Pharmacological modulation of developmental and synaptic phenotypes in human SHANK3 deficient stem cell-derived neuronal models.

Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine's effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis.

BACKGROUND: The clinical value of antibiotic prophylaxis in preventing Lyme disease remains uncertain, owing to a meta-analysis lacking sufficient power to demonstrate efficacy and a more recent trial showing effectiveness but lacking precision. Our objective was to update our prior meta-analysis on antibiotic prophylaxis for the prevention of Lyme disease, to obtain a more precise estimate of treatment effect. METHODS: Clinical trials were identified by searching MEDLINE, Embase, the Cochrane Library and trial registries, and by an assessment of the bibliographies of retrieved articles and reviews. Trials were selected if their patients were randomly allocated to a treatment or placebo group within 72 h following an Ixodes tick bite and had no clinical evidence of Lyme disease at enrollment. Details of the trial design, patient characteristics, interventions and outcomes were extracted from each article. Study quality was assessed using the Jadad scale. RESULTS: Four placebo-controlled clinical trials were included for review. Among 1082 randomized subjects, the risk of Lyme disease in the placebo group was 2.2% [95% confidence interval (CI), 1.2%-3.9%] compared with 0.2% (95% CI, 0.0%-1.0%) in the antibiotic-treated group. Antibiotic prophylaxis significantly reduced the odds of developing Lyme disease compared with placebo (pooled odds ratio=0.084; 95% CI, 0.0020-0.57; P=0.0037). CONCLUSIONS: The available evidence to date supports the use of antibiotic prophylaxis for the prevention of Lyme disease in endemic areas following an Ixodes tick bite. Pooled data from four placebo-controlled trials suggests that one case of Lyme disease is prevented for about every 50 patients who are treated with antibiotics.

Maternal dexamethasone treatment alters myosin isoform expression and contractile dynamics in fetal arteries.

We tested the hypothesis that maternal glucocorticoid treatment modulates 17-kDa myosin light chain (myosin LC17) isoform expression and contractile dynamics in fetal ovine carotid arteries. In the single course group, ewes received 6 mg dexamethasone or placebo over 48 h. In the repeated course group, ewes received 6 mg dexamethasone or placebo weekly for 5 wk. In response to 1 microM phenylephrine, arteries from fetuses of dexamethasone-treated ewes exhibited biphasic contractions, characterized by an intermediate relaxation phase. The relaxation rate constant was significantly higher in arteries from the fetuses of dexamethasone than placebo-treated ewes. The observed biphasic contractions suggest the appearance of functional sarcoplasmic reticulum in the arteries from the fetuses of dexamethasone-treated ewes. The myosin LC17(a) isoform expression was lower in the arteries from the fetuses of the placebo-treated ewes than in those from the ewes. Repeated maternal administration of dexamethasone induced an almost twofold increase in myosin LC17(a) isoform expression in the fetal arteries. In contrast, maternal myosin LC17a isoform expression was not affected by dexamethasone treatment. We speculate that dexamethasone-induced increases in fetal myosin LC17(a) isoform expression represent accelerated differentiation of a subpopulation of vascular smooth muscle cells from the fetal to adult phenotype.