A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R

Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract

Congenital anomalies of kidneys and urinary tract (CAKUT) are the most predominant developmental disorders comprising ∼20-30% of all anomalies identified in the prenatal period. Mutations in hepatocyte nuclear factor 1-beta (HNF-1β) involved in the development of kidneys, liver, pancreas and urogenital tract are currently the most frequent monogenetic cause of CAKUT found in 10-30% of patients depending on screening policy and study design. We aimed to validate criteria for analysis of HNF1B in a prospective cohort of paediatric and adult CAKUT patients.status: publishe

Loss of the PlagL2 Transcription Factor Affects Lacteal Uptake of Chylomicrons

SummaryEnterocytes assemble dietary lipids into chylomicron particles that are taken up by intestinal lacteal vessels and peripheral tissues. Although chylomicrons are known to assemble in part within membrane secretory pathways, the modifications required for efficient vascular uptake are unknown. Here we report that the transcription factor pleomorphic adenoma gene-like 2 (PlagL2) is essential for this aspect of dietary lipid metabolism. PlagL2−/− mice die from postnatal wasting owing to failure of fat absorption. Lipids modified in the absence of PlagL2 exit from enterocytes but fail to enter interstitial lacteal vessels. Dysregulation of enterocyte genes closely linked to intracellular membrane transport identified candidate regulators of critical steps in chylomicron assembly. PlagL2 thus regulates important aspects of dietary lipid absorption, and the PlagL2−/− animal model has implications for the amelioration of obesity and the metabolic syndrome

Human cognitive flexibility depends on dopamine D2 receptor signaling

Item does not contain fulltextRATIONALE: Accumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans. OBJECTIVES: We aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility. METHODS: To this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the dopamine transporter gene, DAT1. RESULTS: Bromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14). CONCLUSIONS: These results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling