Potentially harmful advantage to athletes: a putative connection between UGT2B17 gene deletion polymorphism and renal disorders with prolonged use of anabolic androgenic steroids

ABSTRACT: BACKGROUND AND OBJECTIVE: With prolonged use of anabolic androgenic steroids (AAS), occasional incidents of renal disorders have been observed. Independently, it has also been established that there are considerable inter-individual and inter-ethnic differences, in particular with reference to the uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) gene, in metabolising these compounds. This report postulates the association of deletion polymorphism in the UGT2B17 gene with the occurrence of renal disorders on chronic exposure to AAS. PRESENTATION OF THE HYPOTHESIS: The major deactivation and elimination pathway of AASs is through glucuronide conjugation, chiefly catalyzed by the UGT2B17 enzyme, followed by excretion in urine. Excretion of steroids is affected in individuals with a deletion mutation in the UGT2B17 gene. We hypothesize that UGT2B17 deficient individuals are more vulnerable to developing renal disorders with prolonged use of AAS owing to increases in body mass index and possible direct toxic effects of steroids on the kidneys. Elevated serum levels of biologically active steroids due to inadequate elimination can lead to prolonged muscle build up. An increase in body mass index may cause renal injuries due to sustained elevated glomerular pressure and flow rate. TESTING THE HYPOTHESIS: In the absence of controlled clinical trials in humans, observational studies can be carried out. Real time PCR with allelic discrimination should be employed to examine the prevalence of different UGT2B17 genotypes in patients with impaired renal function and AAS abuse. In individuals with the UGT2B17 deletion polymorphism, blood tests, biofluid analyses, urinalysis, and hair analyses following the administration of an anabolic steroid can be used to determine the fate of the substance once in the body. IMPLICATIONS OF THE HYPOTHESIS: If the hypothesis is upheld, anabolic steroid users with a deletion mutation in the UGT2B17 gene may be exposed to an increased risk of developing renal disorders. In the current detecting - sanctioning anti-doping system, athletes motivated by the potential to evade detection owing to their unique genetic make-up could subject themselves to a serious health consequence. More research on AAS metabolism in the presence of UGT2B17 gene deletion is required. Benefit - harm evaluations in therapeutic use of anabolic steroids should also consider this potential link between UGT2B17 gene deletion polymorphism and renal disorders

A genetic perspective on cetacean evolution

Studies of cetacean evolution using genetics and other biomolecules have come a long way—from the use of allozymes and short sequences of mitochondrial or nuclear DNA to the assembly of full nuclear genomes and characterization of proteins and lipids. Cetacean research has also advanced from using only contemporary samples to analyzing samples dating back thousands of years, and to retrieving data from indirect environmental sources, including water or sediments. Combined, these studies have profoundly deepened our understanding of the origin of cetaceans; their adaptation and speciation processes; and of the past population change, migration, and admixture events that gave rise to the diversity of cetaceans found today

Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene

Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90-109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18-97 years old Caucasian sample (N = 1801, p = 0.007). We found a continuous pattern of increase from 18-75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene-environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p = 0.003). Our results underlie the importance of investigating non-disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population

Three is the magic number -- distance measurement of NGC 3147 using SN 2021hpr and its siblings

The nearby spiral galaxy NGC 3147 hosted three Type Ia supernovae (SNe Ia) in the past decades, which have been subjects of intense follow-up observations. Simultaneous analysis of their data provides a unique opportunity for testing the different light curve fitting methods and distance estimations. The detailed optical follow-up of SN 2021hpr allows us to revise the previous distance estimations to NGC 3147, and compare the widely used light curve fitting algorithms to each other. After the combination of the available and newly published data of SN 2021hpr, its physical properties can be also estimated with higher accuracy. We present and analyse new BVgriz and Swift photometry of SN 2021hpr to constrain its general physical properties. Together with its siblings, SNe 1997bq and 2008fv, we cross-compare the individual distance estimates of these three SNe given by the SALT code, and also check their consistency with the results from the MLCS2k2 method. The early spectral series of SN 2021hpr are also fit with the radiative spectral code TARDIS in order to verify the explosion properties and constrain the chemical distribution of the outer ejecta. After combining the distance estimates for the three SNe, the mean distance to their host galaxy, NGC 3127, is 42.5 $\pm$ 1.0 Mpc, which matches with the distance inferred by the most up-to-date LC fitters, SALT3 and BayeSN. We confirm that SN~2021hpr is a Branch-normal Type Ia SN that ejected $\sim 1.12 \pm 0.28$ M$_\odot$ from its progenitor white dwarf, and synthesized $\sim 0.44 \pm 0.14$ M$_\odot$ of radioactive $^{56}$Ni.Comment: 16 pages, 17 figures, 11 tables; accepted for publication in A&

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

European Association of Cardiothoracic Anesthesiology and Intensive Care (EACTAIC) Fellowship Curriculum: Second Edition.

