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Selected AbstractsChemo-Enzymatic Synthesis of All Isomers of 2-Methylbutane-1,2,3,4-tetraol , Important Contributors to Atmospheric AerosolsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 8 2007Anders Riise Moen Abstract By a combination of stereospecific osmium catalyzed oxidation of dimethyl citraconate and lipase catalysed enantioselective resolution of the formed dimethyl (2R*,3S*)-2,3-dihydroxy-2-methylbutanedioate, followed by reduction, (2R,3S)- and (2S,3R)-2-methylbutane-1,2,3,4-tetraol were isolated. Similar reactions starting with dimethyl mesaconate gave the isomers, (2R,3R)- and (2S,3S)-2-methylbutane-1,2,3,4-tetraol. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Which comes first: atypical antipsychotic treatment or cardiometabolic risk?ACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2009S. M. Stahl Objective:, To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment. Method:, A MEDLINE search using terms for atypical antipsychotics (including individual drug names), metabolic, cardiovascular, weight gain and insulin resistance, cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. Results:, Strong evidence exists for significant cardiometabolic risk differences among several antipsychotic agents. Histamine H1 and serotonin 5HT2C antagonism are associated with risk of weight gain, but receptor targets for dyslipidemia and insulin resistance have not yet been identified. Convincing data indicate that hypertriglyceridemia and insulin resistance may occur in the absence of weight gain with certain antipsychotics. Conclusion:, Although lifestyle and genetics may contribute independent risks of cardiometabolic dysfunction in schizophrenia and other serious mental illness, antipsychotic treatment also represents an important contributor to risk of cardiometabolic dysfunction, particularly for certain drugs and for vulnerable patients. Mental health professionals must learn to recognize the clinical signposts indicating antipsychotic-related cardiometabolic problems to forestall progression to type II diabetes, cardiovascular events and premature death. [source] All-cause mortality and fatal alcohol poisoning in Belarus, 1970,2005DRUG AND ALCOHOL REVIEW, Issue 5 2008YURY E. RAZVODOVSKY Abstract Introduction and Aims. Although alcohol appears to be an important contributor to the burden of disease in the countries of eastern Europe, little systematic research has been undertaken on its impact on mortality in the former Soviet republic of Belarus. There may be a number of factors underlying the particularly negative effect of alcohol on mortality in Belarus, including the pattern of drinking and use of surrogates. A solid body of research and empirical evidence suggests that hazardous patterns of alcohol consumption (binge drinking) lead to quicker and deeper intoxication, increasing the propensity for alcohol-related mortality. Design and Method. To estimate the aggregate level effect of binge drinking on the all-cause mortality rate, trends in the all-cause mortality and fatal alcohol poisoning rates (as a proxy for binge drinking) in Belarus from 1970 to 2005 were analysed employing AutoRegressive Integrated Moving Average (ARIMA) time,series analysis in order to assess a bivariate relationship between the two time,series. Results. The results of time,series analysis suggest a close relationship between all-cause mortality and fatal alcohol poisoning rates at the population level. Conclusions. This study supports the hypothesis that alcohol and all-cause mortality are connected closely in countries where the drinking culture is characterised by heavy drinking episodes and adds to the growing body of evidence that a substantial proportion of total mortality in Belarus is due to acute effects of binge drinking. [source] Inhibition of prostacyclin by indomethacin ameliorates the splanchnic hyposensitivity to glypressin in haemorrhage-transfused common bile duct-ligated ratsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2001F.-Y. Lee Prostacyclin (PGI2) is an important contributor to the mediation of hyporeactivity to vasoconstrictors and the development of hyperdynamic circulation in portal hypertensive states. Inhibition of PGI2 synthesis in haemorrhage-transfused partially portal vein-ligated rats could ameliorate the splanchnic hyposensitivity to glypressin, a long-acting vasopressin analogue. This study investigated whether the hyposensitivity to glypressin also exists in rats with common bile duct ligation (BDL) and whether the inhibition of PGI2 synthesis by indomethacin could potentiate the portal-hypotensive effect of glypressin in bleeding BDL rats. Two series of BDL rats were used. Series 1 investigated the haemodynamic effects of low dose glypressin (0·07 mg kg,1) in BDL rats with or without bleeding by catheterization. In series 2, haemodynamic parameters were measured in stable or bleeding BDL rats that were receiving intravenously high dose glypressin (0·2 mg kg,1) or indomethacin (5 mg kg,1) followed by high dose glypressin. In rats with a hypotensive haemorrhage, 4·5 mL of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. Splanchnic hyposensitivity to glypressin was demonstrated in haemorrhage-transfused BDL rats receiving high, but not low, doses of glypressin. Indomethacin infusion did not cause significant systemic and portal haemodynamic changes in bleeding BDL rats (P > 0·05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin (P < 0·05) and potentiated the increases in mean arterial pressure induced by glypressin infusion (P < 0·001) in bleeding BDL rats. Splanchnic hyposensitivity to glypressin observed in haemorrhage-transfused BDL rats could be ameliorated by the addition of indomethacin, suggesting a role of endogenous PGI2 in its pathophysiology. [source] Association of serum sialic acid and MMP-9 with lipids and inflammatory markersEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2000Kalela Background Inflammation of the arterial wall has emerged to be an important contributor to the process of atherosclerosis, the major cause of coronary heart disease. Several factors are currently under investigation as inflammatory markers of atherosclerosis. Serum sialic acid and matrix metalloproteinase-9 may provide such markers. We studied their association with the lipid profile and with the inflammatory markers C-reactive protein and leukocyte count in a clinically healthy population of men. Materials and methods Cardiovascular risk-related laboratory tests were carried out in 65 consecutive male employees in connection with an occupational health survey in 1996. The subjects were divided into tertiles on the basis of serum sialic acid or matrix metalloproteinase-9 concentration. Results In a stepwise polychotomous logistic regression model adjusting for coronary heart disease risk factors, serum sialic acid concentration was not associated with markers of inflammation but rather with the lipid risk factors of atherosclerosis: inversely with HDL cholesterol (OR = 0.081, 95% CI 0.0068,0.97) and positively with total cholesterol (OR = 2.4, 95% CI 1,5.6). Matrix metalloproteinase-9 levels had a significant positive correlation with the leukocyte count (OR = 2.3, 95% CI 1.4,4). Conclusions Serum sialic acid does not appear to be an indicator of inflammation but is somehow connected with the level of total and HDL cholesterol. Serum matrix metalloproteinase-9 may provide a useful marker of inflammation because it correlates with the leukocyte count and is not associated with the lipid profile. [source] Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosisEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2001V. R. Preedy Alcohol misusers frequently have difficulties in gait, and various muscle symptoms such as cramps, local pain and reduced muscle mass. These symptoms are common in alcoholic patients and have previously been ascribed as neuropathological in origin. However, biochemical lesions and/or the presence of a defined myopathy occur in alcoholics as a direct consequence of alcohol misuse. The myopathy occurs independently of peripheral neuropathy, malnutrition and overt liver disease. Chronic alcoholic myopathy is characterized by selective atrophy of Type II fibres and the entire muscle mass may be reduced by up to 30%. This myopathy is arguably the most prevalent skeletal muscle disorder in the Western Hemisphere and occurs in approximately 50% of alcohol misusers. Alcohol and acetaldehyde are potent inhibitors of muscle protein synthesis, and both contractile and non-contractile proteins are affected by acute and chronic alcohol dosage. Muscle RNA is also reduced by mechanisms involving increased RNase activities. In general, muscle protease activities are either reduced or unaltered, although markers of muscle membrane damage are increased which may be related to injury by reactive oxygen species. This supposition is supported by the observation that in the UK, , -tocopherol status is poor in myopathic alcoholics. Reduced , -tocopherol may pre-dispose the muscle to metabolic injury. However, experimental , -tocopherol supplementation is ineffective in preventing ethanol-induced lesions in muscle as defined by reduced rates of protein synthesis and in Spanish alcoholics with myopathy, there is no evidence of impaired , -tocopherol status. In conclusion, by a complex series of mechanisms, alcohol adversely affects skeletal muscle. In addition to the mechanical changes to muscle, there are important metabolic consequences, by virtue of the fact that skeletal muscle is 40% of body mass and an important contributor to whole-body protein turnover. [source] Enzymatic deconstruction of xylan for biofuel productionGCB BIOENERGY, Issue 1 2009DYLAN DODD Abstract The combustion of fossil-derived fuels has a significant impact on atmospheric carbon dioxide (CO2) levels and correspondingly is an important contributor to anthropogenic global climate change. Plants have evolved photosynthetic mechanisms in which solar energy is used to fix CO2 into carbohydrates. Thus, combustion of biofuels, derived from plant biomass, can be considered a potentially carbon neutral process. One of the major limitations for efficient conversion of plant biomass to biofuels is the recalcitrant nature of the plant cell wall, which is composed mostly of lignocellulosic materials (lignin, cellulose, and hemicellulose). The heteropolymer xylan represents the most abundant hemicellulosic polysaccharide and is composed primarily of xylose, arabinose, and glucuronic acid. Microbes have evolved a plethora of enzymatic strategies for hydrolyzing xylan into its constituent sugars for subsequent fermentation to biofuels. Therefore, microorganisms are considered an important source of biocatalysts in the emerging biofuel industry. To produce an optimized enzymatic cocktail for xylan deconstruction, it will be valuable to gain insight at the molecular level of the chemical linkages and the mechanisms by which these enzymes recognize their substrates and catalyze their reactions. Recent advances in genomics, proteomics, and structural biology have revolutionized our understanding of the microbial xylanolytic enzymes. This review focuses on current understanding of the molecular basis for substrate specificity and catalysis by enzymes involved in xylan deconstruction. [source] Geographies of Corporate Decision-Making and Control: Development, Applications, and Future Directions in Headquarters Location ResearchGEOGRAPHY COMPASS (ELECTRONIC), Issue 4 2010Murray D. Rice This article surveys the body of investigation related to the location of headquarters and other elite corporate decision-making activities, a research field known as quaternary location studies. The discussion includes four main sections following an introduction. The first reviews the initial development of headquarters location research from the early 20th century to 1980. The second section discusses contemporary developments and criticisms of the field that have diversified the field beyond its early focus on large-firm headquarters alone to examine the geography of all activities related to corporate decision making. We posit that incorporation of rapidly growing firms in quaternary research is a key element of this diversification. The third section examines the possibilities for further headquarters location research by making a connection between decision-making location and the literature of techno-economic paradigms. The article concludes by summarizing the current state of the field, and argues that a continued diversification of research interests and perspectives is vital to the advancement of quaternary location studies as an important contributor to improved corporate strategies and more effective public policy. [source] Assessment of the benefits of user involvement in health research from the Warwick Diabetes Care Research User Group: a qualitative case studyHEALTH EXPECTATIONS, Issue 3 2007Antje Lindenmeyer PhD Abstract Objective, To assess the benefits of involving health-care users in diabetes research. Design and participants, For this qualitative case study, semi-structured interviews were conducted with researchers who had worked extensively with the group. During regular meetings of the Research User Group, members discussed their views of the group's effectiveness as part of the meeting's agenda. Interviews and discussions were transcribed, coded using N-Vivo software and analysed using constant comparative methods. Results, Involvement of users in research was generally seen as contributing to effective and meaningful research. However, the group should not be considered to be representative of the patient population or participants of future trials. An important contributor to the group's success was its longstanding nature, enabling users to gain more insight into research and form constructive working relationships with researchers. The user-led nature of the group asserted itself, especially, in the language used during group meetings. A partial shift of power from researchers to users was generally acknowledged. Users' main contribution was their practical expertise in living with diabetes, but their involvement also helped researchers to remain connected to the ,real world' in which research would be applied. While the group's work fulfilled established principles of consumer involvement in research, important contributions relying on personal interaction between users and researchers were hard to evaluate by process measures alone. Conclusions, We demonstrated the feasibility, acceptability and effectiveness of this longstanding, experienced, lay-led research advisory group. Its impact on research stems from the continuing interaction between researchers and users, and the general ethos of learning from each other in an on-going process. Both process measures and qualitative interviews with stakeholders are needed to evaluate the contributions of service users to health research. [source] Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice,HEPATOLOGY, Issue 5 2009Nora Bijl Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. The hyperinsulinemia that occurs as a consequence of insulin resistance is thought to be an important contributor to the development of fatty liver. We have shown that the iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase, is a potent enhancer of insulin signaling in rodent models for insulin resistance and type 2 diabetes. The present study was designed to assess the impact of AMP-DNM on insulin levels, liver triglyceride synthesis, and gene expression profile. Treatment of ob/ob mice with AMP-DNM restored insulin signaling in the liver, corrected blood glucose values to levels found in lean mice, and decreased insulin concentration. The expression of sterol regulatory element-binding protein 1c target genes involved in fatty acid synthesis normalized. AMP-DNM treatment significantly reduced liver to body weight ratio and reversed hepatic steatosis, comprising fat as well as inflammatory markers. In addition, AMP-DNM treatment corrected to a large extent the gene expression profile of ob/ob mice livers toward the profile of lean mice. Conclusion: Pharmacological lowering of glycosphingolipids with the iminosugar AMP-DNM is a promising approach to restore insulin signaling and improve glucose homeostasis as well as hepatic steatosis. (HEPATOLOGY 2009.) [source] Somatic microindels: analysis in mouse soma and comparison with the human germline,,HUMAN MUTATION, Issue 1 2007Kelly D. Gonzalez Abstract Microindels, defined as mutations that result in a colocalized microinsertion and microdeletion with a net gain or loss of between 1 and 50 nucleotides, may be an important contributor to cancer. We report the first comprehensive analysis of somatic microindels. Our large database of mutations in the lacI transgene of Big Blue® mice contains 0.5% microindels, 2.8% pure microinsertions, and 11.5% pure microdeletions. There appears to be no age, gender, or tissue-type specificity in the frequency of microindels. Of the independent somatic mutations that result in a net in-frame insertion or deletion, microindels are responsible for 13% of protein expansions and 6% of protein contractions. These in-frame microindels may play a crucial role in oncogenesis and evolution via "protein tinkering" (i.e., modest expansion or contraction of proteins). Four characteristics suggest that microindels are caused by unique mechanisms, not just simple combinations of the same mechanisms that cause pure microinsertions and pure microdeletions. First, microinsertions and microdeletions commonly occur at hotspots, but none of the 30 microindels are recurrent. Second, the sizes of the deletions and insertions in microindels are larger and more varied than in pure microdeletions and pure microinsertions. Third, microinsertions overwhelmingly repeat the adjacent base (97%) while the insertions in microindels do so only infrequently (17%). Fourth, analysis of the sequence contexts of microindels is consistent with unique mechanisms including recruitment of translesion DNA synthesis polymerases. The mouse somatic microindels have characteristics similar to those of human germline microindels, consistent with similar causative mechanisms in mouse and human, and in soma and germline. Hum Mutat 28(1), 69,80, 2007. Published 2006 Wiley-Liss, Inc. [source] A population- and family-based study of Canadian families reveals association of HLA DRB1*0103 with colonic involvement in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 1 2003Dr. Mark S. Silverberg Abstract The aim of this study was to identify major histocompatibility complex alleles associated with the development and clinical features of inflammatory bowel disease (IBD). Genotyping at the human leukocyte antigen (HLA) DRB1 and DQB1 loci was performed on individuals from 118 Caucasian IBD sibling pair families and on 216 healthy controls. Both population- and family-based association tests were used to analyze data obtained on the entire study population and on clinical subgroups stratified by diagnosis, ethnicity, and disease distribution. HLA DRB1*0103 was significantly associated with IBD (OR = 6.0, p = 0.0001) in a case,control analysis of non-Jewish IBD-affected individuals. This association was apparent among both Crohn's disease (OR = 5.23, p = 0.0007) and ulcerative colitis (OR = 7.9, p = 0.0001) patients and was confirmed in the non-Jewish IBD population by results of family-based association analysis using the transmission disequilibrium test. HLA DQB1*0501 was also associated with IBD (OR = 1.64, p = 0.02) in the non-Jewish population, but statistically significant association of this allele with disease was not detected for Crohn's disease and ulcerative colitis separately. No significant associations were identified among the Jewish patients. In the non-Jewish IBD families, IBD was as strongly associated with the DRB1*0103 DQB1*0501 haplotype as with the DRB1*0103 allele alone. The carrier frequency of the DRB1*0103 allele was found to be 10-fold higher in Crohn's disease patients with pure colonic involvement than in healthy controls (38.5% vs. 3.2%; p = 0.0002). These data demonstrate the association of the HLA DRB1*0103 allele with both Crohn's disease and ulcerative colitis and with large intestine,restricted disease in non-Jewish IBD patients and therefore identify HLA DRB1*0103 as a potentially important contributor to disease susceptibility and to expression of colonic involvement in IBD. [source] Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quidINTERNATIONAL JOURNAL OF CANCER, Issue 6 2008Chien-Hung Lee Abstract The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case-control study was conducted. Here, 406 patients with pathology-proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low-to-moderate (0.1,30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low-to-moderate drinkers, a smoking-dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk. © 2007 Wiley-Liss, Inc. [source] Effect of variable message signs on driver speed behavior on a section of expressway under adverse fog conditions,A driving simulator approachJOURNAL OF ADVANCED TRANSPORTATION, Issue 1 2006V. Ganesh Babu Kolisetty Abstract Variable message signs (VMS) are used to provide dynamic information and one current application is to show different speed limits under different conditions. As speed is an important contributor to road accidents and also affects driver speed behavior, the present study focuses on how effective traffic advisory information is when helping drivers to divert from potentially dangerous conditions. Graphical representation of an Expressway section made it easy to isolate the effects of speed etc. by drivers with information provided through VMS under adverse fog conditions. Understanding and reacting to the VMS system by drivers is essential for its success. If drivers do not react by changing speed behavior then the VMS system will fail and further implementation may cease. In this paper an Analysis of Variance model, which is appropriate to the proposed experimental conditions, is used to study how subjects (drivers) will perceive provided information and also to find the effect of VMS on driver speed behavior on the simulated Expressway section. [source] The occurrence of Campylobacter in river water and waterfowl within a watershed in southern Ontario, CanadaJOURNAL OF APPLIED MICROBIOLOGY, Issue 3 2010M.I. Van Dyke Abstract Aims:, Quantitative PCR and a culture method were used to investigate Campylobacter occurrence over 3 years in a watershed located in southern Ontario, Canada that is used as a source of drinking water. Methods and Results:, Direct DNA extraction from river water followed by quantitative PCR analysis detected thermophilic campylobacters at low concentrations (<130 cells 100 ml,1) in 57,79% of samples taken from five locations. By comparison, a culture-based method detected Campylobacter in 0,23% of samples. Water quality parameters such as total Escherichia coli were not highly correlated with Campylobacter levels, although higher pathogen concentrations were observed at colder water temperatures (<10°C). Strains isolated from river water were primarily nalidixic acid-susceptible Campylobacter lari, and selected isolates were identified as Campylobacter lari ssp. concheus. Campylobacter from wild birds (seagulls, ducks and geese) were detected at a similar rate using PCR (32%) and culture-based (29%) methods, and although Campylobacter jejuni was isolated most frequently, C. lari ssp. concheus was also detected. Conclusions:,Campylobacter were frequently detected at low concentrations in the watershed. Higher prevalence rates using quantitative PCR was likely because of the formation of viable but nonculturable cells and low recovery of the culture method. In addition to animal and human waste, waterfowl can be an important contributor of Campylobacter in the environment. Significance and Impact of the Study:, Results of this study show that Campylobacter in surface water can be an important vector for human disease transmission and that method selection is important in determining pathogen occurrence in a water environment. [source] Catheter Ablation of Recurrent Scar-Related Ventricular Tachycardia Using Electroanatomical Mapping and Irrigated Ablation Technology: Results of the Prospective Multicenter Euro-VT-StudyJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2010HILDEGARD TANNER M.D. Catheter Ablation of Ventricular Tachycardia.,Introduction: Ventricular tachycardia (VT) late after myocardial infarction is an important contributor to morbidity and mortality. This prospective multicenter study assessed the efficacy and safety of electroanatomical mapping in combination with open-saline irrigated ablation technology for ablation of chronic recurrent mappable and unmappable VT in remote myocardial infarction. Methods and Results: In 8 European institutions, 63 patients (89% males) were enrolled in the study. All patients had remote myocardial infarction and presented with a median number of 17 (range 1,380) VTs in the preceding 6 months. Incessant VT was present in 14 patients (22%). Left ventricular ejection fraction measured 30 ± 13%. A mean of 3 VTs were targeted per patient and 22% of all patients had only unmappable VT. The mean follow-up period was 12 ± 3 months. A total of 164 VTs were targeted during catheter ablation. Ablation was acutely successful in 51 patients (81%). One patient (1.5%) experienced a major complication with degeneration of VT into ventricular fibrillation necessitating cardiopulmonary resuscitation maneuvers. However, no death occurred acutely or within the first 30 days after catheter ablation. During the follow-up, 19 of the initially successful ablated patients (37%) and 31 of all ablated patients (49%) developed some type of VT recurrence. Conclusions: The results of this multicenter study demonstrate the high acute success rate and a low complication rate of irrigated tip catheter ablation of all clinical relevant VTs in remote myocardial infarction. However, during the follow-up a relevant number of recurrences occurred. (J Cardiovasc Electrophysiol, Vol. 21, pp. 47,53, January 2010) [source] Impulse conduction and gap junctional remodelling by endothelin-1 in cultured neonatal rat ventricular myocytesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009Y. Reisner Abstract Endothelin-1 (ET-1) is an important contributor to ventricular hypertrophy and failure, which are associated with arrhythmogenesis and sudden death. To elucidate the mechanism(s) underlying the arrhythmogenic effects of ET-1 we tested the hypothesis that long-term (24 hrs) exposure to ET-1 impairs impulse conduction in cultures of neonatal rat ventricular myocytes (NRVM). NRVM were seeded on micro-electrode-arrays (MEAs, Multi Channel Systems, Reutlingen, Germany) and exposed to 50 nM ET-1 for 24 hrs. Hypertrophy was assessed by morphological and molecular methods. Consecutive recordings of paced activation times from the same cultures were conducted at baseline and after 3, 6 and 24 hrs, and activation maps for each time period constructed. Gap junctional Cx43 expression was assessed using Western blot and confocal microscopy of immunofluorescence staining using anti-Cx43 antibodies. ET-1 caused hypertrophy as indicated by a 70% increase in mRNA for atrial natriuretic peptide (P < 0.05), and increased cell areas (P < 0.05) compared to control. ET-1 also caused a time-dependent decrease in conduction velocity that was evident after 3 hrs of exposure to ET-1, and was augmented at 24 hrs, compared to controls (P < 0.01). ET-1 increased total Cx43 protein by ,40% (P < 0.05) without affecting non- phosphorylated Cx43 (NP-Cx43) protein expression. Quantitative confocal microscopy showed a ,30% decrease in the Cx43 immunofluorescence per field in the ET-1 group (P < 0.05) and a reduced field stain intensity (P < 0.05), compared to controls. ET-1-induced hypertrophy was accompanied by reduction in conduction velocity and gap junctional remodelling. The reduction in conduction velocity may play a role in ET-1 induced susceptibility to arrhythmogenesis. [source] Different cellular localization, translocation, and insulin-induced phosphorylation of PKB, in HepG2 cells and hepatocytesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2002Noor Afshan Syed Abstract Protein kinase B (PKB), a serine/threonine protein kinase, prevents apoptosis and promotes cellular transformation. PKB activity is stimulated by insulin. In this report, we examined the relative amounts of expression, location, and translocation upon insulin stimulation of PKB, in normal primary hepatocytes and carcinoma cells, HepG2 cells. Non-phosphorylated PKB, was present in both types of unstimulated cells. The phosphorylated form of the enzyme was present in the nucleus of unstimulated HepG2 cells but not in normal hepatocytes. In the cytoplasm, PKB, was found in greater abundance in the hepatocytes as compared in HepG2 cells. Insulin induced the translocation of phosphorylated PKB, from the nucleus to the nuclear membrane in HepG2 cells. In contrast, insulin caused translocation and phosphorylation of PKB, from the cytosol to the plasma membrane in normal hepatocytes. In addition, there is a higher expression of PKB, in the HepG2 cells as compared to normal primary hepatocytes. These findings provide an important distinction between hepatocellular HepG2 cells and normal liver cells and suggest that the presence of constitutively active nuclear PKB in the transformed cells might be an important contributor in cell transformation and immortality of hepatoma cells. J. Cell. Biochem. 86: 118,127, 2002. © 2002 Wiley-Liss, Inc. [source] Grassland diversity related to the Late Iron Age human population densityJOURNAL OF ECOLOGY, Issue 3 2007MEELIS PÄRTEL Summary 1Species-rich semi-natural grasslands in Europe developed during prehistoric times and have endured due to human activity. At the same time, intensive grassland management or changes in land use may result in species extinction. As a consequence, plant diversity in semi-natural calcareous grasslands may be related to both historical and current human population density. 2We hypothesize that current vascular plant diversity in semi-natural calcareous grasslands is positively correlated with the Late Iron Age (c. 800,1000 years ago) density of human settlements (indicated by Late Iron Age fortresses and villages) due to enhancement of grassland extent and species dispersal, and negatively correlated with current human population density due to habitat loss and deterioration. 3We described the size of the community vascular plant species pool, species richness per 1 m2 and the relative richness (richness divided by the size of the species pool) in 45 thin soil, calcareous (alvar) grasslands in Estonia. In addition to historical and current human population density we considered simultaneously the effects of grassland area, connectivity to other alvar grasslands, elevation above sea level (indicating grassland age), soil pH, soil N, soil P, soil depth, soil depth heterogeneity, geographical east,west gradient, precipitation and spatial autocorrelation. 4Both the size of the community species pool and the species richness are significantly correlated with the Late Iron Age human population density. In addition, species richness was unimodally related to the current human population density. The relative richness (species ,packing density') was highest in the intermediate current human population densities, indicative of moderate land-use intensity. 