Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.

Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment.

Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

Objectives: Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate.

Design: Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies.

Congenital hyperinsulinism in a newborn with a novel homozygous mutation (p.Q392H) in the ABCC8 gene.

Congenital hyperinsulinism is the most frequent cause of persistent hypoglycemia in infancy. We present the case of a preterm, large-for-gestation-age infant with congenital hyperinsulinism who was found to have a novel p.Q392H homozygous mutation in the ABCC8 gene.

Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy.

Context: Octreotide, a somatostatin analog, is commonly used in diazoxide unresponsive congenital hyperinsulinism (CHI) patients as a second-line therapy.

Objective: The aims of this study were to evaluate the dose range, side effects, and long-term follow-up of octreotide therapy in a large cohort of CHI patients.

Setting: The study was conducted at an international referral center for the management of CHI.

A combination of nifedipine and octreotide treatment in an hyperinsulinemic hypoglycemic infant.

Hyperinsulinemic hypoglycemia (HH) is the commonest cause of persistent hypoglycemia in the neonatal and infancy periods. Mutations in the ABCC8 and KCNJ11 genes, which encode subunits of the ATP-sensitive potassium channel in the pancreatic beta cell, are identified in approximately 50% of these patients. The first-line drug in the treatment of HH is diazoxide.

Absorption, distribution, metabolism, and excretion of the novel antibacterial prodrug tedizolid phosphate.

Tedizolid phosphate is a novel antibacterial prodrug with potent activity against Gram-positive pathogens. In vitro and in vivo studies demonstrated that the prodrug is rapidly converted by nonspecific phosphatases to the biologically active moiety tedizolid. Single oral dose radiolabeled (14)C-tedizolid phosphate kinetic studies in human subjects (100 µCi in 204 mg tedizolid phosphate free acid) confirmed a rapid time to maximum tedizolid concentration (Tmax, 1.

Influences on domestic well water testing behavior in a Central Maine area with frequent groundwater arsenic occurrence.

In 2001 the Environmental Protection Agency (EPA) adopted a new standard for arsenic (As) in drinking water of 10 μg/L, replacing the old standard of 50 μg/L. However, for the 12% of the U.S.

Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia.

Aim: We describe the novel clinical observation of protein induced hyperinsulinaemic hypoglycaemia following remission of transient neonatal diabetes mellitus (TNDM) in a patient with 6q24 methylation defect.

Methods: A male infant of non-consanguineous Caucasian parents, born at 40 weeks of gestation with a birth weight of 3330 g (-0.55 standard deviation score) presented with hyperglycaemia in the first week of life and was diagnosed with 6q24 TNDM.

Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

Context: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency.

Permanent neonatal diabetes mellitus in Jordan.

Objective: Permanent neonatal diabetes mellitus (PNDM) is a rare heterogeneous form of diabetes that develops within the first 6 months of life. The objective of this study is to define the genetic etiology and incidence of permanent neonatal diabetes mellitus in Jordan.

Methods: This study was conducted in Jordan at the National Center of Diabetes, Endocrinology and Genetics, Amman, between 2006 and 2012.

Implementation of an employment intervention in mental health teams: a naturalistic 1-year employment outcome study in people with severe mental illness.

Background: In the UK, the severely mentally ill have high rates of unemployment.

Aims: To (1) evaluate implementation of an employment intervention and (2) test the effectiveness of training an existing staff member in providing the employment intervention (Model A) against the provision of a dedicated employment specialist to a team (Model B).

Methods: An employment service was implemented in five mental health teams, with three teams having an existing team member trained and two teams receiving an additional member of staff to carry out the employment intervention.

The influence of age and exercise modality on growth hormone bioactivity in women.

Objective: Prior research has indicated that the loss of skeletal muscle mass and bone mineral density observed with aging is related to the prominent age-related decline in the concentration of serum growth hormone (GH). However, there is limited data on the effects of aging on GH responses to acute bouts of heavy resistance exercise (HRE) and aerobic exercise (AE).

