity is a major risk factor towards the development of obstructive sleep apnea, while significant weight loss (both conservatively managed and surgically assisted) has a variable effect upon its severity. Differences in the effect of weight loss on obstructive sleep apnea may be due to underlying craniofacial characteristics. OBJECTIVES: To determine whether craniofacial characteristics can predict OSA treatment response to significant weight loss. METHODS: We analyzed craniofacial measurements from lateral cephalograms performed at baseline on 57 patients enrolled in a previously reported 2-year randomized clinical weight loss trial (laparoscopic adjustable gastric band surgery versus conservatively [dietician and very low calorie diet] treated). Group mean weight loss was ∼ 13% (mean weight loss 131 to 114 kg), with corresponding reduction in mean apnea-hypopnea index (AHI) from 61 to 41 events/h. Computer assisted lateral cephalogram analysis was undertaken by three trained staff blinded to treatment. We analyzed lateral cephalogram and demographic data at baseline (cross-sectional) and change over two years (interventional) in 54 patients. MEASUREMENTS AND MAIN RESULTS: Baseline cross-sectional analysis indicated no cephalometric measurement correlated significantly with baseline AHI when corrected for neck circumference. The percentage change in AHI over 2 years correlated with a shorter menton-gonion distance (i.e., mandibular body length). The % change in AHI correlated with the % weight change (R(2) = 0.25, p < 0.001) and mandibular body length (R(2) = 0.19, p = 0.002). The % change in AHI correlated with combined weight change and mandibular body length (combined R(2) = 0.31, p < 0.001). CONCLUSIONS: Weight loss as a therapeutic option for severe OSA with severe obesity may be predicted by shorter mandibular body length as measured by lateral cephalometry. CITATION: Naughton MT, Monteith BD, Manton DJ, Dever P, Schachter LM, O'Brien PE, Dixon JB. Shorter mandibular length is associated with a greater fall in AHI with weight loss. J Clin Sleep Med 2015;11(4):451–456

Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia

BackgroundA subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia.Methods and resultsIn order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia.ConclusionsThese findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia