Transfer of 45Ca and 36Cl at the blood-nerve barrier of the sciatic nerve in rats fed low or high calcium diets

Unidirectional fluxes of 45Ca, 36Cl, and of [3H]mannitol from blood into the sciatic nerve and cerebral cortex were determined from 5- and 15-min uptakes of these tracers after an intravenous (i.v.) bolus injection in awake rats. Rats were fed diets for 8 wk, that had either a low (0.01% wt/wt), normal (0.67%), or high (3%) Ca content. Plasma [Ca] was 32% less and 11% more in rats fed low (LOCA) and high Ca diets (HICA), respectively, than in rats fed a normal Ca diet (CONT). The mean permeability-surface area product (PA) of 45Ca at the blood-nerve barrier was about eightfold higher than at the blood-brain barrier in the same animals and did not differ significantly between groups (greater than 0.05). Mean PA ratios of 45Ca/36Cl for the blood-nerve and blood-brain barriers in CONT rats, 0.52 +/- 0.04 and 0.40 +/- 0.02, respectively, were not significantly different from corresponding ratios in LOCA and HICA groups, and corresponded to the aqueous limiting diffusion ratio (0.45). Our results show no evidence for concentration-dependent transport of Ca over a plasma [Ca] range of 0.8-1.4 mmol/liter at the blood-nerve barrier of the rat peripheral nerve, and suggest that Ca and Cl exchange slowly between nerve and blood via paracellular pathways.     

Novel second-generation rexinoid induces growth arrest and reduces cancer cell stemness in human neuroblastoma patient-derived xenografts

IntroductionThe poor therapeutic efficacy seen with current treatments for neuroblastoma may be attributed to stem cell-like cancer cells (SCLCCs), a subpopulation of cancer cells associated with poor prognosis and disease recurrence. Retinoic acid (RA) is a differentiating agent used as maintenance therapy for high-risk neuroblastoma but nearly half of children treated with RA relapse. We hypothesized that 6-Methyl-UAB30 (6-Me), a second-generation rexinoid recently developed with a favorable toxicity profile compared to RA, would reduce cancer cell stemness in human neuroblastoma patient-derived xenografts (PDXs).MethodsCells from three neuroblastoma PDXs were treated with 6-Me and proliferation, viability, motility, and cell-cycle progression were assessed. CD133 expression, sphere formation, and mRNA abundance of stemness and differentiation markers were evaluated using flow cytometry, in vitro extreme limiting dilution analysis, and real-time PCR, respectively.ResultsTreatment with 6-Me decreased proliferation, viability, and motility, and induced cell-cycle arrest and differentiation in all three neuroblastoma PDXs. In addition, 6-Me treatment led to decreased CD133 expression, decreased sphere-forming ability, and decreased mRNA abundance of Oct4, Nanog, and Sox2, indicating decreased cancer cell stemness.Conclusions6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma.     

Iris vasculopathy in galactose-fed rats

Increased iris vessel permeability observed in diabetics has also been reported to occur in diabetic animals and galactose-fed rats. The potential role of aldose reductase in the induction of iris vessel changes has been investigated in rats fed a 50% galactose diet with/without the aldose reductase inhibitors AL 1576, sorbinil or ponalrestat for 7 to 18 months. Compared to normal control rats, long-term galactose-fed rats display a breakdown of the blood-aqueous barrier due to iris vessel changes that include focal straightening, dilation, constriction, increased permeability, ischemia and new vessel proliferation. The onset and progression of these iridal vessel changes were prevented by the aldose reductase inhibitors AL 1576 and sorbinil, and reduced by Ponalrestat. Computerized analyses of lumen areas of iris vessels indicated an 18-fold decrease in the vascular area near the pupillary boarder in untreated galactose-fed rats compared with age-matched controls and galactose-fed rats treated with aldose reductase inhibitors. These observations linking iris vessel changes with galactose-feeding, coupled with the fact that aldose reductase inhibitors also prevent these changes, strongly suggest a link between the sorbitol pathway and the appearance and progression of iris vessel changes.     

Antihypertensive effect of rhizome part of Acorus calamus on renal artery occlusion induced hypertension in rats

