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Aims The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases ( NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases ( UGT) and glutathione S-transferases ( GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. Methods Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release ( IR) tablet (100 mg) and after repeated administration of modified release ( MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). Results Flupirtine IR was rapidly but incompletely absorbed (∼72%). Repeated administration of flupirtine MR showed lower bioavailability (∼60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2. Conclusions Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1. [ABSTRACT FROM AUTHOR]

Background: Triptans are only effective in terminating cluster headache (CH) attacks in 70-80% of patients. Pharmacogenetic aspects of the serotonin metabolism, specifically variation in the 5-HTTLPR may be involved. Methods: Genetic association study in a well-defined cohort of 148 CH patients with information on drug response to triptans. CH was diagnosed according to the criteria of the International Headache Society. Genotypes of the 43-bp insdel (rs4795541) and A > G (rs25531) polymorphisms in the 5-HTTLPR promoter region were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between bi-allelic and tri-allelic genotypes and triptan non-response with genotype models. Results: Mean age at study entry among patients was 44.6 ± 10.5 years, 77.7% were men. The genotype distribution both for the bi-allelic and the tri-allelic polymorphism was in Hardy-Weinberg equilibrium. We did not find an association of the bi-allelic polymorphism with triptan non-response. While the effect estimates for the S variant of the tri-allelic polymorphisms suggested increased odds of triptan non-response in CH patients (multivariable-adjusted odds ratio [95% confidence interval]: L*L* genotype—reference; L*S* genotype—1.33 [0.53-3.32]; S*S* genotype—1.46 [0.54-3.98]), the results were not statistically significant. Conclusions: Data from our study do not indicate a role of bi-allelic and tri-allelic genotypes of the 5-HTTLPR polymorphism in triptan non-response in CH. [ABSTRACT FROM AUTHOR]

Heritability estimates for body mass index (BMI) variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s) in the exclusively maternally inherited mitochondrial DNA (mtDNA) might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs) were available from genome-wide association study SNP arrays (Affymetrix 6.0). For discovery, we analyzed association in a case-control (CC) sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI≥30 kg/m2) and n = 2,373 normal weight and lean controls (BMI<25 kg/m2). SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger) in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002) located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039). These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048). Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their offspring could not be substantiated by the findings of the present study. [ABSTRACT FROM AUTHOR]

Background/aims: The application of intranasal oxytocin enhances facial emotion recognition in normal subjects and in subjects with autism spectrum disorders (ASD). In addition, various features of social cognition have been associated with variants of the oxytocin receptor gene (OXTR). Therefore, we tested for associations between mind-reading, a measure for social recognition and OXTR polymorphisms. Methods: 76 healthy adolescents and young adults were tested for associations between OXTR rs53576, rs2254298, rs2228485 and mind-reading using the 'Reading the Mind in the Eyes Test' (RMET). Results: After Bonferroni correction for multiple comparisons, rs2228485 was associated with the number of incorrect answers when subjects evaluated male faces ( P =0.000639). There were also associations between OXTR rs53576, rs2254298 and rs2228485 and other RMET dimensions according to P <0.05 (uncorrected). Conclusion: This study adds further evidence to the hypothesis that genetic variations in the OXTR modulate mind-reading and social behaviour. [ABSTRACT FROM AUTHOR]

Background Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient's prognosis. Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM. Methods Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples. Results Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM. Conclusions In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival. [ABSTRACT FROM AUTHOR]

Background: Associations between thyroid function and hepatic steatosis defined by enzymatic and sonographic criteria are largely unknown in the general population. Thus, the aim of the present study was to investigate the association between thyroid function tests and sonographic as well as enzymatic criteria of liver status in a large population-based study, the Study of Health in Germany (SHIP). Methods: Data from 3661 SHIP participants without a self-reported history of thyroid or liver disease were analyzed. Hepatic steatosis was defined as the presence of a hyperechogenic ultrasound pattern of the liver and increased serum alanine transferase concentrations. Serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) concentrations were associated with hepatic steatosis using multinomial regression models adjusted for sex, age, physical activity, alcohol consumption, waist circumference, and food intake pattern. Results: We detected no consistent association of serum TSH and FT3 concentrations with hepatic steatosis. In contrast, serum FT4 concentrations were inversely associated with hepatic steatosis in men (odds ratio (OR)=0.04 [95% confidence interval (CI)=0.01; 0.17]) and women (OR=0.06 [95% CI=0.01; 0.42]). Conclusions: Results from the present cross-sectional study suggest that low FT4 concentrations are associated with hepatic steatosis. Longitudinal and intervention studies are warranted to investigate whether hypothyroidism increases the risk of hepatic steatosis or vice versa. [ABSTRACT FROM AUTHOR]

Background.- An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated. Objective.- To investigate this association among Caucasians. Methods.- Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value <.004 as significant. Results.- Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03). Conclusions.- Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies. [ABSTRACT FROM AUTHOR]

( Headache 2011;51:201-207) An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene ( MTHFR) and cluster headache is plausible, but has not been investigated. To investigate this association among Caucasians. Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value <.004 as significant. Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03). Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies. [ABSTRACT FROM AUTHOR]

1. Preconditioning has been proposed to protect the myocardium by inhibiting glycogen-synthase kinase (GSK) 3β. The aim of the present study was to test whether transfection of ventricular myocytes with inactive GSK3β would mimic preconditioning and whether a constitutively active form of GSK3β would prevent protection by an opioid receptor agonist. 2. Isolated ventricular myocytes from adult rats were infected with live adenovirus containing either a wild-type (wtGSK), constitutively active (caGSK) or dominant-negative (dnGSK) GSK3β plasmid. Cells were loaded with tetramethylrhodamine ethyl ester (TMRE) and exposed to H2O2 (100 μmol/L) for 40 min before mitochondrial membrane potential (ΔΨm) was assessed using flow cytometric analysis. 3. Fluorescence intensity was reduced in H2O2-treated cells compared with untreated cells, presumably because oxidant injury opened mitochondrial permeability transition pores, causing mitochondria to lose TMRE. The selective GSK3β inhibitor SB216763, as well as the δ-opioid receptor agonist [d-Ala2-d-Leu5]-enkephalin (DADLE) (1 μmol/L), protected cells against peroxide-induced loss of ΔΨm. 4. Cells transfected with dnGSK (1 μmol/L) were equally protected against peroxide stress, when given throughout the TMRE and H2O2 treatment, confirming a protective effect of GSK3β with a highly selective inhibition. Cells transfected with wtGSK did not show any difference in responses to H2O2, SB216763 or DADLE compared with untransfected cells, suggesting that adenovirus infection itself had no effect. In contrast, caGSK-transfected myocytes could no longer be protected with DADLE, suggesting a role for GSK3β between the surface receptor and the mitochondria. 5. These experiments confirm that inhibition of GSK3β protects the myocytes, but also that the preconditioning mimetic DADLE loses its protective effect when a constitutively active GSK3β is present. [ABSTRACT FROM AUTHOR]

Ebner A, Thyrian JR, Lange A, Lingnau M-L, Scheler-Hofmann M, Rosskopf D, Zygmunt M, Haas J-P, Hoffmann W, Fusch C. Survey of Neonates in Pomerania (SNiP): a population-based birth study – objectives, design and population coverage. Paediatric and Perinatal Epidemiology 2010; 24: 190–199. Neonatal health is of major concern to parents, midwives, physicians and society as a whole, yet a prospective population-based birth cohort to collect comprehensive data on multiple issues including medical, social, environmental and genetic aspects remains to be established in Germany. The survey of newborns in Pomerania (SNiP) described in this paper attempts to take up this goal. The objectives of SNiP are to establish (a) a population-based birth cohort providing detailed information about neonatal health, morbidity and mortality, (b) a biobank with newborn DNA and serum from cord blood, placenta tissue samples and DNA obtained from oral mucosal swabs of the mothers, (c) a prospective study design by re-examination of the SNiP population prior to attendance at primary school. From March 2003 until November 2008 all childbearing mothers in a well-defined region in North-Eastern Germany were asked to participate with their newborns. Detailed data on health status of the newborn, pregnancy, medical and family history, socio-economic status and maternal life style were obtained via face-to-face interview, standardised questionnaires and medical records. Placental tissue samples, cord blood plasma and DNA were continuously collected; sampling of maternal DNA from mouth swabs started in 2007. As a result, during the study period n = 6747 births and n = 6828 babies were enrolled. A population coverage of 95% was achieved. The active participation rate was 75%. A non-responder analysis revealed no meaningful selection bias. Thus, SNiP is a population-based, representative study in Germany that is able to describe the health and living conditions of newborns and their families comprehensively. It can contribute to existing knowledge and to similar cohort studies since data are accessible by researchers. [ABSTRACT FROM AUTHOR]

Macrolide antibiotics penetrate in the lung against steep concentration gradients into the epithelial lining fluid (ELF) and broncho-alveolar cells (BAC). Since they interact with ABCB1, ABCC2, and organic anion transporting proteins (OATPs), which are localized to lung tissue, pulmonary concentration may be influenced by rifampicin (RIF), an inducer and modulator of efflux and uptake transporters. We measured concentrations of tulathromycin (TM) in plasma, ELF and BAC in 21 warm-blooded foals 24 and 192 h after first and last intramuscular injection of 2.5 mg/kg TM once weekly for 6 weeks. In 11 foals, TM was combined with RIF (10 mg/kg twice daily), and mRNA expression of ABCB1 and ABCC2 in BAC was assessed before and after RIF. Affinity of TM to ABCB1 and ABCC2 was measured by transport assays using cell monolayers and membrane vesicles of MDCKII and 2008 cells transfected with ABCB1 and ABCC2, respectively. At steady state, TM concentrated manifold in ELF and BAC. Comedication of RIF significantly decreased the AUC of TM (18.5 ± 4.0 versus 24.4 ± 3.7 µg × h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 ± 0.05 versus 0.24 ± 0.05 µg/ml; 192 h, 0.05 ± 0.01 versus 0.06 ± 0.01 µg/ml) and BAC (24 h, 0.84 ± 0.36 versus 1.56 ± 1.02 µg/ml; 192 h, 0.60 ± 0.23 versus 1.23 ± 0.90 µg/ml, all p < 0.05). Treatment with rifampicin did not markedly induce ABCB1 and ABCC2 expression. TM had no affinity to ABCB1 and ABCC2 in vitro. Concentration of TM in the lung of foals was significantly lowered by comedication of rifampicin most likely caused by extrapulmonary mechanisms leading to lower plasma concentrations. [ABSTRACT FROM AUTHOR]

Obesity and metabolic syndrome are associated with low serum testosterone levels. Hepatic steatosis contributes to the metabolic syndrome and might be regarded as its hepatic manifestation. In this study, we sought to investigate the relationship between hepatic steatosis, serum testosterone and dehydroepiandrosterone sulphate (DHEAS) levels in men. This is a cross-sectional population-based study. We used data of 1912 men recruited for the population-based Study of Health in Pomerania, which was conducted in a region with high prevalence of metabolic syndrome and related diseases. Hepatic steatosis was defined according to sonographic criteria. The relationship of hepatic steatosis with serum testosterone and DHEAS levels was analysed by multivariable logistic regression. Men with low serum testosterone levels had a higher risk of hepatic steatosis than men with high serum testosterone levels. Adjustment for age and further confounders attenuated this association, but did not affect statistical significance (odds ratio 2.36; 95% confidence interval 1.66–3.37; p < 0.05). In the full model, the highest risk of hepatic steatosis was found in subjects with the highest serum DHEAS levels (odds ratio 1.59; 95% confidence interval 1.04–2.43; p < 0.05). Exclusion of men with high alcohol consumption did not affect these results substantially. Hepatic steatosis is associated with low serum testosterone and high serum DHEAS levels. These associations are independent of alcohol consumption. [ABSTRACT FROM AUTHOR]

Objective: The aim of this analysis was to assess the prospective association of serum testosterone and dehydroepiandrosterone sulfate (DHEAS) levels with incident metabolic syndrome (MetS) in men.Research Design and Methods: Data were obtained from the Study of Health in Pomerania (SHIP), a population-based prospective cohort of adults aged 20-79 years. Analyses were conducted in 1,004 men without baseline MetS defined by National Cholesterol Education Program Adult Treatment Panel III guidelines. Testosterone and DHEAS were categorized by age-specific quartiles and Poisson regression models with relative risks (RRs) and 95% CIs were estimated.Results: After a median follow-up time of 5.0 years, 480 men (47.8%) developed MetS. Testosterone levels decreased with increasing number of MetS components. Testosterone in the lowest quartile predicted MetS (RR 1.38 [95% CI 1.13-1.69]), particularly among men aged 20-39 years (2.06 [1.29-3.29]), even after adjustment for age, smoking, alcohol consumption, physical activity, waist circumference, self-related health, and time of blood sampling. DHEAS levels were not related to incident MetS (0.99 [0.83-1.19]).Conclusions: Low testosterone but not DHEAS predicts development of MetS in a population-based cohort of 1,004 men aged 20-79 years. Especially in young men aged 20-39 years, results suggest low testosterone as a strong predictor for incident MetS. Assessment of testosterone in young and middle-age men may allow early interventions in the general population. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The aim of this analysis was to assess the prospective association of serum testosterone and dehydroepiandrosterone sulfate (DHEAS) levels with incident metabolic syndrome (MetS) in men. RESEARCH DESIGN AND METHODS--Data were obtained from the Study of Health in Pomerania (SHIP), a population-based prospective cohort of adults aged 20-79 years. Analyses were conducted in 1,004 men without baseline MetS defined by National Cholesterol Education Program Adult Treatment Panel III guidelines. Testosterone and DHEAS were categorized by age-specific quartiles and Poisson regression models with relative risks (RRs) and 95% CIs were estimated. RESULTS--After a median follow-up time of 5.0 years, 480 men (47.8%) developed MetS. Testosterone levels decreased with increasing number of MetS components. Testosterone in the lowest quartile predicted MetS (RR 1.38 [95% CI 1.13-1.69]), particularly among men aged 20-39 years (2.06 [1.29-3.29]), even after adjustment for age, smoking, alcohol consumption, physical activity, waist circumference, self-related health, and time of blood sampling. DHEAS levels were not related to incident MetS (0.99 [0.83-1.19]). CONCLUSIONS--Low testosterone but not DHEAS predicts development of MetS in a population-based cohort of 1,004 men aged 20-79 years. Especially in young men aged 20-39 years, results suggest low testosterone as a strong predictor for incident MetS. Assessment of testosterone in young and middle-age men' may allow early interventions in the general population. Diabetes 58:2027-2031, 2009 [ABSTRACT FROM AUTHOR]

To explore the pharmacogenomics of warfarin using the extreme-discordant-phenotype (EDP) methodology. The target phenotype was the stable warfarin dose prescribed to 353 patients. Pharmacogenetic polymorphisms assessed were coagulation factor VII ( FVII) -401G>T and FVII -402G>A, VKORC1 3673G>A, and CYP2C9*2, *3, *5, and *11 alleles. The EDP analyses contrasted the frequencies of these polymorphisms at different cutoff points (5th through 30th percentiles of the warfarin dose distribution) at opposite ends of the warfarin dose distribution. Significant differences existed in FVII -402G>A genotype frequency at the 5th percentile with an over-representation of the wildtype GG genotype at low warfarin doses and in VKORC1 3673G>A and CYP2C9 polymorphisms at all cutoff points where the variant alleles were overrepresented at low warfarin doses. The EDP methodology provides increased statistical power for detection of small contributions of genetic polymorphisms to multiplex drug-response phenotypes, such as warfarin dose requirement for adequate anticoagulation. [ABSTRACT FROM AUTHOR]

Objective: There has been debate whether polymorphisms within the serotonin transporter-linked polymorphic region (5-HTTLPR) moderate susceptibility to post- traumatic stress disorder (PTSD). The authors investigated 5-HTTLPR genotypes and their interaction with the number of traumatic events in the prediction of PTSD in a general population sample. Method: Analyses were based on data from 3,045 subjects who participated in the Study of Health in Pomerania. All participants were assessed with the PTSD module of the Structured Clinical Interview for DSM-IV. The short (5)/long (L) polymorphism of 5-HTTLPR (rs4795541) and the A-G polymorphism (rs25531) were genotyped. Results: Among the participants, 1,663 had been exposed to at least one traumatic event, and 67 (4.0%) developed PTSD. Among those who had experienced less than three traumatic events, the life-time prevalence of PTSD was 26%, 35%, and 4.3% for those with zero, one, and two LA alleles, respectively, but the life- time prevalence was 0%, 7.3%, and 19.6%, respectively, among those with three or more traumatic experiences. This finding suggests that there is an additive excess risk for frequent trauma in the LA/LA genotype, which was confirmed by the relative excess risk due to interaction (RERI). In allelic analysis, RERI was 33. Thus, the odds ratio for PTSD in LA allele carriers exposed to three or more traumas was 3.3 times higher as a result of the interaction between PTSD and the LA allele. Conclusions: An additive gene-environment interaction with the high expression LA allele of 5-HTTLPR and frequent trauma in PTSD was found. The attributable proportion indicated that more than 60% of all LA allele carriers who were exposed to three or more traumas developed PTSD as a result of an interaction between genotype and exposure. [ABSTRACT FROM AUTHOR]

Background: Gastric inhibitory polypeptide (GIP) is postulated to be involved in type 2 diabetes mellitus and obesity. It exerts its function through its receptor, GIPR. We genotyped three GIPR SNPs (rs8111428, rs2302382 and rs1800437) in German families with at least one obese index patient, two case-control studies and two cross-sectional population-based studies. Methods: Genotyping was performed by MALDI-TOF, ARMS-PCR and RFLP. The family-study: 761 German families with at least one extremely obese child or adolescent (n = 1,041) and both parents (n = 1,522). Case-control study: (a) German obese children (n = 333) and (b) obese adults (n = 987) in comparison to 588 adult lean controls. The two cross-sectional population-based studies: KORA (n = 8,269) and SHIP (n = 4,310). Results: We detected over-transmission of the A-allele of rs2302382 in the German families (pTDT-Test = 0.0089). In the combined case-control sample, we estimated an odd ratio of 1.54 (95%CI 1.09;2.19, pCA-Test = 0.014) for homozygotes of the rs2302382 A-allele compared to individuals with no A-allele. A similar trend was found in KORA where the rs2302382 A-allele led to an increase of 0.12 BMI units (p = 0.136). In SHIP, however, the A-allele of rs2302382 was estimated to contribute an average decrease of 0.27 BMI units (p-value = 0.031). Conclusion: Our data suggest a potential relevance of GIPR variants for obesity. However, additional studies are warranted in light of the conflicting results obtained in one of the two population-based studies. [ABSTRACT FROM AUTHOR]

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: −0.23 to −0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 × 10−8 to 1.0 × 10−32. Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women. [ABSTRACT FROM AUTHOR]

The activity state of cofilin, which controls actin dynamics, is driven by a phosphorylation–dephosphorylation cycle. Phosphorylation of cofilin by LIM-kinases results in its inactivation, a process supported by 14-3-3ζ and reversed by dephosphorylation by slingshot phosphatases. Here we report on a novel cellular function for the phosphorylation–dephosphorylation cycle of cofilin. We demonstrate that muscarinic receptor-mediated stimulation of phospholipase D1 (PLD1) is controlled by LIM-kinase, slingshot phosphatase as well as 14-3-3ζ, and requires phosphorylatable cofilin. Cofilin directly and specifically interacts with PLD1 and upon phosphorylation by LIM-kinase1, stimulates PLD1 activity, an effect mimicked by phosphorylation-mimic cofilin mutants. The interaction of cofilin with PLD1 is under receptor control and encompasses a PLD1-specific fragment (aa 585–712). Expression of this fragment suppresses receptor-induced cofilin–PLD1 interaction as well as PLD stimulation and actin stress fiber formation. These data indicate that till now designated inactive phospho-cofilin exhibits an active cellular function, and suggest that phospho-cofilin by its stimulatory effect on PLD1 may control a large variety of cellular functions. [ABSTRACT FROM AUTHOR]

Background.—The hypocretin receptor 2 ( HCRTR2) G1246A polymorphism has been associated with the risk for cluster headache. Since the hypothalamic hypocretin/orexin system projects throughout the nervous system and affects multiple vegetative functions including generation of rhythmicity, vasomotion, autonomic symptoms as well as modulation of nociception, it may also be linked with migraine. Objective.—We thus sought to evaluate whether the HCRTR2 G1246A polymorphism is associated with the risk for migraine. Methods.—We prospectively established a cohort of 146 unrelated patients with migraine. The control group consisted of 279 healthy volunteers. We genotyped patients and controls for the HCRTR2 G1246A polymorphism and examined an association with presence or absence of migraine. Results.—Genotype and allele frequencies were not significantly different between migraine patients and controls (genotype distribution: χ2= 4.13, 2 df, P= .13; allele distribution: χ2= 0.9, 1 df, P= .34). Conclusion.—Our study does not support a major contribution of the HCRTR2 G1246A polymorphism to the pathogenesis of migraine in contrast to its effects in cluster headache. [ABSTRACT FROM AUTHOR]

Background: Genetic susceptibility contributes to the aetiology of gallbladder diseases as shown by multiple epidemiological studies. A major gallstone susceptibility locus ( Lith6) was identified in 2003 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in apolipoprotein B mRNA-editing protein ( APOBEC1) and peroxisome proliferator-activated receptor γ ( PPARG) are located in this interval. Aims: To investigate APOBEC1 and PPARG as candidate genes for common symptomatic gallstone disease in humans. Patients and methods: Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset 50) were compared with 718 sex-matched control individuals. An independent additional sample included 368 gallstone patients and 368 controls. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms were genotyped for PPARG ( N=32) and APOBEC1 ( N=11). Results: The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.45. No evidence of association of the two genes in the single-point tagging markers, coding variants and in the sliding window haplotype analysis was detected (all nominal single point P-values >0.04). A logistic regression analysis including age, sex and BMI as covariates was also negative (nominal P-values ≥0.08). Conclusions: In the investigated German samples, no evidence of association of APOBEC1 and PPARG with gallstone susceptibility was detected. Systematic fine mapping of the complete Lith6 region is required to identify the causative genetic variants for gallstone in mice and humans. [ABSTRACT FROM AUTHOR]

With an overall prevalence of 10–20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value PCCA = 4.1 × 10−9), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 × 10−7) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8–2.6, P = 1.4 × 10−14) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile. [ABSTRACT FROM AUTHOR]

Background: Both reduced postsynaptic dopamine D2 receptor function and the character variable self-directedness (SDD) are related to the level of alcohol consumption. We examined for interactions between DRD2 exon 8(rs6276), a polymorphism which has been associated with various alcohol-related phenotypes, SDD and alcohol consumption. Methods:A total of 144 male and 186 female probands with alcohol dependence or abuse diagnoses and without were included in the study. All subjects were assessed with the alcohol section of the Semi-Structured Assessment for the Genetics of Alcoholism and the Temperament and Character Inventory. Results: Male probands with A/A genotype reported significantly higher alcohol consumption in a typical week (ANOVA; p = 0.024); those with A/A genotype and low SDD showed particularly high consumption levels (interaction DRD2 × SDD: p = 0.019). Alcohol dependence/abuse (DSM-IV) but not nicotine dependence was also relevant for higher alcohol consumption (trend: p = 0.052). In the female group, only alcohol disorders predicted alcohol consumption. Conclusions:Our findings support a role for a gene-personality interaction of DRD2 exon 8 × SDD in alcohol consumption in males. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background.—Oxygen and triptans are drugs of first choice to abort cluster headache attacks. However, clinical predictors of treatment response are unavailable. Objective.—We aimed to identify predictors of acute treatment response among patients with cluster headache. Methods.—We investigated 246 cluster headache patients with available information on personal, headache, and lifestyle characteristics as well as effectiveness of acute medication use. We used logistic regression models to identify potential predictors of triptan and oxygen response. Results.—Triptans were effective in 137 of the 191 users and oxygen in 134 of the 175 users. We only identified increasing age (OR 0.96, 95% CI 0.93–0.99; P= .013) as a negative predictor for triptan response, while nausea/vomiting (OR 0.41, 95% CI 0.18–0.91; P= .029) and restlessness (OR 0.09, 95% CI 0.01–0.66; P= .019) were negative predictors of oxygen response. Conclusions.—Few clinical features seem to predict treatment nonresponse in cluster headache. More refined studies aiming at physiological and genetic characteristics seem promising in the future. [ABSTRACT FROM AUTHOR]

Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na+ have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the renin–angiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs. [ABSTRACT FROM AUTHOR]

Background and Aims: The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs).Methods: The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection.Results: After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0 ± 4.20 ng/mL versus 4.67 ± 2.72 ng/mL, P = .017, and 282 ± 73.8 ng/mL versus 107 ± 35.3 ng/mL, P = .012, respectively). The area under the curve of ezetimibe was not affected (102 ± 37.6 ng · h/mL versus 140 ± 86.3 ng · h/mL, P = not significant), whereas that of the glucuronide was markedly increased (2150 ± 687 ng · h/mL versus 1030 ± 373 ng · h/mL, P = .012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6 ± 2.2 mg versus 10.4 ± 1.8 mg, P = .036), whereas renal excretion of the glucuronide was strongly elevated (4.8 ± 1.9 mg versus 2.0 ± 1.2 mg, P = .049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration.Conclusions: Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2.Clinical Pharmacology & Therapeutics (2006) 80, 477–485; doi: 10.1016/j.clpt.2006.07.006 [ABSTRACT FROM AUTHOR]

Background.—Cluster headache (CH) is a rare but severe headache form with a distinct clinical presentation. Misdiagnoses and mismanagement among these patients are high. Objective.—To characterize clinical features and medical treatment in patients with CH. Methods.—We established a cohort of 246 clinic-based and non-clinic-based CH patients. The diagnosis of CH was verified according to International Headache Society (IHS) criteria. We used standardized questionnaires to assess associated factors as well as success or failure of treatments. Results.—The majority (75.6%) was not treated before at our clinic—77.6% were males; 74.8% had episodic CH, 16.7% had chronic CH, in the remaining patients, the periodicity was undetermined because they were newly diagnosed. Cranial autonomic features were present in 98.8%, nausea and vomiting in 27.8%, and photophobia or phonophobia in 61.2% of CH patients. Most (67.9%) reported restlessness during attacks and 23% a typical migrainous aura preceding the attacks. The rate of current smoking was high (65.9%). Half of the patients reported that alcohol (red wine in 70%) triggered CH attacks. Eighty-seven percent reported the use of drugs of first choice (triptans 77.6%, oxygen 71.1%) with sumatriptan subcutaneous injection being the most effective drug for acute therapy (81.2%). The most frequently used preventive medications were verapamil (70.3%) and glucocorticoids (57.7%) with equally high effectiveness. Conclusions.—Apart from the IHS criteria additional features like nausea/vomiting and migrainous aura may guide the diagnosis of CH. A large number of CH patients do not receive adequate treatments. [ABSTRACT FROM AUTHOR]

