Background:
Sodium/glucose co-transporter 2 (SGLT2) inhibitors exert robust cardioprotective effects against heart failure in diabetes patients and there is intense interest to identify the underlying molecular mechanisms that afford this protection. As the induction of the late component of the cardiac sodium channel current (late-I
Na
) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-I
Na
.
Methods:
Electrophysiological, in silico molecular docking, molecular, calcium imaging and whole heart perfusion techniques were employed to address this question.
Results:
The SGLT2 inhibitor empagliflozin reduced late-I
Na
in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the LQT3 mutations R1623Q or ∆KPQ. Empagliflozin, dapagliflozin and canagliflozin are all potent and selective inhibitors of H
2
O
2
-induced late-I
Na
(IC
50s
= 0.79, 0.58 and 1.26 µM respectively) with little effect on peak-I
Na
. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-I
Na
activator veratridine in a similar manner to tetrodotoxin, ranolazine and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a 3D homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anaesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 inflammasome and improved functional recovery after ischemia.
Conclusions:
Our results provide evidence that late-I
Na
may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
Flexible bronchoscopy (FB) is commonly performed by respiratory physicians for diagnostic as well as therapeutic purposes. However, bronchoscopy practices vary widely across India and worldwide. The three major respiratory organizations of the country supported a national-level expert group that formulated a comprehensive guideline document for FB based on a detailed appraisal of available evidence. These guidelines are an attempt to provide the bronchoscopist with the most scientifically sound as well as practical approach of bronchoscopy. It involved framing appropriate questions, review and critical appraisal of the relevant literature and reaching a recommendation by the expert groups. The guidelines cover major areas in basic bronchoscopy including (but not limited to), indications for procedure, patient preparation, various sampling procedures, bronchoscopy in the ICU setting, equipment care, and training issues. The target audience is respiratory physicians working in India and well as other parts of the world. It is hoped that this document would serve as a complete reference guide for all pulmonary physicians performing or desiring to learn the technique of flexible bronchoscopy.
Timely identification and treatment of various co-morbidities is likely to break undernutrition-disease cycle, and to decrease mortality and improve outcome.
Fibromatosis colli or pseudotumor of infancy of the sternocleidomastoid muscle is a rare cause of a benign neck mass in neonates and infants. If diagnosed correctly, it can be managed conservatively, and unnecessary investigations can be avoided.
Background:The aim of this school-based, cross-sectional survey was to investigate the prevalence and risk factors of permanent Molar Incisor Hypomineralization among 7-9 years old school children in Muradnagar.Methods:This cross-sectional study was performed among 7-9 years old school children in Muradnagar. Estimated sample size was 992 in this study. Multistage cluster sampling technique was used in this study in which schools were the clusters which were selected randomly. The study proforma was divided into 2 parts, first part comprised of demographic status, socio-economic status, questionnaires on risk factors of Molar Incisor Hypomineralisation such as prenatal, perinatal and postnal history upto 3 years, feeding pattern, fluoride and other pollutants exposure history, dental history, history of trauma to teeth/face, family history of enamel defects which was asked to the mothers and filled by one examiner in a face to face interview. The second part comprised of recording format of clinical variables assessed by investigator to be recorded by the recording clerk. Molar incisor hypomineralisation were recorded using Modified Developmental Defect of Enamel index developed by Clarkson J.J. and O’ Mullane D.M. in 1989 and dental caries by using Decayed Missing Filled Tooth index (World Health Organization Modification 1997) in which WHO probe was used for examination of dental caries as recommended by WHO in the Oral Health Surveys, Fourth edition; 1997 (Spanish version). Before 1997 modification dental explorer was used for the examination of dental caries. Chi square test, Pearson’s Correlation test, Logistic Regression Analysis and Unpaired t-test were used for analysing the data.Results:The overall prevalence rate of Molar incisor hypomineralisation was 21.4% in this study. Age, problems during pregnancy, normal delivery and childhood illness/ infections are the risk factors which have highest strength of association.Conclusion:In the present study Molar incisor hypomineralisation was found to affect 2 out of every 10 children examined which was higher than that observed in other studies on Indian children.
Objectives:To study the efficacy of combination of Flacourtia jangomas leaf and stem (1:1) methanolic extract (MEFJ) in streptozotocin (STZ)-induced diabetic rats and to investigate the qualitative phytochemical present in the extract. The study also aims to evaluate acute and short-term general toxicity of the extract in rats.Material and Methods:MEFJ of leaves and stem was subjected to preliminary qualitative phytochemical investigations by using standard procedures. The extract (400 mg/kg p.o.) was screened for antidiabetic activity in STZ-induced diabetic rats (30 mg/kg, i.p.). Acute oral toxicity study for the test extract of the plant was carried out using OECD/OCED guideline 425.Results:Phytochemical analysis of MEFJ of leaves and stem revealed the presence of flavonoids, saponins, carbohydrates, steroids, tannins, and phenolic compounds. In acute toxicity study, no toxic symptoms were observed for MEFJ up to dose 2000 mg/kg. Oral administration of MEFJ for 21 days exhibited highly significant (P < 0.01) hypoglycemic activity and also correction of altered biochemical parameters, namely cholesterol and triglycerides significantly (P < 0.05). Urine analysis on 1st day showed the presence of glucose and traces of ketone in the entire group except normal control group. However, on 21st day glucose and ketone traces were absent in MEFJ- and glibenclamide-treated groups while they were present in diabetic control. The data were analyzed using analysis of variance followed by Dunnett’s test.Conclusion:The observations confirm that methanolic extract of the leaf and stem of the plant has antidiabetic activity and is also involved in correction of altered biological parameters. It also warrants further investigation to isolate and identify the hypoglycemic principles in this plant so as to elucidate their mode of action.
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