Unsupervised home use of an overnight closed-loop system over 3-4 weeks: a pooled analysis of randomized controlled studies in adults and adolescents with type 1 diabetes.

AIMS: To compare overnight closed-loop and sensor-augmented pump therapy in patients with type 1 diabetes by combining data collected during free-living unsupervised randomized crossover home studies. METHODS: A total of 40 participants with type 1 diabetes, of whom 24 were adults [mean ± standard deviation (s.d.) age 43 ± 12 years and glycated haemoglobin (HbA1c) 8.0 ± 0.9%] and 16 were adolescents (mean ± s.d. age 15.6 ± 3.6 years and HbA1c 8.1 ± 0.8%), underwent two periods of sensor-augmented pump therapy in the home setting, in combination with or without an overnight closed-loop insulin delivery system that uses a model predictive control algorithm to direct insulin delivery. The order of the two interventions was random; each period lasted 4 weeks in adults and 3 weeks in adolescents. The primary outcome was time during which sensor glucose readings were in the target range of 3.9-8.0 mmol/l. RESULTS: The proportion of time when sensor glucose was in the target range (3.9-8.0 mmol/l) overnight (between 24:00 and 08:00 hours) was 18.5% greater during closed-loop insulin delivery than during sensor-augmented therapy (p < 0.001). Closed-loop therapy significantly reduced mean overnight glucose levels by 0.9 mmol/l (p < 0.001), with no difference in glycaemic variability, as measured by the standard deviation of sensor glucose. Time spent above the target range was reduced (p = 0.001), as was time spent in hypoglycaemia (<3.9 mmol/l; p = 0.014) during closed-loop therapy. Lower mean overnight glucose levels during closed-loop therapy were brought about by increased overnight insulin delivery (p < 0.001) without changes to the total daily delivery (p = 0.84). CONCLUSION: Overnight closed-loop insulin therapy at home in adults and adolescents with type 1 diabetes is feasible, showing improvements in glucose control and reducing the risk of nocturnal hypoglycaemia.Juvenile Diabetes Research Foundation (#22-2009-802) and Diabetes UK (BDA07/0003549) with additional support for the Artificial Pancreas work by National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK085621), and National Institute for Health Research Cambridge Biomedical Research Centre. Abbott Diabetes Care supplied continuous glucose delivery devices and sensors and modified devices to facilitate real-time connectivity.This if the final version of the article. It was originally published by Wiley in Diabetes, Obesity and Metabolism at http://onlinelibrary.wiley.com/doi/10.1111/dom.12427/abstrac

Mapping genetic determinants of host susceptibility to Pseudomonas aeruginosa lung infection in mice.

Background: P. aeruginosa is one of the top three causes of opportunistic human bacterial infections. The remarkable variability in the clinical outcomes of this infection is thought to be associated with genetic predisposition. However, the genes underlying host susceptibility to P. aeruginosa infection are still largely unknown. Results: As a step towards mapping these genes, we applied a genome wide linkage analysis approach to a mouse model. A large F2 intercross population, obtained by mating P. aeruginosa-resistant C3H/HeOuJ, and susceptible A/J mice, was used for quantitative trait locus (QTL) mapping. The F2 progenies were challenged with a P. aeruginosa clinical strain and monitored for the survival time up to 7 days post-infection, as a disease phenotype associated trait. Selected phenotypic extremes of the F2 distribution were genotyped with high-density single nucleotide polymorphic (SNP) markers, and subsequently QTL analysis was performed. A significant locus was mapped on chromosome 6 and was named P. aeruginosa infection resistance locus 1 (Pairl1). The most promising candidate genes, including Dok1, Tacr1, Cd207, Clec4f, Gp9, Gata2, Foxp1, are related to pathogen sensing, neutrophils and macrophages recruitment and inflammatory processes. Conclusions: We propose a set of genes involved in the pathogenesis of P. aeruginosa infection that may be explored to complement human studie

