Design,synthesis, biological evaluations,molecular docking,and in vivo studies of novel phthalimide analogs

A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53–67% of erythromycin activity on the tested bacteria and 60–70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF‐7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad‐spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11 , which showed good activity toward all the tested cell lines except for MCF‐7. The ability of the promising analogs 5 , 8 , and 11 to bind to topoisomerase II DNA gyrase was investigated. Caspase‐3 activation and Bcl‐2 assay of the best active derivatives 8 , 11 in addition to compound 5 were evaluated. The antifibrotic activity was studied in an in vivo model and the histopathological studies revealed that treatment with the new compound 8 improved the fibrotic liver tissues to normality.

     

Diagnostic evaluation and arrhythmia mechanisms in survivors of unexplained cardiac arrest

Identifying the cause of unexplained cardiac arrest is critical for appropriate management of both survivors and their family members. Aborted cardiac arrests whose cause remains unknown following investigation with a surface ECG, echocardiogram, and coronary angiogram are deemed unexplained. Many of these unexplained arrests are felt to be secondary to concealed forms of cardiac channelopathies and latent or subtle cardiomyopathies. This recognition has led to evaluating a diagnostic role for a series of additional investigations, including advanced imaging, genetic testing, and provocative forms of testing, including sodium channel blockade and treadmill testing. Despite evidence of an improved diagnostic yield through their systematic usage, clinical guidelines have yet to endorse a formal algorithm delineating investigations that must be performed before assigning a label of idiopathic ventricular fibrillation, which has resulted in markedly variables thresholds for concluding this diagnosis. Debate remains regarding the need for an invasive electrophysiology study among these patients, though identification of arrhythmic culprits requiring intracardiac electrograms for diagnostic confirmation have suggested a potential role when an initial comprehensive evaluation is unrevealing. Although progress is being made, the sizeable portion of arrests that remain unexplained despite completion of a comprehensive evaluation highlights an ongoing need for further research and additional tools to help unravel the ongoing mysteries of these near fatal events.     

Perioperative consultative hematology: can you clear my patient for a procedure?

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Prediction of permanent pacemaker implantation after transcatheter aortic valve replacement: The role of machine learning

BACKGROUND Atrioventricular block requiring permanent pacemaker(PPM) implantation is an important complication of transcatheter aortic valve replacement(TAVR).Application of machine learning could potentially be used to predict preprocedural risk for PPM.AIM To apply machine learning to be used to predict pre-procedural risk for PPM.METHODS A retrospective study of 1200 patients who underwent TAVR(January 2014-December 2017) was performed. 964 patients without prior PPM were included for a 30-d ...     

Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway

This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-alpha as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-alpha. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711.