ObjectiveThe rhizomes part of Acorus calamus (AC) having the calcium inhibitory effect and diuretic activity which may potentiate Na+ excretion in hypertension induced by occlusion of renal artery. Therefore this study was aimed to investigate the effect of AC on experimentally induced hypertension.MethodsHypertension in rats was induced by clamping the left renal artery for 4h by arterial clamp (2K1C). At the end of experiment animal were anesthetized with ketamine (50 mg/kg). Carotid artery was cannulated which was connected to pressure transducer for estimation of blood pressure.ResultsEthyl acetate extract of Acorus calamus rhizomes (EAAC) treated rats that underwent hypertension, demonstrated significant (P < 0.01) lower systolic blood pressure and diastolic blood pressure when compared with 2K1C rats indicated blood pressure lowering activity. Plasma renin activity was significantly (P < 0.05) decreased in EAAC treated rats compared to 2K1C rats. EAAC treated rats that underwent hypertension demonstrated significant (P < 0.01) lower mean blood urea nitrogen and creatinine when compared with 2K1C rats. Lipid peroxidation was significantly (P < 0.001) decreased, where as nitric oxide level in tissue was significantly elevated in EAAC treated rats. Antioxidant enzymes like glutathione, superoxide dismutase and catalase were significantly (P < 0.05, P < 0.01, P < 0.001) increased in EAAC treated rats when compared to 2K1C rats.ConclusionsIn conclusions, EAAC treatment attenuated renal artery occlusion induced hypertension via nitric oxide generation and decreases the plasma renin activity.     

Rifaximin,a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg⁻¹, p.o.); Group II (toxic control, MNU 47 mg kg⁻¹, i.v.); Group III (RFX, 25 mg kg⁻¹, p.o.); Group IV (RFX, 50 mg kg⁻¹, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H₂S) and oxidative stress markers (TBAR''s, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats.     

The ‘quadriceps angle’: correlation between clinical and radiographic measurements from a study in North Bengal

Introduction: Quadriceps angle (Q angle) is one of the most important indicators of stability of patello-femoral joint. Orthopedic surgeons often measure the Q angle clinically in patients suffering from patello-femoral joint dysfunction or in subjects particularly young active sportspersons who are prone to injury of this joint. But the clinical method of measurement of Q angle is not standardized, and its value depends on various methods used. But the radiological method of measurement of Q angle is more accurate. However, due to the expense and time involved, the clinical method is preferred over the radiological one in practice. Aim: This study was aimed at studying the correlation and regression between the radiographic Q-angle values and the clinical ones, so that the former can be predicted easily from the latter. Materials and methods: Q angle was measured both clinically and radiographically in both knee joints of 93 adult subjects in North Bengal Medical College and Hospital. Result: Statistically significant correlation followed by the regression analysis could reveal simple linear regression equations for predicting the radiological Q-angle values from the clinical Q angle, derived separately in both males and females in right and left sides, separately. Conclusion: Thus, from a known clinical Q-angle value, we can derive the respective radiological Q angle, indirectly avoiding the entire troublesome maneuver in regular practice. So the present study recommends this method in clinical fields because this is a more rational and ideal approach to estimate the radiological Q angle. Increase in the Q angle beyond 20–22° predisposes to patellar dislocation which should be kept in mind while screening athletes, especially females. This tendency can be countered by quadriceps exercises and appropriate footwear.     

Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Clinical Autonomic Research - In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective...     

Pharmacokinetics and pharmacodynamics of ampreloxetine,a novel,selective norepinephrine reuptake inhibitor,in symptomatic neurogenic orthostatic hypotension

Clinical Autonomic Research - Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic...     

Efficacy and safety of hydroxychloroquine/chloroquine against SARS-CoV-2 infection: A systematic review and meta-analysis

IntroductionHydroxychloroquine (HCQ)/Chloroquine (CQ) has been evaluated for treatment and prophylaxis against SARS-CoV-2 infection in various studies with conflicting results. We performed a systematic review to synthesize the currently available evidence over the efficacy and safety of HCQ/CQ therapy alone against SARS-CoV-2 infection.MethodsWe searched Embase, PubMed, Web of Science, and Cochrane central for randomized controlled trials (RCTs) and prospective cohort studies published until October 15, 2020 and assessing the efficacy of HCQ alone against SARS-CoV-2 infection. We included studies evaluating HCQ/CQ alone as intervention and placebo/standard care as a control group. Retrospective studies and studies using other drugs (namely azithromycin, corticosteroids, immunomodulators, etc.) we excluded. Thirteen RCTs and three prospective cohort studies were included in this review. We pooled data using a random-effect model.ResultsPooled data from 12 studies (9917 participants) showed that HCQs increase mortality as compared to placebo/standard of care (RR 1.10; 95% CI:1.00–1.20). Hydroxychloroquine did not reduce the need for hospitalization in out-patients (RR 0.57; 95% CI 0.31–1.02). HCQ group has a significantly higher rate of any adverse event (RR 2.68; 95% CI 1.55–4.64), as compared to the control group. Also, using HCQ for prophylaxis against SARS-CoV-2 infection did not reduce the risk of acquiring SARS-CoV-2 infection (RR 1.04; 95% CI 0.58–1.88).ConclusionsHCQ therapy for COVID-19 is associated with an increase in mortality and other adverse events. The negative effects are more pronounced in hospitalized patients. Therefore, with the available evidence, HCQ should not be used in prophylaxis or treatment of patients with COVID-19.