A prevalent POLG CAG microsatellite length allele in humans and African great apes.

The human nuclear gene for the catalytic subunit of mitochondrial DNA polymerase gamma ( POLG) contains within its coding region a CAG microsatellite encoding a polyglutamine repeat. Previous studies demonstrated an association between length variation at this repeat and male infertility, suggesting a mechanism whereby the prevalent (CAG)(10) allele, which occurs at a frequency of >80% in different populations, could be maintained by selection. Sequence analysis of the POLG CAG microsatellite region of more than 1000 human chromosomes reveals that virtually all allelic variation at the locus is accounted for by length variation of the CAG repeat.

New-onset sustained ventricular tachycardia and fibrillation early after cardiac operations.

Background: Malignant ventricular tachyarrhythmia early after cardiac surgery is an uncommon arrhythmic complication but has a negative impact on mortality. The purpose of this study was to evaluate the incidence of new-onset sustained postoperative ventricular tachycardia-ventricular fibrillation and to identify risk factors for the dysrhythmia.

Methods: Demographic, clinical, operative, and postoperative data, including a variable of postoperative ventricular tachycardia, were prospectively obtained from 4748 patients undergoing nonemergency coronary artery bypass graft and(or) valve replacement with no history of sustained ventricular tachycardia or sudden death.

Cytochrome p450A1 polymorphisms in a Caucasian population with porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is the most frequent porphyria in humans. The familial type is in contrast to the sporadic type due to an inherited defect of the uroporphyrinogen-II-decarboxylase (URO-D) and both types need additional porphyrinogens to lead to the clinical manifestation of the disease. Various factors such as xenobiotics (i.

A specificity switch in selected cre recombinase variants is mediated by macromolecular plasticity and water.

The basis for the altered DNA specificities of two Cre recombinase variants, obtained by mutation and selection, was revealed by their cocrystal structures. The proteins share similar substitutions but differ in their preferences for the natural LoxP substrate and an engineered substrate that is inactive with wild-type Cre, LoxM7. One variant preferentially recombines LoxM7 and contacts the substituted bases through a hydrated network of novel interlocking protein-DNA contacts.

beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line.

Integrin-mediated signalling has been implicated in asbestos-induced carcinogenesis. In studies here, we examined signal transduction events associated with integrin-directed cell reactions triggered by crocidolite asbestos in the pleural mesothelial cell line 4/4 RM-4. Crocidolite fibres induced a significant time- and dose-dependent activation of the extracellular-signal-regulated kinases ERK1 and ERK2.

Outcome of mitral valve repair or replacement: a comparison by propensity score analysis.

Background: There are no randomized trials comparing outcomes after mitral valve (MV) repair and replacement. Propensity scoring is a powerful tool that has the potential to reduce selection bias in nonrandomized studies.

Methods: From the BC Cardiac Registries, 2,060 patients presented for MV surgery, with or without CABG between 1991 and 2000.

Edge-to-edge repair for functional mitral regurgitation: an echocardiographic study of the hemodynamic consequences.

Background And Aim Of The Study: The study aim was to characterize changes in mitral valve area and flow, and left ventricular (LV) size and function, following edge-to-edge (E-E) repair for severe functional mitral regurgitation (MR). The possibility that preoperative dobutamine stress echocardiography (DSE) might be used to predict post-repair recovery in LV function was also examined.

Methods: Seventeen patients underwent preoperative transthoracic echocardiography (TTE) and DSE, intraoperative transesophageal echocardiography, and three-month postoperative TTE.

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women.

A case-control study was performed to assess the potential influence of CYP19 Arg(264)Cys and CYP1B1 Leu(432)Val polymorphisms on breast cancer risk in a series of Korean breast cancer patients and controls. The results suggest that the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95% CI=1.

Role of alcohol and genetic polymorphisms of CYP2E1 and ALDH2 in breast cancer development.

Objective: We examined the potential association between alcohol consumption and genetic polymorphisms in the alcohol metabolizing enzymes, CYP2E1 and ALDH2, in individual susceptibility to breast cancer in a Korean study population.

Methods: Three hundred and forty-six histologically confirmed breast cancer patients and 377 controls with no present or previous history of cancer were recruited from several teaching hospitals in Seoul during 1995-2001. The CYP2E1 RsaI polymorphism was determined by a real time PCR method, and the ALDH2 Glu487 Lys polymorphism was determined by a PCR method with confronting two-pair primers (PCR-CTPP).

Association between head and neck cancer and microsomal epoxide hydrolase genotypes.

Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH activity has been associated with combinations of these genotypes, and the respective activity categories have been frequently used in the estimation of risks for smoking-related cancers.

A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency.

Epidemiological data, animal studies and interventional studies provide evidence for a potential chemopreventive effect of selenium during development of colorectal cancer. The human glycoprotein Selenoprotein P (SeP) contains up to 50% of plasma selenium content. SeP is expressed in the gastrointestinal tract and the liver, where its expression is downregulated by various proinflammatory cytokines (Il1beta, TGFbeta, IFNgamma).

Breaking bad news--development of a hospital-based training workshop.

The skills required to break bad news have been written about extensively and are taught in medical schools. Recent initiatives have concentrated on improving the skills of doctors and nurses in senior positions, who act as role models for their junior colleagues. A multiprofessional learning situation can be a threatening environment, in which colleagues may worry about exposing some of the weaknesses in their knowledge and skills regarding communication with patients.

Distinct spectrum of mutations induced by crocidolite asbestos: clue for 8-hydroxydeoxyguanosine-dependent mutagenesis in vivo.

DNA damage due to reactive oxygen or nitrogen species is proposed to be involved in the molecular mechanism of asbestos-induced carcinogenicity. However, indications for this hypothesis came mainly from in vitro assays using cultured cells or cell-free systems. In the present study, the mutagenicity of crocidolite fibers and the underlying molecular mechanisms were investigated in vivo.

Identification of an element within the promoter of human selenoprotein P responsive to transforming growth factor-beta.

Selenoprotein P (SeP) is a plasma protein that contains up to 10 selenocysteine residues and accounts for about 50% of total selenium in human plasma. We have previously shown that SeP expression in the human liver cell line HepG2 is inhibited by transforming growth factor (TGF)-beta1 on a transcriptional level. Smad proteins are the transcriptional mediators of TGF-beta signalling and putative Smad-binding elements (SBE) comprising the core sequence CAGACA are present at two positions in the SeP promoter.

Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.

Human mitochondrial DNA polymerase, encoded by POLG, contains a polyglutamine tract encoded by a CAG microsatellite repeat. Analysis of POLG genotypes in different populations identified an association between absence of the common, ten-repeat allele and male infertility typified by a range of sperm quality defects but excluding azoospermia.

Modulation of selenoprotein P expression by TGF-beta(1) is mediated by Smad proteins.

Selenoprotein P (SeP) is a selenium-rich plasma protein which accounts for more than 50% this study, the effect of TGF-beta(1) on the expression of SeP in the human liver cell line HepG2 was investigated. Western analysis revealed a dose-dependent reduction of SeP content in cell supernatant. RT-PCR analysis of SeP-mRNA expression demonstrated a marked inhibition and a reporter gene under control of the SeP promoter was negatively regulated by TGF-beta(1).

Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue.

Tobacco use is causally associated with head and neck squamous cell cancer (HNSCC). Here, we present the results of a case-control study that investigated the effects that the genetic variants of the cytochrome (CYP)1A1, CYP1B1, glutathione-S-transferase (GST)M1, GSTT1, and GSTP1 genes have on modifying the risk of smoking-related HNSCC. Allelisms of the CYP1A1, GSTT1, GSTM1, and GSTT1 genes alone were not associated with an increased risk.

Real-time genotyping of cytochrome P4501A1 A4889G and T6235C polymorphisms.

Single nucleotide polymorphisms, such as the cytochrome P450 1A1 (CYP1A1) A4889G and T6235C variants, have been reported to be associated with an increased cancer risk. In order to study their role in molecular-epidemiological studies, we developed a single-step procedure for genotyping these two CYP1A1 polymorphisms using real-time polymerase chain reaction (PCR) and subsequent melting curve analysis. Genotypes of 300 unrelated Caucasians, without prior history of cancer, were determined by real-time PCR and compared to genotypes obtained by restriction fragment length polymorphism PCR.

Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-beta(1).

Previous studies showed that TGF-beta down-regulates aryl hydrocarbon (AhR) expression in human lung carcinoma cells A549. Here we analyzed the molecular mechanisms by which TGF-beta modulates AhR expression. A 5799-nucleotide 5'-flanking region of human AhR gene was isolated.

Effective treatment of hyperhomocysteinemia in heart transplant recipients with and without renal failure.

Background: Elevated total plasma homocysteine (tHcy) levels have been associated with vascular disease and higher mortality in patients with coronary artery disease. Graft coronary disease is a major cause of mortality in long-term survivors of heart transplantation, and hyperhomocysteinemia may be one of its causes. The objectives of our study were to establish the effectiveness of a 3 stage homocysteine-lowering algorithm in a group of 84 heart transplant (HTx) patients and to evaluate the effect of renal function on the response to homocysteine-lowering therapy.

Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway.

The tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to increase the expression of prostaglandin endoperoxide H synthase (PGHS)-2. This study focused on the regulatory mechanism of TCDD-mediated transcriptional activation of PGHS-2. Treatment of rat hepatocytes with TCDD led to a dose-dependent induction of PGHS-2 mRNA levels associated with an increased synthesis of prostaglandin E(2), whereas expression of PGHS-1 was not affected.

Xenobiotic metabolism, genetic polymorphisms and male infertility.

Male reproductive function may be impaired by various occupational and environmental chemical agents. The majority of these xenobiotics, however, require metabolic activation in order to exert adverse effects via covalent interactions between intermediate metabolites and cellular macromolecules such as DNA or protein. In addition, metabolization may alter endocrine-disrupting properties of xenobiotics.