Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). We examined if 1 to 5 months of daily cemdomespib therapy may improve neuropathic symptoms in three mouse models of CMTX1 (Cx32 deficient (Cx32def), T55I-Cx32def, and R75W-Cx32 mice). Daily drug therapy significantly improved motor nerve conduction velocity (MNCV) and grip strength in all three models, but the compound muscle action potential was only improved in Cx32def mice. Drug efficacy required Hsp70 as improvements in MNCV, and the grip strength was abrogated in Cx32def × Hsp70 knockout mice. Five months of novologue therapy was associated with improved neuromuscular junction morphology, femoral motor nerve myelination, reduction in foamy macrophages, and a decrease in Schwann cell c-jun levels. To determine if c-jun may be downstream of Hsp70 and necessary for drug efficacy, c-jun expression was specifically deleted in Schwann cells of Cx32def mice. While the deletion of c-jun worsened the neuropathy, cemdomespib therapy remained effective in improving MNCV and grip strength. Our data show that cemdomespib therapy improves CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.
Background: Evaluate the impact of higher body mass index (BMI) on the maternal and perinatal outcome in pregnancies complicated by obesity.Methods: This is prospective cohort study conducted in obstetrics and gynaecology department. The 86 women with BMI>25 kg/m2 (cases) were compared with 90 women with BMI<25 kg/m2 (control) with regard to ante-natal complications, intervention in labour, maternal morbidity and neonatal outcome. Outcome of these variables in both groups were calculated statistically.Results: Obese women were significantly more likely to have gestational hypertension (OR=5.14; p=0.023) preeclampsia (OR=2.72; p=0.0445), gestational diabetes (OR=5.78; p=0.0133), abnormal weight gain (p=0.0001), induced labour (OR=2.26; p=0.04), cesarean delivery (OR=3.09; p=0.001), wound infection (OR=2.59; p=0.01) and adverse neonatal outcome.Conclusions: Obesity is an independent risk factor for adverse pregnancy outcomes and hence preventable steps should be taken for reducing the maternal and perinatal morbidity and mortality.
Heterotopic pregnancy is a rare clinical condition where both intrauterine and extrauterine pregnancy coexists. In a spontaneous conception, the diagnosis is difficult to make, but an important one to consider in the presence of acute abdominal pain, haemorrhagic shock and intrauterine pregnancy. Presenting a case of 27-year-old female G3P1A1L1 with previous C-section who presented with chief complaints of acute abdominal pain and signs of haemorrhagic shock at a gestational age of 10 weeks 1 day. The diagnosis of ruptured ectopic pregnancy coexisting with viable intrauterine gestation was made with ultrasound findings as well as clinical features necessitating emergency exploratory laparotomy. Successful treatment was done for ruptured ectopic pregnancy and intrauterine pregnancy was found viable which continued to full term uneventfully and live MCH of 3.5 kg was delivered by C-section.
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