Effect of SAMe-TT2R2 score and genetic polymorphism on the quality of anticoagulation control in Qatari patients treated with warfarin

Journal of Thrombosis and Thrombolysis - There is no strong evidence on pharmacogenetics role on the quality of INR control after the initiation phase and on the maintenance of stable INR on the...     

Acrolein-Exposed Normal Human Lung Fibroblasts in Vitro: Cellular Senescence,Enhanced Telomere Erosion,and Degradation of Werner’s Syndrome Protein

Background: Acrolein is a ubiquitous environmental hazard to human health. Acrolein has been reported to activate the DNA damage response and induce apoptosis. However, little is known about the effects of acrolein on cellular senescence.Objectives: We examined whether acrolein induces cellular senescence in cultured normal human lung fibroblasts (NHLF).Methods: We cultured NHLF in the presence or absence of acrolein and determined the effects of acrolein on cell proliferative capacity, senescence-associated β-galactosidase activity, the known senescence-inducing pathways (e.g., p53, p21), and telomere length.Results: We found that acrolein induced cellular senescence by increasing both p53 and p21. The knockdown of p53 mediated by small interfering RNA (siRNA) attenuated acrolein-induced cellular senescence. Acrolein decreased Werner’s syndrome protein (WRN), a member of the RecQ helicase family involved in DNA repair and telomere maintenance. Acrolein-induced down-regulation of WRN protein was rescued by p53 knockdown or proteasome inhibition. Finally, we found that acrolein accelerated p53-mediated telomere shortening.Conclusions: These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein down-regulation.Citation: Jang JH, Bruse S, Huneidi S, Schrader RM, Monick MM, Lin Y, Carter AB, Klingelhutz AJ, Nyunoya T. 2014. Acrolein-exposed normal human lung fibroblasts in vitro: cellular senescence, enhanced telomere erosion, and degradation of Werner’s syndrome protein. Environ Health Perspect 122:955–962; http://dx.doi.org/10.1289/ehp.1306911     

Effect of CYP2C9 gene polymorphisms on response to treatment with sulfonylureas in a cohort of Egyptian type 2 diabetes mellitus patients

Oral hypoglycemics are a widely prescribed group of drugs for the management of type 2 diabetes mellitus. Sulfonylureas (SUs) are the cornerstone of type 2 diabetes pharmacotherapy. The enzyme cytochrome P450 2C9 (CYP2C9) is the main enzyme that catalyzes the biotransformation of SUs. It is encoded by the polymorphic gene CYP2C9 with two allelic variants namely CYP2C9*2 and CYP2C9*3 coding for variant allozymes with reportedly decreased metabolic capacity resulting in decreased SUs clearance and consequently prolonged and exacerbated action. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide, a second-generation sulfonylurea. Hundred type 2 diabetic patients were enrolled in the study. Genotyping was done on the LightCycler 2 by real-time polymerase chain reaction (PCR) hybridization probe assay. The results are the following: 53 patients were carriers of the wild genotype (CYP2C9*1/*1), 20 were heterozygous for the variant CYP2C9*2 allele (CYP2C9*1/*2), 18 were heterozygous for the variant CYP2C9*3 allele (CYP2C9*1/*3), and 9 were double heterozygous for both mutant alleles (CYP2C9*2/*3); of those double mutant genotype patients, two were also homozygous for the mutant CYP2C9*2 allele (CYP2C9*2/*2) and one patient was homozygous for the mutant CYP2C9*3 allele (CYP2C9*3/*3). Although there was no significant difference in drug dosage between the four groups, there was however a significant association of the CYP2C9*2/*3 genotype with better glycemic control. As conclusion, the better glycemic control observed can probably be attributed to slower metabolism of SUs by the carriers of the CYP2C9*2/*3 genotype and consequently longer half-life or exacerbated effect of the SUs administered.     

A Cognitively Inspired Clustering Approach for Critique-Based Recommenders

Cognitive Computation - The purpose of recommender systems is to support humans in the purchasing decision-making process. Decision-making is a human activity based on cognitive information. In the...     

Vagus Nerve Stimulation and Other Neuromodulation Methods for Treatment of Traumatic Brain Injury

The objective of this paper is to review the current literature regarding the use of vagus nerve stimulation (VNS) in preclinical models of traumatic brain injury (TBI) as well as discuss the potential role of VNS along with alternative neuromodulation approaches in the treatment of human TBI. Data from previous studies have demonstrated VNS-mediated improvement following TBI in animal models. In these cases, VNS was observed to enhance motor and cognitive recovery, attenuate cerebral edema and inflammation, reduce blood brain barrier breakdown, and confer neuroprotective effects. Yet, the underlying mechanisms by which VNS enhances recovery following TBI remain to be fully elucidated. Several hypotheses have been offered including: a noradrenergic mechanism, reduction in post-TBI seizures and hyper-excitability, anti-inflammatory effects, attenuation of blood–brain barrier breakdown, and cerebral edema. We present other potential mechanisms by which VNS acts including enhancement of synaptic plasticity and recruitment of endogenous neural stem cells, stabilization of intracranial pressure, and interaction with the ghrelin system. In addition, alternative methods for the treatment of TBI including deep brain stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, and focused ultrasound stimulation are discussed. Although the primary source data show that VNS improves TBI outcomes, it remains to be determined if these findings can be translated to clinical settings.

     

Diagnostic significance of miR‐21, miR‐141, miR‐18a and miR‐221 as novel biomarkers in prostate cancer among Egyptian patients

Prostate cancer (PC) is considered as the fifth cause of cancer deaths worldwide. The exact etiopathogenesis is unclear; however, genetic predisposition, hormonal influencers, lifestyle and environmental factors act as major contributors. It has been found that several miRNAs may play a crucial role in cancer initiation and progression. Here, in this study, we evaluated the peripheral blood levels of miR‐21, miR‐141, miR‐221 and miR‐18a expression among 80 prostate cancer patients (50 localised and 30 metastatic) and 30 benign prostatic hyperplasia patients compared to 50 normal control subjects, using RT‐PCR. Our results of analysis of miR‐21, miR‐141, miR‐18a and miR‐221 in the plasma of PC patients showed that miR‐18a is a powerful discriminator of PC patients from healthy controls as it had the highest AUC (0.966; 95% CI, 0.937–1.000), while miR‐221 provided better differentiation of metastatic from localised PC (sensitivity was 92.9% at 100% specificity), and when we combine miR‐18a and miR‐221 for differentiating patients with MPC, it will increase the sensitivity to 96.4% at a specificity of 100% (AUC, 0.997; 95% CI, 0.988–1.0) (p < .000). This current study recommends that analysis of these miRNAs might have clinical value in enhancing PSA testing.     

Renal cell carcinoma with inferior vena caval involvement

Renal cell carcinoma extends into the lumen of the inferior vena cava in approximately 4% of patients at the time of diagnosis. Surgical removal of the intracaval tumor thrombus with radical nephrectomy is the preferred treatment for this malignancy. From January 1977 to June 1990, 31 such patients were examined for combined problems of renal carcinoma and intracaval tumor extension. Twenty-six of these patients underwent radical nephrectomy and vena caval thrombectomy. Ten patients had tumor thrombus confined to the infrahepatic vena cava, 11 had retrohepatic caval involvement, and 5 had extension to the level of the diaphragm or into the right atrium. Surgical approach was dictated by the level of caval involvement. Control of the suprahepatic vena cava plus temporary occlusion of hepatic arterial and portal venous inflow were necessary in some cases; cardiopulmonary bypass was required for transatrial removal of more extensive tumors. Five of the 26 patients had evidence before operation of distant metastatic disease; none of these survived beyond 12 months. The 5-year actuarial survival rate of the 21 patients without known preoperative metastatic disease was 57%. Complete surgical excision of all gross tumor appears to be critical for long-term survival in these patients.     

Medicine or ecstasy? The importance of the logo

Some pharmaceutical tablets have an appearance that resembles that of ecstasy (a logo and often a name referring to it, a given shape and/or a colour). These are sometimes sold in the street as ‘ecstasy’. In order to assess the knowledge of this phenomenon, surveys were conducted among designer drug users (DDUsers), pharmacists and pharmaceutical firms. Three surveys were conducted: the first one was conducted among DDUsers by means of an anonymous questionnaire; the second one consisted of a 1‐month postal survey within a network of 155 community pharmacies in the Aquitaine region, Southwestern France and the third one consisted of a postal questionnaire sent to 71 pharmaceutical firms. Nineteen users, 77 pharmacists and 25 pharmaceutical firms participated in the surveys. All DDUsers knew the existence of what they call ecstasy ‘swindles’, but less than one quarter of the pharmacists and one third of pharmaceutical firms were aware of the potential recreational and involuntary misuse of medicines. The phenomenon of ‘swindle’ in the illicit market is not new. However, the sale of medicines because of their appearance or logo seems to be quite rare. In order to limit this diversion, prevention should be reinforced. In addition, recommendations on the appearance of medicine tablets should be set up by regulatory agencies in charge of medicine approval.