5Community species pool size decreased non-linearly with increasing soil N, and was highest at intermediate elevation. Small-scale richness was greater when sites were well connected and when the elevation was intermediate. Spatial autocorrelation was also significant for both species pool size and small-scale richness. 6In summary, human land-use legacy from prehistoric times is an important aspect in plant ecology, which could be an important contributor to the current variation in biodiversity. [source] Productivity and economic growth in Kenyan agriculture, 1964,1996AGRICULTURAL ECONOMICS, Issue 1 2002Anders Gerdin Abstract This paper analyses the patterns of productivity and economic growth in the aggregated Kenyan agriculture between 1964 and 1996. In the 1964,1973 period, the average output growth exceeded 4% but stagnated to an average of 1.2% during 1988,1996. Over the whole period, capital was the most important contributor to output growth. Mean growth rates of intermediate inputs subsequently decreased and were negative in 1988,1996. Labour was the least significant source of growth. The mean total factor productivity growth was less than 0.4% and decreased over time. The contribution of productivity growth to output growth increased from 10.2% in 1964,1973 to 26.8% in 1988,1996. [source] Neuronal coupling via connexin36 contributes to spontaneous synaptic currents of striatal medium-sized spiny neuronsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2008Damian M. Cummings Abstract Gap junctions provide a means for electrotonic coupling between neurons, allowing for the generation of synchronous activity, an important contributor to learning and memory. Connexin36 (Cx36) is largely neuron specific and provides a target for genetic manipulation to determine the physiological relevance of neuronal coupling. Within the striatum, Cx36 is more specifically localized to the interneuronal population, which provides the main inhibitory input to the principal projection medium-sized spiny neurons. In the present study, we examined the impact of genetic ablation of Cx36 on striatal spontaneous synaptic activity. Patch-clamp recordings were performed from medium-sized spiny neurons, the primary target of interneurons. In Cx36 knockout mice, the frequencies of both excitatory and inhibitory spontaneous postsynaptic currents were reduced. We also showed that activation of dopamine receptors differentially modulated the frequency of GABAergic currents in Cx36 knockout mice compared with their wild-type littermates, suggesting that dopamine plays a role in altering the coupling of interneurons. Taken together, the present findings demonstrate that electrical coupling of neuronal populations is important for the maintenance of normal chemical synaptic interactions within the striatum. © 2008 Wiley-Liss, Inc. [source] The proximal hip joint capsule and the zona orbicularis contribute to hip joint stability in distractionJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2009Hiroshi Ito Abstract The structure and function of the proximal hip joint capsule and the zona orbicularis are poorly understood. We hypothesized that the zona orbicularis is an important contributor to hip stability in distraction. In seven cadaveric hip specimens from seven male donors we distracted the femur from the acetabulum in a direction parallel to the femoral shaft with the hip in the neutral position. Eight sequential conditions were assessed: (1) intact specimen (muscle and skin removed), (2) capsule vented, (3) incised iliofemoral ligament, (4) circumferentially incised capsule, (5) partially resected capsule (distal to the zona orbicularis), (6) completely resected capsule, (7) radially incised labrum, and (8) completely resected labrum. The reduction of the distraction load was greatest between the partially resected capsule phase and completely resected capsule phase at 1, 3, and 5 mm joint distraction (p,=,0.018). The proximal to middle part of the capsule, which includes the zona orbicularis, appears grossly and biomechanically to act as a locking ring wrapping around the neck of the femur and is a key structure for hip stability in distraction. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 989,995, 2009 [source] The enteropathogenic Escherichia coli type III secretion system effector Map binds EBP50/NHERF1: implication for cell signalling and diarrhoeaMOLECULAR MICROBIOLOGY, Issue 2 2006Nandi Simpson Summary Enteropathogenic Escherichia coli (EPEC) is the single most important contributor to child diarrhoea in developing countries. Nevertheless, the mechanism responsible for EPEC diarrhoea remains elusive. Using the yeast two-hybrid system to determine the target host cell protein of the EPEC type III secretion system effector Map led to identification of ezrin/radixin/moesin (ERM)-binding phosphoprotein 50 (EBP50), also known as Na+/H+ exchanger regulatory factor 1 (NHERF1). Protein interaction is mediated by the carboxy-terminal Thr-Arg-Leu (TRL) motif of Map and the PSD-95/Disk-large/ZO-1 domain 1 (PDZ1) of EBP50/NHERF1. Although EBP50/NHERF1 is recruited to site of EPEC adhesion in a Map-independent mechanism, co-immunoprecipitation and immunostaining revealed that Map binds to, induces proteolysis of, and colocalizes with EBP50/NHERF1 during infection of cultured epithelial cells. The TRL motif of Map was involved in Map-induced filopodia formation and brush border elongation on infected HeLa and Caco-2 cells respectively. As EBP50/NHERF1 regulates ion channels in the intestine we assessed the involvement of Map in diarrhoea using the Citrobacter rodentium mouse model of EPEC. We report significantly greater diarrhoea following infections with wild-type C. rodentium compared with C. rodentium,map. These results provide new insights into the mechanisms of EPEC diarrhoea. [source] Challenging conventional wisdom: The etiologic role of dopamine oxidative stress in Parkinson's diseaseMOVEMENT DISORDERS, Issue 3 2005J. Eric Ahlskog PhD Abstract Oxidative stress is well documented in Parkinson's disease (PD) and has been attributed to dopamine oxidative metabolism. However, evidence of oxidative stress is found in a variety of neurodegenerative disorders, suggesting that more general factors are responsible or that cytodestructive processes secondarily generate oxyradical