Safety and efficacy of 24-h closed-loop insulin delivery in well-controlled pregnant women with type 1 diabetes: a randomized crossover case series

OBJECTIVE: To evaluate the safety and efficacy of closed-loop insulin delivery in well-controlled pregnant women with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: A total of 12 women with type 1 diabetes (aged 32.9 years, diabetes duration 17.6 years, BMI 27.1 kg/m(2), and HbA(1c) 6.4%) were randomly allocated to closed-loop or conventional CSII. They performed normal daily activities (standardized meals, snacks, and exercise) for 24 h on two occasions at 19 and 23 weeks' gestation. Plasma glucose time in target (63-140 mg/dL) and time spent hypoglycemic were calculated. RESULTS: Plasma glucose time in target was comparable for closed-loop and conventional CSII (median [interquartile range]: 81 [59-87] vs. 81% [54-90]; P = 0.75). Less time was spent hypoglycemic (<45 mg/dL [0.0 vs. 0.3%]; P = 0.04), with a lower low blood glucose index (2.4 [0.9-3.5] vs. 3.3 [1.9-5.1]; P = 0.03), during closed-loop insulin delivery. CONCLUSIONS: Closed-loop insulin delivery was as effective as conventional CSII, with less time spent in extreme hypoglycemia.This work was funded by a Diabetes UK project grant (BDA 07/003551). H.R.M. was funded by a National Institute for Health Research (NIHR) research fellowship (PDF/08/01/036). The research was conducted with support from the Juvenile Diabetes Research Foundation, Abbott Diabetes Care (FreeStyle Navigator continuous glucose monitors and sensors), the investigator-initiated study program of the Animas Corporation (Animas 2020 insulin pump), the Medical Research Council Center for Obesity and Related Metabolic Diseases, the NIHR Cambridge Biomedical Research Center, and Addenbrooke's Clinical Research Facility (Cambridge, U.K.). No funder had any role in the study design; data collection, analysis, and interpretation; or manuscript preparation

Replication profile of PCDH11X and PCDH11Y, a gene pair located in the non-pseudoautosomal homologous region Xq21.3/Yp11.2

In order to investigate the replication timing properties of PCDH11X and PCDH11Y, a pair of protocadherin genes located in the hominid-specific non-pseudoautosomal homologous region Xq21.3/Yp11.2, we conducted a FISH-based comparative study in different human and non-human primate (Gorilla gorilla) cell types. The replication profiles of three genes from different regions of chromosome X (ZFX, XIST and ATRX) were used as terms of reference. Particular emphasis was given to the evaluation of allelic replication asynchrony in relation to the inactivation status of each gene. The human cell types analysed include neuronal cells and ICF syndrome cells, considered to be a model system for the study of X inactivation. PCDH11 appeared to be generally characterized by replication asynchrony in both male and female cells, and no significant differences were observed between human and gorilla, in which this gene lacks X-Y homologous status. However, in differentiated human neuroblastoma and cerebral cortical cells PCDH11X replication profile showed a significant shift towards allelic synchrony. Our data are relevant to the complex relationship between X-inactivation, as a chromosome-wide phenomenon, and asynchrony of replication and expression status of single genes on chromosome X

The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population

Context: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective: We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design: We performed a case-control study. Setting: This study was performed at a hospital clinic. Patients: Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements: Our study determined the prevalence of a metabolic syndrome in our cohort. Results: A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (± standard deviation) age was 33.2 ± 1.0 years. Compared with age-, sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 ± 1.2 mmol/L vs control, 4.9 ± 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 ± 17.0 pmol/L vs control, 14.2 ± 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 ± 1.2 mmol/L) compared with control subjects (1.3 ± 0.8 mmol/L; P < 0.001), but total cholesterol, high-density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 ± 18 mm Hg vs control subjects, 129 ± 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 ± 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions: Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation

Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

The impact of egg incubation temperature on the personality of oviparous reptiles

Personality traits, defined as differences in the behavior of individual animals of the same species that are consistent over time and context, such as ‘boldness,’ have been shown to be both heritable and be influenced by external factors, such as predation pressure. Currently, we know very little about the role that early environmental factors have upon personality. Thus, we investigated the impact of incubation temperature upon the boldness on an oviparous reptile, the bearded dragon (Pogona vitticeps). Eggs, from one clutch, were incubated at two different average temperatures within the normal range. After hatching the lizards were raised under the same environmental conditions. Novel object and novel environment tests were used to assess personality. Each test was repeated in both the short term and the long term. The results revealed that incubation temperature did impact upon ‘boldness’ but only in the short term and suggests that, rather than influencing personality, incubation temperature may have an effect on the development of behavioral of oviparous reptiles at different stages across ontogeny

The relationship between a child's postural stability and manual dexterity

The neural systems responsible for postural control are separate from the neural substrates that underpin control of the hand. Nonetheless, postural control and eye-hand coordination are linked functionally. For example, a stable platform is required for precise manual control tasks (e.g. handwriting) and thus such skills often cannot develop until the child is able to sit or stand upright. This raises the question of the strength of the empirical relationship between measures of postural stability and manual motor control. We recorded objective computerised measures of postural stability in stance and manual control in sitting in a sample of school children (n = 278) aged 3–11 years in order to explore the extent to which measures of manual skill could be predicted by measures of postural stability. A strong correlation was found across the whole sample between separate measures of postural stability and manual control taken on different days. Following correction for age, a significant but modest correlation was found. Regression analysis with age correction revealed that postural stability accounted for between 1 and 10 % of the variance in manual performance, dependent on the specific manual task. These data reflect an interdependent functional relationship between manual control and postural stability development. Nevertheless, the relatively small proportion of the explained variance is consistent with the anatomically distinct neural architecture that exists for ‘gross’ and ‘fine’ motor control. These data justify the approach of motor batteries that provide separate assessments of postural stability and manual dexterity and have implications for therapeutic intervention in developmental disorders

CHARGE syndrome

CHARGE syndrome was initially defined as a non-random association of anomalies (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness). In 1998, an expert group defined the major (the classical 4C's: Choanal atresia, Coloboma, Characteristic ears and Cranial nerve anomalies) and minor criteria of CHARGE syndrome. Individuals with all four major characteristics or three major and three minor characteristics are highly likely to have CHARGE syndrome. However, there have been individuals genetically identified with CHARGE syndrome without the classical choanal atresia and coloboma. The reported incidence of CHARGE syndrome ranges from 0.1–1.2/10,000 and depends on professional recognition. Coloboma mainly affects the retina. Major and minor congenital heart defects (the commonest cyanotic heart defect is tetralogy of Fallot) occur in 75–80% of patients. Choanal atresia may be membranous or bony; bilateral or unilateral. Mental retardation is variable with intelligence quotients (IQ) ranging from normal to profound retardation. Under-development of the external genitalia is a common finding in males but it is less apparent in females. Ear abnormalities include a classical finding of unusually shaped ears and hearing loss (conductive and/or nerve deafness that ranges from mild to severe deafness). Multiple cranial nerve dysfunctions are common. A behavioral phenotype for CHARGE syndrome is emerging. Mutations in the CHD7 gene (member of the chromodomain helicase DNA protein family) are detected in over 75% of patients with CHARGE syndrome. Children with CHARGE syndrome require intensive medical management as well as numerous surgical interventions. They also need multidisciplinary follow up. Some of the hidden issues of CHARGE syndrome are often forgotten, one being the feeding adaptation of these children, which needs an early aggressive approach from a feeding team. As the child develops, challenging behaviors become more common and require adaptation of educational and therapeutic services, including behavioral and pharmacological interventions