Activation of central GABAB receptors offsets the cyclosporine counteraction of endotoxic cardiovascular outcomes in conscious rats

We have previously shown that cyclosporine (CSA) counteracts cardiovascular manifestations induced by endotoxemia (lipopolysaccharide, LPS) such as hypotension and cardiac autonomic dysfunction in conscious rats. In this study, we investigated whether the facilitation of central γ‐amino butyric acid (GABA) neurotransmission blunts these favorable influences of CSA. The LPS‐CSA interaction was determined in the absence and presence of drugs that activate GABA_A or GABA_B receptors or elevate synaptic GABA levels in the central nervous system. The consequent i.v. administration of CSA (10 mg/kg) blunted the LPS‐evoked hypotension, tachycardia, and reductions in time‐ and frequency‐domain indices of heart rate variability (measures of cardiac autonomic control) evoked by LPS (10 mg/kg i.v.). The ability of CSA to reverse the LPS effects disappeared in rats treated intracisternally (i.c.) with baclofen (selective GABA_B agonist, 2 μg/rat) but not muscimol (selective GABA_A agonist, 1 μg/rat), indicating a preferential compromising action for central GABA_B receptors on the advantageous effects of CSA. Moreover, the improvement by CSA of LPS‐evoked cardiovascular derangements was also eliminated after concurrent i.c. administration of vigabatrin (GABA transaminase inhibitor, 200 μg/rat) or tiagabine (GABA reuptake inhibitor, 100 μg/rat). These results demonstrate that the activation of central GABA_B receptors either directly via baclofen or indirectly following interventions that boost GABA levels in central synapses counterbalances the rectifying action of CSA on endotoxemia.     

GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.     

A prospective randomised comparative study of endoscopic band ligation versus injection sclerotherapy of bleeding internal haemorrhoids in patients with liver cirrhosis

Background and study aimsBleeding internal haemorrhoids are common and used to be treated surgically with too many complications. Endoscopic therapy is trying to take the lead. Sclerotherapy and rubber band ligation are the candidates to replace surgical therapy especially in patients with liver cirrhosis. The aim of this study was to compare endoscopic injection sclerotherapy (EIS) to endoscopic rubber band ligation (EBL) regarding effectiveness and complications in the treatment of bleeding internal haemorrhoids in Egyptian patients with liver cirrhosis.Patients and methodsOne hundred and twenty adult patients with liver cirrhosis and bleeding internal haemorrhoids were randomised into two equal groups; the first treated with EBL using Saeed multiband ligator, and the second with EIS using either ethanolamine oleate 5% or N-butyl cyanoacrylate. All groups were matched as regards age, sex, Child score and pre-procedure Doppler values. Patients were followed up clinically and with abdominal ultrasound/Doppler for 6 months. Endoscopic and endosonography/Doppler was done before and one month after the procedure. Pre and post-procedure data were recorded and analysed.ResultsBoth techniques were highly effective in the control of bleeding from internal haemorrhoids with a low rebleeding [10% in the EBL group and 13.33% in the EIS group] and recurrence [20% in the EBL group 20% in the EIS group] rates. Child score had a positive correlation with rebleeding and recurrence in EIS group only.Pain score and need for analgesia were significantly higher while patient satisfaction was significantly lower in EIS compared to EBL [p < 0.05]. No significant difference between ethanolamine and cyanoacrylate subgroups was found [p > 0.05].ConclusionsBoth EBL and EIS were effective in the treatment of bleeding internal haemorrhoids in patients with liver cirrhosis. EBL had significantly less pain and higher patient satisfaction than EIS. EBL was also safer in patients with advanced cirrhosis.     

Neonatal mortality in Jordan: secondary analysis of Jordan Population and Family Health Survey (JPFHS) data

Objective: This study aimed to analyze the 2009 Jordan Population and Family Health Survey (JPFHS) data to determine the level, trend, and distribution of neonatal mortality (NNM) in Jordan and determine its associated factors.

Methods: Nationally representative data on NNM were extracted from the JPFHS data. Using multivariate analyses, the strength of associations between 12 clinical/sociodemographic variables and neonatal mortality were quantified after controlling for potential confounders.

Results: The weighted NNM rate for 2005–2009 period was 16 deaths per 1000 live births, with the early NNM rate and late NNM rates were 10 deaths per 1000 live births and six deaths per 1000 live births, respectively. Fluctuations of NNM according to year of birth and geographic variations were noted. Risk of NNM increased among male newborns, as mother’s education level decreased, in mothers 40–49 years old, in multiple gestations-low birth weight neonates, and as birth interval was <3 years.

Conclusions: The NNR rate for 2005–2009 period of 16 deaths per 1000 live births indicates that there are opportunities to decrease it. Risk factors of neonatal mortality with respect to predictors of death during first days of life and variables related to geographic variations require particular focus to improve the quality of obstetric and neonatal health services and to decrease neonatal mortality.