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Modest Increase (modest + increase)
Selected AbstractsModest increase in plasma homocysteine follows levodopa initiation in Parkinson's diseaseMOVEMENT DISORDERS, Issue 12 2004Padraig E. O'Suilleabhain MB Abstract Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) ,mol/L increased to 10.1 (3.1) ,mol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L -dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 ,mol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined. © 2004 Movement Disorder Society [source] Genetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance.DIABETIC MEDICINE, Issue 10 2002Functional analysis of Ala513Pro, Gly1158Glu IRS- Abstract Aims To define further the role of IRS-1 mutations in human syndromes of severe insulin resistance. Methods The IRS-1 gene was scanned for mutations in 83 unrelated affected subjects and 47 unaffected individuals using fluorescent single-strand conformation polymorphism (fSSCP) analysis. A novel heterozygous mutation, Gly1158Glu, was found in one affected subject. Four and two subjects were heterozygous for the previously reported variants Gly972Arg and Ala513Pro, respectively. The previously identified variant Gly819Arg was found in one affected and one unaffected subject. While Gly972Arg has been described to alter the signalling properties of IRS-1, no functional studies of Ala513Pro or Gly1158Glu have been reported. Results Chinese hamster ovary (CHO) cells stably over-expressing the insulin receptor were transiently transfected with vectors expressing either wild-type, Glu1158 or Pro513 IRS-1. A modest increase in insulin-stimulated tyrosine phosphorylation of Glu1158 IRS-1 was observed. However, this did not result in any significant change in the association of Grb2 or the p85, subunit of PI3-kinase or of PI3-kinase activity. In parallel studies, the Pro513 IRS-1 variant was indistinguishable from wild-type IRS-1. Conclusions While subtle effects of these variants cannot be excluded in this system, it is unlikely that these variants are responsible for the extreme insulin resistance seen in the subjects harbouring them. Although IRS proteins play a central role in insulin signalling, functionally significant mutations in the IRS-1 gene are a rare cause of human syndromes of severe insulin resistance. [source] Bacterial and mammalian-cell genotoxicity of mixtures of chlorohydroxyfuranones, by-products of water chlorinationENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2004Jorma Mäki-Paakkanen Abstract The genotoxic responses of mixtures of four chlorohydroxyfuranones (CHFs), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), 3-chloro- 4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) and 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), were compared with the genotoxicity of the individual compounds. Genotoxicity was evaluated in the Salmonella reversion assay (Ames test), the in vitro Chinese hamster ovary (CHO) cell Hprt mutation assay, and in the CHO chromosome aberration test. When tested individually, the concentrations of the chemicals that were chosen for the mixtures induced no or only a modest increase in the genotoxic effects, and caused little or no cytotoxicity. In the Ames test, the genotoxic responses caused by the mixtures of CHFs did not follow simple additivity. Synergism was observed with strains TA97 and TA98, and antagonism with strain TA100. In the CHO/Hprt mutation assay, the mutagenic response of the mixtures was inconsistent, with near additivity seen with a mixture of CHFs that resulted in 12% cell survival. In contrast, the four CHFs together consistently caused more structural chromosome damage (mainly chromatid-type breaks and exchanges) compared to the sum of net effects of the four CHFs tested alone. Also, a potentiating effect was consistently seen for the cytotoxicity of the CHF mixtures both in the CHO/Hprt mutation assay and the chromosome aberration test. The present results indicate that the genotoxic effects of CHF mixtures can be greater than additive. Such effects may be worth considering in the cancer risk assessment of chlorinated drinking water. Environ. Mol. Mutagen. 43:217,225, 2004. © 2004 Wiley-Liss, Inc. [source] Does cannabis use predict the first incidence of mood and anxiety disorders in the adult population?ADDICTION, Issue 8 2007Margriet Van Laar ABSTRACT Aims To investigate whether cannabis use predicted the first incidence of mood and anxiety disorders in adults during a 3-year follow-up period. Design and participants Data were derived from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective study in the adult population of 18,64 years. The analysis was carried out on 3881 people who had no life-time mood disorders and on 3854 people who had no life-time anxiety disorders at baseline. Measurements Life-time cannabis use and DSM-III-R mood and anxiety disorders, assessed with the Composite International Diagnostic Interview (CIDI). Findings After adjustment for strong confounders, any use of cannabis at baseline predicted a modest increase in the risk of a first major depression (odds ratio 1.62; 95% confidence interval 1.06,2.48) and a stronger increase in the risk of a first bipolar disorder (odds ratio 4.98; 95% confidence interval 1.80,13.81). The risk of ,any mood disorder' was elevated for weekly and almost daily users but not for less frequent use patterns. However, dose,response relationships were less clear for major depression and bipolar disorder separately. None of the associations between cannabis use and anxiety disorders remained significant after adjustment for confounders. Conclusions The associations between cannabis use and the first incidence of depression and bipolar disorder, which remained significant after adjustment for strong confounders, warrant research into the underlying mechanisms. [source] Receptor-mediated phagocytosis of rat macrophages is regulated differentially for opsonized particles and non-opsonized particles containing ,-glucanIMMUNOLOGY, Issue 2 2001Jonathan S. Reichner Summary Experiments were conducted to test the hypothesis that opsonic and non-opsonic phagocytic capacities are differentially regulated by resting and wound-derived macrophages. Furthermore, the phagocytosis of non-opsonized zymosan and ,-glucan particles was quantified to determine whether cells differentially regulate non-opsonic lectinophagocytosis in accordance with the carbohydrate composition of the ligand. In that regard, wound macrophages exhibited profound differential regulation in lectinophagocytosis with a seven-fold increase in phagocytosis of ,-glucan particles following overnight culture but with a relatively modest increase in internalization of mannan-containing zymosan. Cultured peritoneal macrophages increased uptake of both particles similarly. Upon activation with interferon-,/lipopolysaccharide (IFN-,/LPS), wound macrophages selectively suppressed ,-glucan ingestion, while phagocytosis of zymosan particles was unaffected. Lectinophagocytosis was decreased in activated peritoneal macrophages regardless of particle composition and was due in part to a nitric oxide-dependent mechanism which was without a role in regulation of wound macrophage lectinophagocytosis. Overnight culture of wound macrophages suppressed their capacity for opsonic-dependent phagocytosis independently of activation, whereas suppression of phagocytosis by peritoneal macrophages was activation-dependent. Regulation of all three phagocytic pathways was achieved distinctly by peritoneal and wound-derived macrophages, with changes found in the percentage of resident peritoneal macrophages capable of phagocytosis, whereas the phagocytic capacity of wound macrophages was primarily affected by the number of particles ingested by individual cells. Taken together, these findings demonstrate that the differential regulation of phagocytic pathways encompasses the nature of the phagocytic particle, the site from which macrophages are obtained, their response to activating agents and the mechanism through which the cell population alters its phagocytic potential. [source] Esophageal cancer in Central and Eastern Europe: Tobacco and alcoholINTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Mia Hashibe Abstract Esophageal cancer mortality rates in Central and Eastern Europe have been increasing steadily and are expected to increase further in the future. To evaluate the role of risk factors for esophageal cancer in this population, a multicenter study was conducted, with investigation of tobacco and alcohol as one of the principal aims. We have included 192 squamous cell carcinoma (SCC) and 35 adenocarcinoma cases of the esophagus diagnosed at designated hospitals in 5 centers from Romania, Russia, the Czech Republic and Poland. Controls were frequency matched from patients in the same hospital as the cases (n = 1,114). Our results showed that the risk of esophageal SCC may be increased by approximately 7-fold for current smokers (OR = 7.41, 95% CI 3.98,13.79) and by 3-fold for ever alcohol drinkers (OR = 2.86, 95% CI 1.06,7.74). Dose-response relations were evident for both the frequency and duration of tobacco and of alcohol on the risk of esophageal SCC. Risk estimates for tobacco smoking were highest for lower esophageal SCCs, while risk estimates for alcohol drinking were highest for upper esophageal SCCs; though differences were not statistically significant. For adenocarcinoma of the esophagus, our results suggested a more modest increase in risk because of tobacco smoking than that for SCC of the esophagus and no association with alcohol consumption, although our sample size was small. A synergistic interaction between tobacco and alcohol was observed for the risk of esophageal SCC, highlighting the importance of both factors for esophageal cancers in Central and Eastern Europe. © 2006 Wiley-Liss, Inc. [source] HDL-c is a powerful lipid predictor of cardiovascular diseasesINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 11 2007E. Bruckert Summary Relationship between HDL-c and cardiovascular diseases:, Beyond the role of low-density lipoprotein cholesterol (LDL-c) in the development of atherosclerosis, growing evidence suggest that high-density lipoprotein cholesterol (HDL-c) is a powerful predictor of cardiovascular disease. Indeed, epidemiological, mechanistic and intervention studies suggest that low HDL-c is a major cardiovascular risk factor and that increasing HDL-c plasma levels may be beneficial, particularly in patients with low HDL-c levels. The inverse association between HDL-c concentrations and cardiovascular risk is continuous without threshold value. Thus, any categorical definition of low HDL-c is arbitrary. Protective effects of HDL:, HDL particles are highly heterogeneous in structure and intravascular metabolism. Antiatherogenic properties of HDL include its role in the reverse cholesterol transfer, besides its antioxidant, anti-inflammatory and antiapoptotic activities. What should clinicians do?:, From a practical point of view, HDL-c should be systematically measured to assess the cardiovascular risk in patients. The first step to consider in subjects with low HDL-c is to look for specific causes and give advice to change inappropriate lifestyle components associated with low HDL-c, such as smoking, lack of physical exercise and overweight. Patients with very low HDL-c need a thorough evaluation by specialist physicians. Statins are associated with a modest increase of HDL-c (5%) while fibrates and nicotinic acid increase HDL-c by 10% and 20% respectively. [source] Response of recruitment to light availability across a tropical lowland rain forest communityJOURNAL OF ECOLOGY, Issue 6 2009Nadja Rüger Summary 1. ,Many hypotheses about species coexistence involve differential resource use and trade-offs in species' life-history traits. Quantifying resource use across most species in diverse communities, although, has seldom been attempted. 2. ,We use a hierarchical Bayesian approach to quantify the light dependence of recruitment in 263 woody species in a 50-ha long-term forest census plot in Panama. Data on sapling recruitment were obtained using the 1985,1990 and 1990,1995 census intervals. Available light was estimated for each recruit from yearly censuses of canopy density. 3. ,We use a power function (linear log,log relationship) to model the light effect on recruitment. Different responses of recruitment to light are expressed by the light effect parameter b. The distribution of b had a central mode at 0.8, suggesting that recruitment of many species responds nearly linearly to increasing light. 4. ,Nearly every species showed increases in recruitment with increasing light. Just nine species (3%) had recruitment declining with light, while 198 species (75%) showed increasing recruitment in both census intervals. Most of the increases in recruitment were decelerating, i.e. the increase was less at higher light (b < 1). In the remaining species, the response to light varied between census intervals (24 species) or species did not have recruits in both intervals (41 species). 5. ,Synthesis. Nearly all species regenerate better in higher light, and recruitment responses to light are spread along a continuum ranging from modest increase with light to a rather strict requirement for high light. These results support the hypothesis that spatio-temporal variation in light availability may contribute to the diversity of tropical tree species by providing opportunities for niche differentiation with respect to light requirements for regeneration. [source] Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environmentAGING CELL, Issue 2 2009Nica M. Borradaile Summary Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD+ salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease. [source] The effects of rising food prices on poverty in MexicoAGRICULTURAL ECONOMICS, Issue 2008Jorge N. Valero-Gil Food price changes; Poverty; Mexico Abstract We evaluate the impact of the rise in food prices during 2006,2008 on the poverty and extreme poverty rates in Mexico. We concentrate on the poor's consumption of staple foods, and analyze the change in their consumption brought about by changed prices. We also allow households receiving income from the farming and livestock sector to benefit from increases in prices of food products. We find a modest increase in poverty using 2006,2007 prices; however, there is a daunting effect on the poor once the 2008 prices are taken into account. After considering the positive effects of public policies announced in 2008, such as reduced taxes and tariffs on food products and greater subsidies to the extremely poor, the poverty rate measured through consumption increases from 25% to 33.5%, and the extreme poverty rate from 10.58% to 15.95%, given the increase in food prices. Further analysis using the theory of optimal taxes suggests policies oriented towards relieving the food price pressure on the Mexican poor should aim at lowering the prices of eggs, vegetable oil, milk, and chicken. [source] Partnership Instability and Child Well-BeingJOURNAL OF MARRIAGE AND FAMILY, Issue 4 2007Cynthia Osborne We use data from three waves of the Fragile Families Study (N= 2,111) to examine the prevalence and effects of mothers' partnership changes between birth and age 3 on children's behavior. We find that children born to unmarried and minority parents experience significantly more partnership changes than children born to parents who are married or White. Each transition is associated with a modest increase in behavioral problems, but a significant number of children experience 3 or more transitions. The association between instability and behavior is mediated