Genetic variation of CYP3A and its influence on the pharmacokinetics of tacrolimus, a calcineurin inhibitor

Background: Tacrolimus (Tac) a calcineurin inhibitor (CNI), is a potent immunosuppressive drug which is widely used in organ transplant recipients. The drug has a narrow therapeutic window and high inter-individual pharmacokinetic variability. Tac is metabolized by cytochrome P450 3A (CYP3A) enzymes. The CYP3A5 activity is largely determined by the single nucleotide variant (SNV) CYP3A5*3 (c.219-237A>G; rs776746), which results in alternate mRNA splicing and a non-functional protein.Methods: An observational prospective study was carried out at nephrology centre of army hospital where the consenting patients were enrolled in the study. The whole blood sample drawn was utilized to analyze for plasma drug concentration of Tac and genotyping for the CYP3A*5 polymorphism by the method as described by Cheung et al.Results: 100 patients participated with an average of 98±8 days after transplantation. Recipients having heterozygous CYP3A5*1 genotype manifested 70% lower mean steady state concentration of Tac (C0/D ratio) 1.67±0.43 μg*l-1/mg in comparison to homozygote carriers of CYP3A5*3 5.60±1.94 μg*l-1/mg p<0.001.Conclusions: Study suggested that Indian sub population closely mimics Caucasian population in terms of genotype expression for CYP3A5*3, who are expressing a non-functional enzyme for metabolism. Also, this study reinforces that population genotype CYP3A5*1 is significantly associated with lower C0/D ratio for Tac than the ones expressing homozygous CYP3A5*3 genotype. It also established the importance of pre-transplant genotyping, for better individualization of Tac doses. Further studies are suggested for population pharmacokinetic modelling study in future to derive starting dosage of Tac based on profiling of CYP3 genetics in recipients

Transbilayer distributions of red cell membrane phospholipids in unilamellar vesicles

The phospholipid organization in unilamellar vesicles comprised of various purified phospholipid components of monkey erythrocyte membrane was ascertained using phospholipase A2 and trinitrobenzenesulfonic acid as external membrane probes. The vesicles were formed by sonication or detergent dialysis and fractionated by centrifugation or gel permeation chromatography. Experiments were done to confirm that the phospholipase A2 treatments did not cause lysis or induce fusion of the vesicles. This enzyme hydrolysed only the glycerophospholipids in the outer surface of the vesicles. The amounts of the external phospholipids determined by this enzymatic method were verified using the chemical probe, trinitrobenzenesulfonic acid. The choline-containing phospholipids and phosphatidylethanolamine localized randomly in the two surfaces of sonicated vesicles (outer diameter, about 30 nm), whereas phosphatidylserine preferentially distributed in the inner monolayer. This phosphatidylserine asymmetry virtually disappeared in detergent dialysed vesicles (outer diameter, about 45 nm). Furthermore, inclusion of cholesterol in both the types of vesicles resulted in more random glycerophospholipid distributions across the plane of vesicles bilayer, presumably due to the cholesterol-induced increases in the size of vesicles. These results demonstrate that the transbilayer distribution of erythrocyte membrane phospholipids in unilamellar vesicles are controlled mainly by the surface curvature rather than by interlipid interactions, and therefore suggest that phospholipid-phospholipid and phospholipid-cholesterol interactions should not play any significant role in determining the membrane phospholipid asymmetry in red cells. It is proposed that this asymmetry primarily originates from differential bindings of phospholipids with membrane proteins in the two leaflets of the membrane bilayer

Effect of altered polar headgroup of phosphatidylethanolamines on transbilayer aminophospholipid distribution in sonicated vesicles

The transbilayer aminophospholipid distributions in small unilamellar vesicles comprising of phosphatidylethanolamine or its analogs (bearing modifications in the polar headgroup) and egg phosphatidylcholine were ascertained using trinitrobenzenesulfonic acid as external membrane probe. These vesicles, containing 10-30 mol % phosphatidylethanolamine or its analogs, were formed by sonication and fractionated by centrifugation. Phosphatidylethanolamine at low concentrations (10 mol %) preferentially localized in the outer monolayer. This preference appeared to be reversed at higher phosphatidylethanolamine concentrations (30 mol %). Unlike this finding, phosphatidylethanolamine bearing ethyl, phenyl and benzyl substituents at the carbon atom adjacent to the amino group distributed mainly in the outer surface irrespective of their concentrations. Similar results were obtained when the phosphate and amino groups were separated by three methylene residues. These observations suggest that the effective polar headgroup volume and/or hydrogen-bonding capacity of phospholipids are the important factors that determine their distribution in small unilamellar vesicles

A study of coronary artery variations in patients undergoing invasive coronary angiography

Invasive coronary Angiography (ICA) is a readily available invasive imaging modality that provides high-resolution anatomical information of the coronary arteries. Studies of coronary artery dominance and variants may helpful for management of coronary artery diseases. Aim: The aim of this study was to evaluate the prevalence of coronary artery dominance and variation in patients undergoing invasive coronary angiography. Methods: This was a descriptive research study design.  20-90 years age group patients undergoing invasive coronary angiography were enrolled in our study. Wide ranges of data were collected as well as evaluation of medical reports in order to distinguish perception over this “Coronary Artery Variations & Anomalies” and prevalence in this country context.  In all patients in which a coronary anomaly, origin, course and/or termination of the coronary arteries had been originally reported. Results: A total of 390 patients undergoing coronary angiography were evaluated for coronary artery variations and anomalies. Majority of the patients (32%) were 50-60 year age group. Most of the patients (77%) had right dominant circulation. Ramus intermedius was the common anatomical variant found in 13.4% cases. Conclusions: ICA is a first line method for detecting coronary artery dominance, variation and anomalies, lead to helping in diagnosing and management of coronary artery diseases

Interface induced perpendicular magnetic anisotropy in Co/CoO/Co thin film structure: An in-situ MOKE investigation

Co /CoO/Co polycrystalline film was grown on Si (001) substrate and magnetic properties have been investigated using in-situ magneto-optic Kerr effect during growth of the sample. Magnetic anisotropy with easy axis perpendicular to the film surface has been observed in top Co layer, whereas bottom layer was found to be soft with in-plane magnetization without any influence of top layer. Ex-situ in-plane and out-of-plane diffraction measurements revealed that the growth of Co on oxidized interface takes place with preferential orientation of c-axis perpendicular to the film plane, which results in the observed perpendicular magnetic anisotropy. Texturing of the c-axis is expected to be a result of minimization of the interface energy due to hybridization between Co and oxygen at the interface.Comment: 9 pages, 3 figures, under review in IOP journa

Authentication Techniques That Work Well With Mobile and Distributed Systems

In the modern technological world, the existence of minuscule devices that are able to exchange data and build networks is necessary for the completion of numerous activities. In many of these applications, the confidentiality and dependability of the information that is being transferred are of the utmost importance. The purpose of this article is to offer two novel ways for authenticating short conversations that are encrypted, with the end objective of fulfilling the requirements of mobile and ubiquitous software. We take advantage of the fact that the message that has to be verified must also be encrypted in order to propose a set of authentication codes that are not only provably secure but also surpass every other message authentication code that has been published in the past. The recommended procedures make use of encryption techniques to provide an additional layer of protection, with the goal of enhancing the performance of the conventional authentication primitives

Simple and effective method to protect from toxic fumes of methyl methacrylate (bone cement) in operation theatre

Methyl methacrylate is a monomer of acrylic resin widely used in a variety of medical, dental, and industrial applications. Its extensive use in surgery, particularly for arthroplasties, has often raised concerns regarding potential human toxicity for orthopaedic surgeons, surgical nurses, and other operating-room staff who are occupationally exposed to the compound