products. Increasing evidence points away from dopamine metabolism as an important contributor to PD neurodegeneration. Predictions from the dopamine oxidative stress hypothesis of PD reveal multiple inconsistencies. Although the clinical and therapeutic importance of the nigrostriatal dopaminergic system is undeniable, PD neuropathology is much more widespread. © 2004 Movement Disorder Society [source] The Asian birth outcome gapPAEDIATRIC & PERINATAL EPIDEMIOLOGY, Issue 4 2006Cheng Qin Summary Asians are often considered a single group in epidemiological research. This study examines the extent of differences in maternal risks and birth outcomes for six Asian subgroups. Using linked birth/infant death certificate data from the State of California for the years 1992,97, we assessed maternal socio-economic risks and their effect on birthweight, preterm delivery (PTD), neonatal, post-neonatal and infant mortality for Filipino (87 120), Chinese (67 228), Vietnamese (45 237), Korean (23 431), Cambodian/Laotian (21 239) and Japanese (18 276) live singleton births. The analysis also included information about non-Hispanic whites and non-Hispanic blacks in order to give a sense of the magnitude of risks among Asians. Logistic regression models explored the effect of maternal risk factors and PTD on Asian subgroup differences in neonatal and post-neonatal mortality, using Japanese as the reference group. Across Asian subgroups, the differences ranged from 2.5- to 135-fold for maternal risks, and 2.2-fold for infant mortality rate. PTD was an important contributor to neonatal mortality differences. Maternal risk factors contributed to the disparities in post-neonatal mortality. Significant differences in perinatal health across Asian subgroups deserve ethnicity-specific interventions addressing PTD, teen pregnancy, maternal education, parity and access to prenatal care. [source] Change in waist circumference over 11 years and current waist circumference independently predict elevated CRP in Filipino women,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 3 2010Julienne N. Rutherford C-reactive protein, a marker of chronic, low-grade inflammation, is strongly associated with current central adiposity, and has been linked to elevated risk of cardiovascular disease. Less is known about the contribution of longitudinal change in waist circumference to current inflammation. We evaluated the extent to which current waist circumference and change over an 11-year interval contribute independently to low-grade systemic inflammation measured in a group of 1,294 women, 35,69 years, participating in the Cebu Longitudinal Nutrition and Health Survey in the Philippines. Waist circumference was measured at the time of blood draw for CRP analysis in 2005 and during an earlier survey in 1994. A waist circumference delta variable was constructed by subtracting current circumference from past circumference. We used logistic regression models to predict having an elevated plasma CRP concentration (3 mg L,1 < CRP < 10 mg L,1). Waist circumference in 2005 was a strong predictor of elevated CRP (OR 1.10, 95% CI = 1.08, 1.12, P < 0.001). In combined models, increase in circumference over 11 years was a significant and independent predictor of elevated CRP risk (OR = 1.023, 95% CI = 1.00, 1.05, P < 0.05). Considering the average increase over time, the cumulative risk of elevated CRP due to increased central adiposity was 25.7%. However, women who reduced their waist circumference between 1994 and 2005 had greatly reduced risk (6.2%), suggesting that even long-term inflammatory burden can be reversed by weight loss. Although current waist circumference is an important contributor to risk of elevated systemic inflammation in this as in other populations, history of central adiposity may be an independent phenomenon. Am. J. Hum. Biol. 2010. © 2009 Wiley-Liss, Inc. [source] Impact and Quantification of the Sources of Error in DNA Pooling DesignsANNALS OF HUMAN GENETICS, Issue 1 2009A. Jawaid Summary The analysis of genome wide variation offers the possibility of unravelling the genes involved in the pathogenesis of disease. Genome wide association studies are also particularly useful for identifying and validating targets for therapeutic intervention as well as for detecting markers for drug efficacy and side effects. The cost of such large-scale genetic association studies may be reduced substantially by the analysis of pooled DNA from multiple individuals. However, experimental errors inherent in pooling studies lead to a potential increase in the false positive rate and a loss in power compared to individual genotyping. Here we quantify various sources of experimental error using empirical data from typical pooling experiments and corresponding individual genotyping counts using two statistical methods. We provide analytical formulas for calculating these different errors in the absence of complete information, such as replicate pool formation, and for adjusting for the errors in the statistical analysis. We demonstrate that DNA pooling has the potential of estimating allele frequencies accurately, and adjusting the pooled allele frequency estimates for differential allelic amplification considerably improves accuracy. Estimates of the components of error show that differential allelic amplification is the most important contributor to the error variance in absolute allele frequency estimation, followed by allele frequency measurement and pool formation errors. Our results emphasise the importance of minimising experimental errors and obtaining correct error estimates in genetic association studies. [source] Extracellular calreticulin is present in the joints of patients with rheumatoid arthritis and inhibits FasL (CD95L),mediated apoptosis of T cellsARTHRITIS & RHEUMATISM, Issue 10 2010Joanna M. Tarr Objective The binding of FasL (CD95L) to its receptor, Fas (CD95), induces apoptosis. Studies have shown that in patients with rheumatoid arthritis (RA), T lymphocytes are resistant to FasL-induced apoptosis in vivo but are susceptible to FasL-induced apoptosis in vitro. Dysfunction in this mechanism may be an important contributor to the pathophysiology of RA. Thus, the present study was undertaken to determine which factors might inhibit FasL,Fas binding in vivo and those that would inhibit apoptosis of T lymphocytes in an in vitro model system. Methods Human Jurkat T cells rendered apoptotic by FasL exposure were analyzed by flow cytometry. Necrosis was determined according to measurement of lactate dehydrogenase release. Quantification of calreticulin in plasma and synovial fluid and of calreticulin,FasL binding was performed by enzyme-linked immunosorbent assay. Measurement of nitrite/nitrate in the plasma and synovial fluid was carried out by chemiluminescence assay. Results Extracellular calreticulin was present at a significantly higher concentration in the plasma (median 10.3 ng/ml, interquartile range [IQR] 14.8 ng/ml) and synovial fluid (median 10.3 ng/ml, IQR 12.0 ng/ml) of RA patients (each P < 0.05) compared with the plasma (median 3.1 ng/ml, IQR 1.3 ng/ml) and synovial fluid (median 2.9 ng/ml, IQR 0.9 ng/ml) of patients with psoriatic arthritis and the plasma of healthy control subjects (median 2.9 ng/ml, IQR 0.9 ng/ml). Calreticulin concentrations in the synovial fluid correlated with the tender and swollen joint counts and the activity scores on the 28-joint Disease Activity Score assessment. Calreticulin also bound directly to FasL. In vitro, calreticulin (2,16 ng/ml) inhibited FasL-induced apoptosis of Jurkat T cells. Conclusion Calreticulin was present at higher concentrations in the plasma and synovial fluid of RA patients. Calreticulin had the capacity to bind directly to FasL and to inhibit FasL-mediated apoptosis of Jurkat T cells, and thus might play a role in inhibiting apoptosis of inflammatory T cells in RA. [source] Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis,,ARTHRITIS & RHEUMATISM, Issue 1 2006Paulo J. Nicola Objective Although mortality among patients with rheumatoid arthritis (RA) is higher than in the general population, the relative contribution of comorbid diseases to this mortality difference is not known. This study was undertaken to evaluate the contribution of congestive heart failure (CHF) and ischemic heart disease (IHD), including myocardial infarction, to the excess mortality in patients with RA, compared with that in individuals without RA. Methods We assembled a population-based inception cohort of individuals living in Rochester, Minnesota, in whom RA (defined according to the criteria of the American College of Rheumatology [formerly, the American Rheumatism Association]) first developed between 1955 and 1995, and an age- and sex-matched non-RA cohort. All subjects were followed up until either death, migration from the county, or until 2001. Detailed information from the complete medical records was collected. Statistical analyses included the person-years method, cumulative incidence, and Cox regression modeling. Attributable risk analysis techniques were used to estimate the number of RA deaths that would be prevented if the incidence of CHF was the same in patients with RA and non-RA subjects. Results The study population included 603 patients with RA and 603 subjects without RA. During followup, there was an excess of 123 deaths among patients with RA (345 RA deaths occurred, although only 222 such deaths were expected). The mortality rates among patients with RA and non-RA subjects were 39.0 and 29.2 per 1,000 person-years, respectively. There was a significantly higher cumulative incidence of CHF (but not IHD) in patients with RA compared with non-RA subjects (37.1% versus 27.7% at 30 years of followup, respectively; P < 0.001). The risk of death associated with either CHF or IHD was not significantly different between patients with RA and non-RA subjects. If the risk of developing CHF was the same in patients with RA and individuals without RA, the overall mortality rate difference between RA and non-RA hypothetically would be reduced from 9.8 to 8.0 excess deaths per 1,000 person-years; that is, 16 (13%) of the 123 excess deaths could be prevented. Conclusion CHF, rather than IHD, appears to be an important contributor to the excess overall mortality among patients with RA. CHF contributes to this excess mortality primarily through the increased incidence of CHF in RA, rather than increased mortality associated with CHF in patients with RA compared with non-RA subjects. Eliminating the excess risk of CHF in patients with RA could significantly improve their survival. [source] Bcl-3 is an interleukin-1,responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 geneARTHRITIS & RHEUMATISM, Issue 12 2002Sarah F. Elliott Objective To define the role of Bcl-3, a member of the inhibitor of nuclear factor ,B (NF-,B) family and a known regulator of NF-,B, in interleukin-1 (IL-1),induced matrix metalloproteinase 1 (MMP-1) transcription in chondrocytes and synovial fibroblasts. Methods SW-1353 cells, a human chondrosarcoma cell line, were stimulated with IL-1,, and the harvested RNA was subjected to microarray analysis and quantitative real-time reverse transcription,polymerase chain reaction (RT-PCR). The SW-1353 cells were stimulated with IL-1 or transfected with a plasmid that constitutively expressed Bcl-3, and then MMP-1 messenger RNA (mRNA) expression was assayed by quantitative real-time RT-PCR. SW-1353 cells were transfected with antisense oligonucleotides to Bcl-3, and IL-1,induced MMP-1 mRNA expression was assayed by quantitative RT-PCR. SW-1353 cells and rabbit synovial fibroblasts were transfected with a 4.3-kb human MMP-1 promoter construct along with Bcl-3 and NF-,B1 expression constructs, and MMP-1 transcription was assayed. Results Microarray analysis and real-time RT-PCR showed Bcl-3 to be an IL-1,,responsive gene in SW-1353 cells. Exogenous expression of Bcl-3 in SW-1353 cells activated MMP-1 transcription. Endogenous Bcl-3 expression was required for IL-1, induction of MMP-1 gene expression. Bcl-3 also activated MMP-1 transcription in primary synovial fibroblasts. We showed previously that NF-,B1 contributes to IL-1, induction of MMP-1 transcription in stromal cells. We showed here that Bcl-3 can cooperate with NF-,B1 to activate MMP-1 transcription in SW-1353 cells. Conclusion These data define a new role for Bcl-3 in joint cells as an IL-1,,responsive early gene involved in cell-mediated cartilage remodeling. Our findings implicate Bcl-3 as an important contributor to chronic inflammatory disease states, such as osteoarthritis and rheumatoid arthritis. [source] | ||||||||||||||||||||||||||||||||||||||||