Effects of human recombinant growth hormone on exercise capacity, cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency

Objective Epidemiological studies suggest that adult-onset growth hormone deficiency (AGHD) might increase the risk of death from cardiovascular causes. Methods This was a 6-month double-blind, placebo-controlled, randomised, cross-over trial followed by a 6-month open-label phase. Seventeen patients with AGHD received either recombinant human growth hormone (rGH) (0.4 mg injection daily) or placebo for 12 weeks, underwent washout for 2 weeks, and were then crossed over to the alternative treatment for a further 12 weeks. Cardiac magnetic resonance imaging, echocardiography, and cardiopulmonary exercise testing were performed at baseline, 12 weeks, 26 weeks, and the end of the open phase (12 months). The results were compared with those of 16 age- and sex-matched control subjects. Results At baseline, patients with AGHD had a significantly higher systolic blood pressure, ejection fraction, and left ventricular mass than the control group, even when corrected for body surface area. Treatment with rGH normalised the insulin-like growth factor 1 concentration without an effect on exercise capacity, cardiac structure, or cardiac function. Conclusion Administration of rGH therapy for 6 to 9 months failed to normalise the functional and structural cardiac differences observed in patients with AGHD when compared with a control group

Physical accessibility and utilization of health services in Yemen.

BACKGROUND: Assessment of physical access to health services is extremely important for planning. Complex methods that incorporate data inputs from road networks and transport systems are used to assess physical access to healthcare in industrialised countries. However, such data inputs hardly exist in many developing countries. Straight-line distances between the service provider and resident population are easily obtained but their relationship with driving distance and travel time is unclear. This study aimed to investigate the relationship between different measures of physical access, including straight-line distances, road distances and travel time and the impact of these measures on the vaccination of children in Yemen. METHODS: Coordinates of houses and health facilities were determined by GPS machine in Urban and rural areas in Taiz province, Yemen. Road distances were measured by an odometer of a vehicle driven from participants' houses to the nearest health centre. Driving time was measured using a stop-watch. Data on children's vaccination were collected by personal interview and verified by inspecting vaccination cards. RESULTS: There was a strong correlation between straight-line distances, driving distances and driving time (straight line distances vs. driving distance r = 0.92, p < 0.001, straight line distances vs. driving time r = 0.75; p < 0.001, driving distance vs. driving time r = 0.83, p < 0.001). Each measure of physical accessibility showed strong association with vaccination of children after adjusting for socio-economic status. CONCLUSION: Straight-line distances, driving distances and driving time are strongly linked and associated with vaccination uptake. Straight-line distances can be used to assess physical access to health services where data inputs on road networks and transport are lacking. Impact of physical access is clear in Yemen, highlighting the need for efforts to target vaccination and other preventive healthcare measures to children who live away from health facilities

Abnormalities of the ventilatory equivalent for carbon dioxide in patients with chronic heart failure

Introduction. The relation between minute ventilation (VE) and carbon dioxide production (VCO2) can be characterised by the instantaneous ratio of ventilation to carbon dioxide production, the ventilatory equivalent for CO2 (VEqCO2). We hypothesised that the time taken to achieve the lowest VEqCO2 (time to VEqCO2 nadir) may be a prognostic marker in patients with chronic heart failure (CHF). Methods. Patients and healthy controls underwent a symptom-limited, cardiopulmonary exercise test (CPET) on a treadmill to volitional exhaustion. Results. 423 patients with CHF (mean age 63±12 years; 80% males) and 78 healthy controls (62% males; age 61±11 years) were recruited. Time to VEqCO2 nadir was shorter in patients than controls (327±204 s versus 514±187 s; P=0.0001). Univariable predictors of all-cause mortality included peak oxygen uptake (X 2 =53.0), VEqCO2 nadir (X 2 =47.9), and time to VEqCO2 nadir (X 2 =24.0). In an adjusted Cox multivariable proportional hazards model, peak oxygen uptake (X 2 =16.7) and VEqCO2 nadir (X 2 =17.9) were the most significant independent predictors of all-cause mortality. Conclusion. The time to VEqCO2 nadir was shorter in patients with CHF than in normal subjects and was a predictor of subsequent mortality. © 2012 Lee Ingle et al

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

Objective: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. Design: Mutational analysis of MC2R by direct sequencing. Patients: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). Results: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. Conclusions: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosi

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich Ataxia

Copyright © 2014 Anjomani Virmouni et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Background - Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats), YG8R (90 and 190 GAA repeats) and YG22R (190 GAA repeats). Methodology/Principal Findings - We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R. Conclusions/Significance - Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.European Union, Ataxia UK and FARA