Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement

Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood

Seasonality of the red blood cell stress response in rainbow trout (Oncorhynchus mykiss)

The β-adrenergic stress response in red blood cells (RBCs) of rainbow trout shows seasonal changes in expression. We have explored the mechanisms underpinning this response by following over a period of 27 months changes in β-adrenergic receptor (β-AR) binding characteristics, β-adrenergically stimulated RBC Na+/H+ exchanger (βNHE) activity, together with β-AR and βNHE mRNA levels and plasma steroid hormone and lactate levels. These parameters were measured at approximately monthly intervals in a single population of fish held under semi-natural conditions. Membrane-bound, high-affinity β-ARs were present in RBCs at all sampling times, varying from 668 ± 112 to 2654 ± 882 receptors cell-1 (mean ± SEM; n=8). βNHE activity, however, was reduced by 57 and 34% in December 1999 and February 2001, respectively, compared to an otherwise sustained influx that averaged 110.4 ± 2.3 mmol l-1 RBCs h-1 (n = 119). Only one reduction coincided with a spawning period but both were preceded by transient increases in circulating testosterone. βNHE activity measured under standard conditions was not correlated with the number or affinity of β-ARs nor with water temperature, but both β-AR numbers and βNHE activity were positively related to their respective mRNA levels (P = 0.005 and 0.038, respectively). Pharmaceutical intervention in the transduction cascade linking the β-AR and βNHE failed to indicate any failure of the transduction elements in RBCs displaying low βNHE activity. Similarly, we failed to demonstrate any link between seasonal cortisol fluctuations and seasonally reduced βNHE activity. However, the βNHE activity of age-separated RBC fractions showed that younger RBCs had a significantly higher βNHE response than older RBCs, consistent with the seasonal reductions in βNHE being linked to turnover of red cells and erythropoiesis. Testosterone is known to induce erythropoiesis and we conclude that seasonal reductions in βNHE are not caused by changes in β-AR numbers, but may be linked to testosterone-induced erythropoiesis

The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status

Background: The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. Methods: 17 women with Type 1 diabetes mellitus (T1DM) and 9 age-matched healthy women with a median age of 22.6 yrs (range, 17.4, 23.8) were studied by 3T-MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity. Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). Results: Although women with T1DM had similar BMI and bone marrow adiposity to the controls, they had higher visceral and subcutaneous adiposity on MRI (p<0.05) and total body FM by DXA (p=0.03). Overall, in the whole cohort, a clear inverse association was evident between bone marrow adiposity and BMD at all sites (p<0.05). These associations remained significant after adjusting for age, BMI, FM, and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with bone marrow adiposity (r,0.4, p=0.03), and a negative association with total body BMD (r,0.5, p=0.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r,–0.4, p=0.04). Conclusion: Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured bone marrow adiposity and DXA-based assessment of bone mineral density. Furthermore, an association between bone marrow adiposity and visceral adiposity supports the notion of a common origin of these two fat depots

Phase Transitions in Higher Derivative Gravity

This paper deals with black holes, bubbles and orbifolds in Gauss-Bonnet theory in five dimensional anti de Sitter space. In particular, we study stable, unstable and metastable phases of black holes from thermodynamical perspective. By comparing bubble and orbifold geometries, we analyse associated instabilities. Assuming AdS/CFT correspondence, we discuss the effects of this higher derivative bulk coupling on a specific matrix model near the critical points of the boundary gauge theory at finite temperature. Finally, we propose another phenomenological model on the boundary which mimics various phases of the bulk space-time.Comment: 33 pages, 12 figures, LaTeX, typos corrected, clarifications in sections 5 and 6, references adde

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015)

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration

Effects of dual task on turning ability in stroke survivors and older adults

Background: Turning is an integral component of independent mobility in which stroke survivors frequently fall. Objective: This study sought to measure the effects of competing cognitive demands on the stepping patterns of stroke survivors, compared to healthy age-match adults, during turning as a putative mechanism for falls. Methods: Walking and turning (90º) was assessed under single (walking and turning alone) and dual task (subtracting serial 3s while walking and turning) conditions using an electronic, pressure-sensitive walkway. Dependent measures were time to turn, variability in time to turn, step length, step width and single support time during three steps of the turn. Turning ability in single and dual task conditions was compared between stroke survivors (n= 17, mean ± SD: 59 ± 113 months post-stroke, 64 ± 10 years of age) and age-matched healthy counterparts (n = 15). Results: Both groups took longer, were more variable, tended to widen the second step and, crucially, increased single support time on the inside leg of the turn while turning and distracted. Conclusions. Increased single support time during turning may represent biomechanical mechanism, within stepping patterns of turning under distraction, for increased risk of falls for both stroke survivors and older adults

On Some New Black String Solutions in Three Dimensions

We derive several new solutions in three-dimensional stringy gravity. The solutions are obtained with the help of string duality transformations. They represent stationary configurations with horizons, and are surrounded by (quasi) topologically massive Abelian gauge hair, in addition to the dilaton and the Kalb-Ramond axion. Our analysis suggests that there exists a more general family, where our solutions are special limits. Finally, we use the generating technique recently proposed by Garfinkle to construct a traveling wave on the extremal variant of one of our solutions.Comment: revtex, 38 pages including 3 figure

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries:interrupted time series regression analysis

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes