Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure

Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46, XY patient with a homozygous disruption of CYP11A1.The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation.Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned

The effects of knee joint angle on neuromuscular activity during electrostimulation in healthy older adults

Introduction Electrostimulation devices stimulate the common peroneal nerve, producing a calf muscle-pump action to promote venous circulation. Whether knee joint angle influences calf neuromuscular activity remains unclear. Our aim was to determine the effects of knee joint angle on lower limb neuromuscular activity during electrostimulation. Methods Fifteen healthy, older adults underwent 60 min of electrostimulation, with the knee joint at three different angles (0°, 45° or 90° flexion; random order; 20 min each). Outcome variables included electromyography of the peroneus longus, tibialis anterior and gastrocnemius medialis and lateralis and discomfort. Results Knee angle did not influence tibialis anterior and peroneus longus neuromuscular activity during electrostimulation. Neuromuscular activity was greater in the gastrocnemius medialis (p = 0.002) and lateralis (p = 0.002) at 90°, than 0° knee angle. Electrostimulation intensity was positively related to neuromuscular activity for each muscle, with a knee angle effect for the gastrocnemius medialis (p = 0.05). Conclusion Results suggest that during electrostimulation, knee joint angle influenced gastrocnemii neuromuscular activity; increased gastrocnemius medialis activity across all intensities (at 90°), when compared to 0° and 45° flexion; and did not influence peroneus longus and tibialis anterior activity. Greater electrostimulation-evoked gastrocnemii activity has implications for producing a more forceful calf muscle-pump action, potentially further improving venous flow

Pathological and Incidental Findings on Brain MRI in a Single-Center Study of 229 Consecutive Girls with Early or Precocious Puberty

Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

The Canadian Bandaging Trial: Evidence-informed leg ulcer care and the effectiveness of two compression technologies

Background: Objective: To determine the relative effectiveness of evidence-informed practice using two high compression systems: four-layer (4LB) and short-stretch bandaging (SSB) in community care of venous leg ulcers. Design and Setting: Pragmatic, multi-centre, parallel-group, open-label, randomized controlled trial conducted in 10 centres. Cognitively intact adults (≥18 years) referred for community care (home or clinic) with a venous ulceration measuring ≥0.7cm and present for ≥1 week, with an ankle brachial pressure index (ABPI) ≥0.8, without medication-controlled Diabetes Mellitus or a previous failure to improve with either system, were eligible to participate.Methods: Consenting individuals were randomly allocated (computer-generated blocked randomization schedule) to receive either 4LB or SSB following an evidence-informed protocol. Primary endpoint: time-to- healing of the reference ulcer. Secondary outcomes: recurrence rates, health-related quality of life (HRQL), pain, and expenditures.Results: 424 individuals were randomized (4LB n = 215; SSB n = 209) and followed until their reference ulcer was healed (or maximum 30 months). An intent-to-treat analysis was conducted on all participants. Median time to ulcer healing in the 4LB group was 62 days [95% confidence interval (CI) 51 to 73], compared with 77 days (95% CI 63 to 91) in the SSB group. The unadjusted Kaplan-Meier curves revealed the difference in the distribution of cumulative healing times was not significantly different between group (log rank χ2 = 0.001, P = 0.98) nor ulcers recurrence (4LB, 10.1%; SSB, 13.3%; p = 0.345). Multivariable Cox Proportional Hazard Modeling also showed no significant between-bandage differences in healing time after controlling for significant covariates (p = 0.77). At 3-months post-baseline there were no differences in pain (no pain: 4LB, 22.7%; SSB, 26.7%; p = 0.335), or HRQL (SF-12 Mental Component Score: 4LB, 55.1; SSB, 55.8; p = 0.615; SF-12 Physical Component Score: 4LB, 39.0; SSB, 39.6; p = 0.675). The most common adverse events experienced by both groups included infection, skin breakdown and ulcer deterioration.Conclusions: The Canadian Bandaging Trial revealed that in the practice context of trained RNs using an evidence-informed protocol, the choice of bandage system (4LB and SSB) does not materially affect healing times, recurrence rates, HRQL, or pain. From a community practice perspective, this is positive news for patient-centred care allowing individual/family and practitioner choice in selecting compression technologies based on circumstances and context.Trial registration: clinicaltrials.gov Identifier: NCT00202267

Lifestyle impact and the biology of the human scrotum

The possession of a scrotum to contain the male gonads is a characteristic feature of almost all mammals, and appears to have evolved to allow the testes and epididymis to be exposed to a temperature a few degrees below that of core body temperature. Analysis of cryptorchid patients, and those with varicocele suggest that mild scrotal warming can be detrimental to sperm production, partly by effects on the stem cell population, and partly by effects on later stages of spermatogenesis and sperm maturation. Recent studies on the effects of clothing and lifestyle emphasize that these can also lead to chronically elevated scrotal temperatures. In particular, the wearing of nappies by infants is a cause for concern in this regard. Together all of the evidence indirectly supports the view that lifestyle factors in addition to other genetic and environmental influences could be contributing to the secular trend in declining male reproductive parameters. The challenge will be to provide relevant and targeted experimental results to support or refute the currently circumstantial evidence.Richard Ivel

Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex® Growth Forum Database Experience.

BACKGROUND/AIMS: We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children. METHODS: Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013. RESULTS: Mean ± SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 ± 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naïve to treatment, this was 7.3 ± 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%). CONCLUSION: Safety and effectiveness data on use of rhIGF-1 in a 'real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia