Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome

Background Prader–Willi syndrome (PWS) children have impaired growth, and abnormal body composition. Previous 1‐year controlled studies showed improvement of height and body composition during GH‐treatment. Objective To evaluate growth, body composition and body proportions during GH‐treatment in a large group of PWS children. Design/patients We performed a randomized controlled GH trial in 91 prepubertal PWS children (42 infants, 49 children, aged 3–14 years). After stratification for age, infants were randomized to GH‐treatment (GH‐group; 1 mg/m²/day; n = 20), or no treatment (control group; n = 22) for 1 year. In the second year all infants were treated with GH. After stratification for BMI, children > 3 years of age were randomized to GH‐treatment (GH‐group; 1 mg/m²/day; n = 27) or no treatment (control group; n = 22) for 2 years. Anthropometric parameters were assessed once in every 3 months. Body composition was measured by Dual Energy X‐ray Absorptiometry. Results Median (interquartile range, iqr) height SDS increased during 2 years of GH in infants from –2·3 (–2·8 to –0·7) to –0·4 (–1·1–0·0) and in prepubertal children from –2·0 (–3·1 to –1·7) to –0·6 (–1·1 to –0·1). In non‐GH‐treated children height SDS did not increase. Head circumference completely normalized during 1 and 2 years of GH in infants and children, respectively. Body fat percentage and body proportions improved in GH‐treated children, but did not completely normalize. Lean body mass SDS improved compared to the control group. Serum IGF‐I increased to levels above the normal range in most GH‐treated children. Conclusions Our randomized study shows that GH‐treatment in PWS children significantly improves height, BMI, head circumference, body composition and body proportions. PWS children are highly sensitive to GH, suggesting that monitoring of serum IGF‐I is indicated.     

Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study

BACKGROUND AND AIMS: Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation. METHODS: Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment. RESULTS: Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement. CONCLUSIONS: The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored.     

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.Key Words: SCN8A, phenytoin, epileptic encephalopathy, sodium channel blockers     

The Immune System and the Role of Inflammation in Perinatal Depression

Major depression during pregnancy is a common psychiatric disorder that arises from a complex and multifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic–pituitary–adrenal axis hyperactivity. Dysregulation of this intricate neuroimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neuropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during pregnancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Th1/Th2 bias towards a predominant Th1/Th17 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy.