Tissue Doppler assessment of left ventricular diastolic function in rheumatic mitral stenosis

BackgroundLeft ventricular systolic and diastolic functions are reported to be altered in mitral stenosis. Although conventional Doppler ultrasound recording of transmitral flow is used in the assessment of left ventricular diastolic function, yet, in patients with mitral stenosis, it is altered by mitral stenosis itself and thus precludes the proper assessment of LV diastolic function.Aim of the workThe aim of this work is to assess LV diastolic function using pulsed tissue Doppler interrogation of mitral annulus motion in patients with rheumatic mitral stenosis.Patients and methodsTwelve patients with established diagnosis of rheumatic mitral stenosis in normal sinus rhythm were obtained from outpatient clinic of Cardiology Department in Mansura specialized hospital. Thirteen age and sex matched controls with completely normal echo-Doppler study were taken for comparison. All patients were subjected to thorough history taking including dyspnea grading according to NYHA score, clinical examination, 12 lead surface electrocardiogram and most importantly echo-Doppler study.ResultsWe found statistically significant higher peak mitral annular E_a velocity from septal, anterior, inferior and lateral portions of the mitral annulus in controls compared with mitral stenosis patients as well as their averaged values. There is no statistically significant difference regarding peak mitral annular A_a velocity from septal, anterior, inferior and lateral portions of the mitral annulus between both groups as well as their averaged values. The ratio of early to late mitral annular velocities from all recorded sites was statistically significantly higher in the controls compared with mitral stenosis patients.ConclusionsTDI of mitral annulus may provide potential diagnostic role for assessment of LV diastolic function in patients with mitral stenosis.     

Bromuconazole-induced hepatotoxicity is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1 gene expression

Despite widespread use of bromuconazole as a pesticide for food crops and fruits, limited studies have been done to evaluate its toxic effects. Here, we evaluated the hepatotoxic effect of bromuconazole using classical toxicological (biochemical analysis and histopathological examination) and gene-based molecular methods. Male rats were treated either orally or topically with bromuconazole at doses equal to no observed adverse effect level (NOAEL) and 1/10 LD50 for 90?d. Bromuconazole increased activities of liver enzymes (ALT, AST, ALP, and ACP), and levels of bilirubin. It also induced hepatic oxidative stress as evidenced by significant decrease in the activities of superoxide dismutase (SOD), and significant increase in levels of malondialdehyde (MDA) in liver. In addition, bromuconazole caused an increase in liver weights and necrobiotic changes (vacuolation and hepatocellular hypertrophy). It also strongly induced the expression of PXR and its downstream target CYP3A1 gene as well as the activity of CYP3A1. However, it inhibited the expression of CAR and its downstream target CYP2B1 gene without significant changing in CYP2B1 activity. Overall, the oral route showed higher hepatotoxic effect and molecular changes than the dermal route and all changes were dose dependent. This is the first investigation to report that bromuconazole-induced liver oxidative damage is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1.     

Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

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Photoaffinity Labeling of Nicotinic Receptors: Diversity of Drug Binding Sites!

For almost 30 years, photoaffinity labeling and protein microsequencing techniques have been providing novel insights about the structure of nicotinic acetylcholine receptors (nAChR) and the diversity of nAChR drug binding sites. Photoaffinity labeling allows direct identification of amino acid residues contributing to a drug binding site without prior knowledge of the location of the binding site within the nAChR or the orientation of the ligand within the binding site. It also distinguishes amino acids that contribute to allosteric binding sites from those involved in allosteric modulation of gating. While photoaffinity labeling was used initially to identify amino acids contributing to the agonist binding sites and the ion channel, it has been used recently to identify binding sites for allosteric modulators at subunit interfaces in the extracellular and the transmembrane domains, and within a subunit's transmembrane helix bundle. In this article, we review the different types of photoaffinity probes that have been used and the various binding sites that have been identified within the structure of nAChR, with emphasis on our recent studies of allosteric modulator binding sites.     

The role of epoxide hydrolases in health and disease

Epoxide hydrolases (EH) are ubiquitously expressed in all living organisms and in almost all organs and tissues. They are mainly subdivided into microsomal and soluble EH and catalyze the hydration of epoxides, three-membered-cyclic ethers, to their corresponding dihydrodiols. Owning to the high chemical reactivity of xenobiotic epoxides, microsomal EH is considered protective enzyme against mutagenic and carcinogenic initiation. Nevertheless, several endogenously produced epoxides of fatty acids function as important regulatory mediators. By mediating the formation of cytotoxic dihydrodiol fatty acids on the expense of cytoprotective epoxides of fatty acids, soluble EH is considered to have cytotoxic activity. Indeed, the attenuation of microsomal EH, achieved by chemical inhibitors or preexists due to specific genetic polymorphisms, is linked to the aggravation of the toxicity of xenobiotics, as well as the risk of cancer and inflammatory diseases, whereas soluble EH inhibition has been emerged as a promising intervention against several diseases, most importantly cardiovascular, lung and metabolic diseases. However, there is reportedly a significant overlap in substrate selectivity between microsomal and soluble EH. In addition, microsomal and soluble EH were found to have the same catalytic triad and identical molecular mechanism. Consequently, the physiological functions of microsomal and soluble EH are also overlapped. Thus, studying the biological effects of microsomal or soluble EH alterations needs to include the effects on both the metabolism of reactive metabolites, as well as epoxides of fatty acids. This review focuses on the multifaceted role of EH in the metabolism of xenobiotic and endogenous epoxides and the impact of EH modulations.