Receptor tyrosine kinase regulation of phospholipase C-ε (PLC-ε), which is under the control of Ras-like and Rho GTPases, was studied with HEK-293 cells endogenously expressing PLC-coupled epidermal growth factor (EGF) receptors. PLC and Ca2+ signaling by the EGF receptor, which activated both PLC-γ1 and PLC-ε, was specifically suppressed by inactivation of Ras-related GTPases with clostridial toxins and expression of dominant-negative Rap2B. EGF induced rapid and sustained GTP loading of Rap2B, binding of Rap2B to PLC-ε, and Rap2B-dependent transiocation of PLC-ε to the plasma membrane. GTP loading of Rap2B by EGF was inhibited by chelation of intracellular Ca2+ and expression of lipase-inactive PLC-γ1 but not of PLC-ε. Expression of RasGRP3, a Ca2+/diacylglycerol-regulated guanine nucleotide exchange factor for Ras-like GTPases, but not expression of various other exchange factors enhanced GTP loading of Rap2B and PLC/Ca2+ signaling by the EGF receptor. EGF induced tyrosine phosphorylation of RasGRP3, but not RasGRP1, apparently caused by c-Src; inhibition of c-Src interfered with EGF-induced Rap2B activation and PLC stimulation. Collectively, these data suggest that the EGF receptor triggers activation of Rap2B via PLC-γ1 activation and tyrosine phosphorylation of RasGRP3 by c-Src, finally resulting in stimulation of PLC-ε. [ABSTRACT FROM AUTHOR]

The aim of this study was the characterization of the human Gβ4 subunit of heterotrimeric G proteins. Human Gβ4 is widely expressed. Its gene is located on chromosome 3 with a genomic structure indistinguishable from that of the genes of Gβ1 to Gβ3, but entirely different from Gβ5. In vitro translation co-precipitation analyses revealed that Gβ4 can form stable dimers with Gγ1, Gγ2, Gγ3, Gγ4, Gγ5, Gγ7, Gγ10, Gγ11, Gγ12, and Gγ13, dimers which were also able to stimulate phospholipase β2. [Copyright &y& Elsevier]

The purpose of this study was to determine the role of p42/p44 mitogen-activated protein kinase (MAPK) in α[sub 1]-adrenergically and cholinergically stimulated protein secretion in rat lacrimal gland acinar cells and the pathways used by these agonists to activate MAPK. Acini were isolated by collagenase digestion and incubated with the α[sub 1]-adrenergic agonist phenylephrine or the cholinergic agonist carbachol, and activation of MAPK and protein secretion were then measured. Phenylephrine and carbachol activated MAPK in a time- and concentration-dependent manner. Inhibition of MAPK significantly increased phenylephrine- and carbachol-induced protein secretion. Inhibition of EGF receptor (EGFR) with AG1478, an inhibitor of the EGFR tyrosine kinase activity, significantly increased phenylephrine- but not carbachol-induced protein secretion. Whereas phenylephrine-induced activation of MAPK was completely inhibited by AG1478, activation of MAPK by carbachol was not. Phenylephrine stimulated tyrosine phosphorylation of the EGFR, whereas carbachol stimulated p60[sup Src], and possibly Pyk2, to activate MAPK. We conclude that, in the lacrimal gland, activation of MAPK plays an inhibitory role in α[sub 1]-adrenergically and cholinergically stimulated protein secretion and that these agonists use different signaling mechanisms to activate MAPK. [ABSTRACT FROM AUTHOR]

Hypercarbic respiratory drive is mainly determined by PCO2 and pH with activity of the intracellular Na+/H+ exchanger (NHE) playing an important role in maintaining intracellular pH and respiratory drive. Because NHE activity varies with genetically different G-protein β3 subunits (GNB3) (C/T polymorphism at nucleotide position 825) different genotypes might alter respiratory regulation. To test the hypothesis that short-term ventilatory responses vary with different GNB3 healthy volunteers with different genotypes (CC, TC, TT) were exposed to either hyperoxic hypercarbia (n=33) or to isocapnic hypoxia (n=31), respectively. There was no difference between CC, TC, and TT genotypes in hypercarbic and hypoxic respiratory drive when assessed as the ratio of minute ventilation over endexpiratory PCO2 changes (ΔVE/ΔPETCO2), maximal tolerable PETCO2, and ratio of changes in ventilation over arterial haemoglobin desaturation (ΔVE/ΔSO2), respectively. Thus, short-term hypercarbic and hypoxic ventilatory drive do not differ between individuals with genotypes encoding different GNB3. Whilst respiratory control may still be influenced by G-protein aberration, other mechanisms seem to have a more important role in controlling ventilation. [ABSTRACT FROM AUTHOR]

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On stimulation of platelets with agonists, for example, thrombin, a rapid rise in intracellular pH is observed. This alkalinization is mediated by an increase in transport activity of the Na+/H+ exchanger isoform NHE1. In addition to this Na+/H+ exchange mechanism, platelets express bicarbonate/chloride exchangers, which also contribute to pHi homeostasis. The main functions of NHE1 in platelets include pHi control, volume regulation, and participation in cell signaling. The isoform NHE1 is highly sensitive toward inhibition by EIPA, Hoe694, and Hoe642. The regulation of NHE1 activity is complex and is not completely understood. It includes the MAP kinase cascade, the Ca/calmodulin system, several heterotrimeric G proteins (Gα12, Gα13, Gαq, and Gαi), small G proteins (ras, cdc42, rhoA), and downstream kinases (e.g., p160ROCK). Volume challenges stimulate tyrosine phosphorylation of cytoplasmic proteins, which ultimately activate NHE1. Thrombin, thromboxane, platelet-activating factor, angiotensin II, endothelin, phorbol ester, and Ca2+ ionophors stimulate NHE1 activity in platelets. Blockade of platelet NHE1 can inhibit platelet activation. With the development of highly specific NHE1 inhibitors, detailed investigation of the relationships between NHE1 activity and platelet activation now becomes feasible. [ABSTRACT FROM AUTHOR]

We examined the functional properties of a Na+/H+ exchanger cloned from Xenopus laevis oocytes (XL-NHE) upon stable transfection into PS120 fibroblasts which lack endogenous Na+/H+ exchange. In contrast to untransfected cells, XL-NHE-transfected cells displayed Na+-dependent alkalinization upon acidification with nigericin. XL-NHE activity was inhibited by amiloride, ethylisopropylamiloride, HOE694 [(3-methylsulphonyl-4-piperidinobenzoyl)-guanidine methanesulphonate] and HOE642 [4-isopropyl-3-methylsulphonylbenzoyl)-guanidine methanesulphonate], Ki values being calculated at 5 µmol/l, 25 nmol/l, 300 nmol/l and 180 nmol/l, respectively. The Na+ dependence of pHi recovery was compatible with simple Michaelis–Menten kinetics, the Km for Na+ being 22.0±3.2 mmol/l and the Hill coefficient for Na+ being approximately 1. XL-NHE was activated by phorbol ester, whereas forskolin exerted no effect, suggesting the involvement of phospholipase C/protein kinase C signalling pathways rather than protein kinase A signalling pathways in XL-NHE stimulation. Using reverse transcription polymerase chain reaction, XL-NHE message could be detected in various Xenopus tissues including heart, brain, skeletal muscle, reticulocytes, A6-kidney cells and oocytes. [ABSTRACT FROM AUTHOR]

Objective: The aim was to investigate the effect of ethylisopropylamiloride (EIPA), an inhibitor of Na+/H+ exchange, and of extracellular pH on the proliferation of immortalised lymphoblasts derived from patients with essential hypertension and normotensive controls. Methods: Na+/H+ exchange activity was determined in cells loaded with the fluorescent pH indicator BCECF. Cell proliferation was determined by FACS analysis, by cell counting, and from the incorporation of [3H]-thymidine. Results: EIPA inhibited the Na+/H+ exchanger with an average K1 value of 14 nM in all cell lines. Cell growth and DNA synthesis were only inhibited at EIPA concentrations >10 μM suggesting a non-specific effect independent of Na+/H+ exchanger blockade. When extracellular pH was varied from 7.1 to 7.7 by changing the HCO3− concentration at constant Pco2, cell proliferation was optimal at pH 7.4, but reduced at acidic and alkaline pH in cells from normotensive and hypertensive subjects. The increased proliferation of lymphoblasts from hypertensive subjects persisted over the whole pH range. Comparable results were obtained when pH was altered by varying the Pco2 at constant HCO3−. Preincubation of cells with pertussis toxin inhibited serum stimulated DNA synthesis by 14.5% and 23.5% (P = 0.02) in cell lines from normotensive and hypertensive subjects. Conclusions: The enhanced Na+/H+ exchanger activity in lymphoblasts from patients with essential hypertension is obviously not the major determinant of the enhanced proliferation of these cells. The increased sensitivity of the growth of “hypersensitive” cell lines to pertussis toxin suggests a cellular alteration which resides upstream of Na+/H+ exchange activity and proliferation control. [ABSTRACT FROM PUBLISHER]

Examines the effects of lysophosphatidic acid in human B lymphocyte. Methodology; Physiology lysophosphatidic acid; Details on B lymphocyte cells; Results of the study.

Background: Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient's prognosis. Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.Methods: Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.Results: Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.Conclusions: In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival. [ABSTRACT FROM AUTHOR]