International audienceThis document represents the first update of the Cardiothoracic and Vascular Anaesthesia Fellowship Curriculum of the European Association of Cardiothoracic Anaesthesiology and Intensive Care. After obtaining feedback from exit interviews with fellows in training, graduate fellows, and program directors, 2 modified online Delphi procedures with questionnaires were conducted. A consensus was reached when two-thirds of responding committee members gave green or yellow ratings on a traffic light system, and >70% indicated strong agreement or agreement on a 5-point Likert scale. The new regulations include the following: (1) more flexibility in the fellows` rotation, as long as the total number of days, rotations, and cases are completed during the training year; (2) recommendation for strict compliance with national working-time guidelines; (3) no extension of fellowship training to compensate for annual and/or sick leave, unless the required minimum number of cases and rotations are not reached; (4) interruption of fellowship training for >12 months is allowed for personal or medical reasons; (5) introduction of a checklist for quantitative assessment of standard clinical skills; (6) recommendations for a uniform structure of exit interviews; (7) possibility of a 1-month training rotation in a postanesthesia care unit instead of an intensive care unit; and (8) provided all other requirements have been met, the allowance of progression from the basic training year to the advanced fellowship training year without first passing the transesophageal echocardiography examination

Multivariate Analysis of Dopaminergic Gene Variants as Risk Factors of Heroin Dependence

BACKGROUND: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. OBJECTIVE: To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients. METHODS: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA). FINDINGS AND CONCLUSIONS: In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955) polymorphism in the promoter

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Making Waves : Collaboration in the time of SARS-CoV-2-rapid development of an international co-operation and wastewater surveillance database to support public health decision-making

The presence of SARS-CoV-2 RNA in wastewater was first reported in March 2020. Over the subsequent months, the potential for wastewater surveillance to contribute to COVID-19 mitigation programmes has been the focus of intense national and international research activities, gaining the attention of policy makers and the public. As a new application of an established methodology, focused collaboration between public health practitioners and wastewater researchers is essential to developing a common understanding on how, when and where the outputs of this non-invasive community-level approach can deliver actionable outcomes for public health authorities. Within this context, the NORMAN SCORE "SARS-CoV-2 in sewage" database provides a platform for rapid, open access data sharing, validated by the uploading of 276 data sets from nine countries to-date. Through offering direct access to underpinning meta-data sets (and describing its use in data interpretation), the NORMAN SCORE database is a resource for the development of recommendations on minimum data requirements for wastewater pathogen surveillance. It is also a tool to engage public health practitioners in discussions on use of the approach, providing an opportunity to build mutual understanding of the demand and supply for data and facilitate the translation of this promising research application into public health practice. (C) 2021 Elsevier Ltd. All rights reserved.Peer reviewe

Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease

OBJECTIVE: Alzheimer disease (AD) is a progressive, degenerative and irreversible neurological disorder with few therapies available. In search for new potential targets, increasing evidence suggests a role for the endocannabinoid system (ECS) in the regulation of neurodegenerative processes. METHODS: We have studied the gene expression status and the epigenetic regulation of ECS components in peripheral blood mononuclear cells (PBMCs) of subjects with late-onset AD (LOAD) and age-matched controls (CT). RESULTS: We found an increase in fatty acid amide hydrolase (faah) gene expression in LOAD subjects (2.30 ± 0.48) when compared to CT (1.00 ± 0.14; *p<0.05) and no changes in the mRNA levels of any other gene of ECS elements. Consistently, we also observed in LOAD subjects an increase in FAAH protein levels (CT: 0.75 ± 0.04; LOAD: 1.11 ± 0.15; *p<0.05) and activity (pmol/min per mg protein CT: 103.80 ± 8.73; LOAD: 125.10 ± 4.00; *p<0.05), as well as a reduction in DNA methylation at faah gene promoter (CT: 55.90 ± 4.60%; LOAD: 41.20 ± 4.90%; *p<0.05). CONCLUSIONS: Present findings suggest the involvement of FAAH in the pathogenesis of AD, highlighting the importance of epigenetic mechanisms in enzyme regulation; they also point to FAAH as a new potential biomarker for AD in easily accessible peripheral cells