Design: The present investigation examined the effects of a HRE protocol and an AE protocol on immunoreactive GH (IGH) and bioactive GH (BGH) in active young and old women.

Dissemination of well water arsenic results to homeowners in Central Maine: influences on mitigation behavior and continued risks for exposure.

Private wells in the United States are unregulated for drinking water standards and are the homeowner's responsibility to test and treat. Testing for water quality parameters such as arsenic (As) is a crucial first step for homeowners to take protective actions. This study seeks to identify key behavioral factors influencing homeowners' decisions to take action after receiving well As test results.

Progressive neuropsychiatric symptoms and motor impairment.

A 42-year-old white man presented with cognitive impairment and behavioral changes followed by rapidly progressive motor and gait impairment. Magnetic resonance imaging revealed striking multifocal white matter signal change, areas of restricted diffusion, diffuse callosal signal change, and atrophy and hyperintensity of the corticospinal tracts. A broad range of etiologies warrant consideration in this case, including degenerative, vascular, inflammatory, metabolic, and neoplastic diseases.

Relationships of physical performance tests to military-relevant tasks in women.

Purpose: This investigation sought to determine the most predictive measures of performance on a repetitive box lifting task (RBLT) and load bearing task (LBT) among 123 women (aged ±4 years, height 165±7 cm, body mass 64±10 kg).

Methods: To determine the relationship of various predictors to performance on the RBLT and LBT, multiple regression analysis was conducted on body mass, height, leg cross-sectional area, upper and lower body muscular strength, lower body explosive power, upper and lower body local muscular endurance, and aerobic capacity.

Results: The mean±SD (range) number of repetitions for the RBLT was 86±23 (20-159).

GATA4 mutations are a cause of neonatal and childhood-onset diabetes.

The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects.

Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations.

Objective: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients.

Effects of fatigue from resistance training on barbell back squat biomechanics.

Exhaustive resistance training programs that have been previously referred to as extreme conditioning protocols have increased in popularity in military and civilian populations in recent years. However, because of their highly fatiguing nature, proprioception is likely altered during such programs that would significantly affect the safety and efficacy of such programs. Therefore, the purpose of this study was to assess the alterations in movement patterns that result from extreme conditioning protocols and to evaluate if these protocols can be deemed safe and effective.

The effects of high intensity short rest resistance exercise on muscle damage markers in men and women.

Within and between sexes, universal load prescription (as assigned in extreme conditioning programs) creates extreme ranges in individual training intensities. Exercise intensity has been proposed to be the main factor determining the degree of muscle damage. Thus, the purpose of this study was to examine markers of muscle damage in resistance-trained men (n = 9) and women (n = 9) from a high intensity (HI) short rest (SR) (HI/SR) resistance exercise protocol.

Factors affecting temporal variability of arsenic in groundwater used for drinking water supply in the United States.

The occurrence of arsenic in groundwater is a recognized environmental hazard with worldwide importance and much effort has been focused on surveying and predicting where arsenic occurs. Temporal variability is one aspect of this environmental hazard that has until recently received less attention than other aspects. For this study, we analyzed 1245 wells with two samples per well.

Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 μg per kilogram per day).

Congenital hyperinsulinism presenting with different clinical, biochemical and molecular genetic spectra.

Congenital hyperinsulinism (CHI) is a common cause of hypoglycemia in infants. We report three cases of CHI with differing clinical, biochemical, and molecular genetic spectra. One patient was unresponsive to medical treatment and died after subtotal pancreatectomy because of complications due to the surgery.

Epinephrine preworkout elevation may offset early morning melatonin concentrations to maintain maximal muscular force and power in track athletes.

The optimal time of day for training has become an important question for many strength and conditioning specialists, and this study was designed to add some insights into this complex question. The primary purpose of this investigation was to examine physical performance within the temporal context of the relationship between physical performance, epinephrine, and melatonin concentrations in the early morning (0530 hours) and late (1500 hours) afternoon in elite collegiate male track and field athletes (jumpers and sprinters). Subjects had a mean (±SD) age, height, and body mass of 20.

Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.

Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development.