Immunohistochemical assessment of intrinsic and extrinsic markers of hypoxia in reproductive tissue: differential expression of HIF1α and HIF2α in rat oviduct and endometrium.

Hypoxia is thought to be critical in regulating physiological processes within the female reproductive system, including ovulation, composition of the fluid in the oviductal/uterine lumens and ovarian follicle development. This study examined the localisation of exogenous (pimonidazole) and endogenous [hypoxia inducible factor 1α and 2α (HIF1α, -2α), glucose transporter type 1 (GLUT1) and carbonic anhydrase 9 (CAIX)] hypoxia-related antigens within the oviduct and uterus of the rat reproductive tract. The extent to which each endogenous antigen co-compartmentalised with pimonidazole was also assessed.

Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.

To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685).

Heritability of QT interval: how much is explained by genes for resting heart rate?

Introduction: Objective of this study was to determine the optimal (most heritable) phenotype for gene finding studies of QT interval in the general population. We also studied the extent to which heritability of QT interval can be explained by genes that also influence resting heart rate.

Methods And Results: Subjects in this classic twin study were 105 monozygotic and 256 dizygotic female twin pairs (mean age: 49.

Measurement of blood E2F3 mRNA in prostate cancer by quantitative RT-PCR: a preliminary study.

The use of serum prostate-specific antigen (PSA) measurements necessitates biopsies for accurate prostate cancer (CaP) diagnosis. Overall efficiency of accurate diagnosis, when PSA levels are used alone, is less than 60%. E2F3 was evaluated as an alternative biomarker using patient blood samples.

Multi-drug resistance gene-1 (MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements.

The intestinal efflux pump P-glycoprotein (P-gp), the product of the multi-drug resistance-1 (MDR-1) gene, significantly influences the pharmacokinetics of several drugs. Ciclosporin is a substrate for P-gp and is metabolized by cytochrome P450 (CYP) 3A enzymes. P-gp activity is affected by several known single nucleotide polymorphisms (SNPs) and haplotypes.

Multidrug resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements.

P-glycoprotein (P-gp) and the drug metabolizing enzymes have major pharmacokinetic effects. Variability in tacrolimus absorption is influenced by P-gp activity which, in turn, is affected by single nucleotide polymorphisms (SNPs) within the multidrug resistance-1 gene (MDR-1). Tacrolimus dose requirements of 206 stable renal transplant patients were related to MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes: C-G-C and T-T-T.

Protein tyrosine phosphatase-1B gene PTPN1: selection of tagging single nucleotide polymorphisms and association with body fat, insulin sensitivity, and the metabolic syndrome in a normal female population.

Protein tyrosine phosphatase-1B negatively regulates leptin and insulin signaling, potentially contributing to hormonal resistance. We selected six tagging single nucleotide polymorphisms (SNPs) representing 18 common variants in the protein tyrosine phosphatase-1B gene (PTPN1) and tested their effect on serum leptin, body fat, and measures of insulin sensitivity and the metabolic syndrome in a large sample of normal female Caucasian twins (n = 2,777; mean age, 47.4 +/- 12.

Genotyping cytochrome P450 3A5 using the Light Cycler.

Cytochrome P450 3A5 (CYP3A5) is involved in the biotransformation of many orally administered drugs, some of which are dose optimized using therapeutic drug monitoring. The CYP3A5 gene exhibits variable inter-individual expression, which is related to a single-nucleotide polymorphism. Producers of the enzyme possess at least one CYP3A5*1 allele.

Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population.

A major quantitative trait locus (QTL) determining leptin levels has been linked to the proopiomelanocortin (POMC) region on chromosome 2. Most studies, based on under 350 lean or obese subjects, have shown no association between POMC SNP 8246 C/T and serum leptin, but significant associations have been reported with RsaI 8246 C/T SNP haplotypes. We have investigated association of four POMC SNPs with body composition and serum leptin in 2758 normal Caucasian female subjects (mean age 47.

Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians.

Previously, we demonstrated that the dose-normalized tacrolimus blood concentration after renal transplantation was associated with a single nucleotide polymorphism (SNP) in the CYP3AP1 gene, probably through linkage with an SNP in the CYP3A5 gene. Individuals with at least one CYP3A5*1 allele synthesize CYP3A5 and CYP3A5*3/*3 homozygotes do not. We now present results with direct typing of the CYP3A5 genotype for this group of 180 kidney-only transplant recipients from a single center.

Common arterial trunk associated with a homeodomain mutation of NKX2.6.

Persistent truncus arteriosus (PTA) is a failure of septation of the cardiac outflow tract (OFT) into the pulmonary artery and the aorta. A common arterial trunk (CAT) is often diagnosed as PTA in the absence of evidence of embryological mechanism. We have used autozygosity mapping of a large consanguineous family segregating CAT to map the causative locus to chromosome 8p21.

The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation.

Previously, we reported that, at 3 months after renal transplantation, individuals with CYP3AP1 genotype CYP3AP1*1 (linked to CYP3A5*1 and strongly associated with expression of CYP3A5) required twofold higher doses of tacrolimus to achieve target blood concentrations than individuals with the genotype CYP3AP1*3/*3 (CYP3A5 nonexpressors). This study assesses the relationship between concentration-controlled dosing during the early period after transplantation, the time to achieve target concentrations and genotype in 178 renal transplant recipients (CYP3AP1*1/*3 or *1/*1: n = 53, CYP3AP1*3/*3: n = 125). Patients with CYP3AP1*1/*3 or *1/*1 had lower mean tacrolimus concentrations during the first week (Median 13.

Quantification of mitochondrial sublimons in human fibrillating atria.

Supraventricular tachycardias, including AF (atrial fibrillation), and mtDNA (mitochondrial DNA) deletions may lead to dilated cardiomyopathy. It is unknown whether mtDNA function is impaired in the human atrium in AF. In the present study, we investigated the role of rearranged mtDNA 'sublimons' in the pathogenesis of AF.

Measurement of cardiac troponin I in striated muscle using three experimental methods.

Background: Qualitative and quantitative measures of cardiac troponin I (cTnI) in striated muscle have been reported as part of diverse investigations. However, there is disparity in the literature regarding the findings of these analyses. The cTnI molecule can exist in phosphorylated, non-phosphorylated, reduced, non-reduced, complexed or non-complexed forms.

Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement.

Background: There is marked heterogeneity in blood concentrations of tacrolimus following standard body-weight-based dosing. This is most apparent in black patients, who have a higher dose requirement when compared with other ethnic groups. Differences in intestinal P-glycoprotein and hepatic and intestinal cytochrome P4503A activity have been postulated as contributing to this problem.

Beta2-adrenergic receptor gene and resting hemodynamics in European and African American youth.

Background: The beta2-adrenergic receptor (ADRB2) contributes to blood pressure (BP) regulation by mediating peripheral vasodilation. Associations between the Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene and BP among multiethnic adult samples have been mixed. The purpose of this study was to investigate the relationship between these polymorphisms and resting hemodynamic function in African American (AA) and European American (EA) youths.

Human piebaldism: six novel mutations of the proto-oncogene KIT.

Human piebaldism is a rare autosomal dominant disorder that comprises congenital patchy depigmentation of the scalp, forehead, trunk and limbs. It is caused by mutations in the cell-surface receptor tyrosine kinase gene (KIT, also c-kit). We screened three families and three isolated cases of piebaldism from different countries for mutations in the KIT gene using automated sequencing methods.

Cardiac troponin T and creatine kinase MB content in skeletal muscle of the uremic rat.

Background: The assertion that creatine kinase MB (CK-MB) and the developmental isoforms of cardiac troponin T (cTnT) are expressed by skeletal muscle in some clinical settings is an extrapolation from nonuremic rodent studies. We studied the content of CK-MB and cTnT in skeletal muscle of the renal-insufficient rat.

Methods: Skeletal muscles (gastrocnemius) were collected from both five-sixths nephrectomized rats (n = 11) and sham-operated controls (n = 11).

Delayed discharges from Oxford city hospitals: who and why?

Objective: To determine the extent and characteristics of discharge delays of younger patients from acute hospital beds in Oxford, England.

Design: Three-month prospective analysis of patients deemed to have delayed discharge.

Measures: The primary measure was the number of days from the patient being no longer in need of acute medical inpatient care to eventual discharge.