by maternal stress and lower quality mothering. The findings imply that policies aimed at reducing maternal stress and partnership instability may improve child well-being. [source] Alcohol and Mitochondria in Cardiac Apoptosis: Mechanisms and VisualizationALCOHOLISM, Issue 5 2005György Hajnóczky Apoptosis of myocytes is likely to contribute to a variety of heart conditions and could also be important in the development of alcoholic heart disease. A fundamental pathway to apoptosis is through mitochondrial membrane permeabilization and release of proapoptotic factors from the mitochondrial intermembrane space to the cytosol. The authors' results show that prolonged exposure of cultured cardiac cells to ethanol (35 mM for 48 hr) promotes Ca2+ -induced activation of the mitochondrial permeability transition pore (PTP). PTP-dependent mitochondrial membrane permeabilization is followed by release of cytochrome c and execution of apoptosis. The authors propose that chronic ethanol exposure, in combination with other stress signals, may allow for activation of the PTP by physiological calcium oscillations, providing a trigger for cardiac apoptosis during chronic alcohol abuse. Coincidence of apoptosis promoting factors occurs in only a small fraction of myocytes, but because of the absence of regeneration, even a modest increase in the rate of cell death may contribute to a decrease in cardiac contractility. Detection of apoptotic changes that are present in only a few myocytes at a certain time in the heart is not feasible with most of the apoptotic assays. Fluorescence imaging is a powerful technology to visualize changes that are confined to a minor fraction of cells in a tissue, and the use of multiphoton excitation permits imaging in situ deep in the wall of the intact heart. This article discusses potential mechanisms of the effect of alcohol on mitochondrial membrane permeabilization and visualization of mitochondria-dependent apoptosis in cardiac muscle. [source] Acute Alcohol Intoxication During Hemorrhagic Shock: Impact on Host Defense From InfectionALCOHOLISM, Issue 4 2004K. L. Zambell Abstract: Background: Acute alcohol intoxication is a frequent underlying condition associated with traumatic injury. Our studies have demonstrated that acute alcohol intoxication significantly impairs the immediate hemodynamic, metabolic, and inflammatory responses to hemorrhagic shock. This study investigated whether acute alcohol intoxication during hemorrhagic shock would alter the outcome from an infectious challenge during the initial 24 hr recovery period. Methods: Chronically catheterized male Sprague Dawley® rats were randomized to acute alcohol intoxication (EtOH; 1.75 g/kg bolus followed by a constant 15 hr infusion at 250,300 mg/kg/hr) or isocaloric isovolemic dextrose infusion (dex; 3 ml + 0.375 ml/hr). EtOH and dex were assigned to either fixed-volume (50%) hemorrhagic shock followed by fluid resuscitation with Ringer's lactate (EtOH/hem, dex/hem) or sham hemorrhagic shock (EtOH/sham, dex/sham). Indexes of circulating neutrophil function (apoptosis, phagocytosis, oxidative burst) were obtained at baseline, at completion of hemorrhagic shock, and at the end of fluid resuscitation. Bacterial clearance, lung cytokine expression, and myeloperoxidase activity were determined at 6 and 18 hr after an intratracheal challenge with Klebsiella pneumoniae (107 colony-forming units). Results: Mean arterial blood pressure was significantly lower in acute alcohol intoxication-hemorrhagic shock animals throughout the hemorrhagic shock. In sham animals, acute alcohol intoxication alone did not produce significant changes in neutrophil apoptosis or phagocytic activity but significantly suppressed phorbol myristic acid (PMA)-stimulated oxidative burst. Hemorrhagic shock produced a modest increase in neutrophil apoptosis and suppression of neutrophil phagocytic capacity but significantly suppressed PMA-stimulated oxidative burst. Acute alcohol intoxication exacerbated the hemorrhagic shock-induced neutrophil apoptosis and the hemorrhagic shock-induced suppression of phagocytosis without further affecting PMA-stimulated oxidative burst. Fluid resuscitation did not restore neutrophil phagocytosis or oxidative burst. Acute alcohol intoxication decreased (,40%) 3-day survival from K. pneumoniae in hemorrhagic shock animals, impaired bacterial clearance during the first 18 hr postinfection, and prolonged lung proinflammatory cytokine expression. Conclusions: These results demonstrate that the early alterations in metabolic and inflammatory responses to hemorrhagic shock produced by acute alcohol intoxication are associated with neutrophil dysfunction and impaired host response to a secondary infectious challenge leading to increased morbidity and mortality. [source] Joint design of trajectory and RF pulses for parallel excitationMAGNETIC RESONANCE IN MEDICINE, Issue 3 2007Chun-Yu Yip Abstract We propose an alternating optimization framework for the joint design of excitation k-space trajectory and RF pulses for small-tip-angle parallel excitation. Using Bloch simulations, we show that compared with conventional designs with predetermined trajectories, joint designs can often excite target patterns with improved accuracy and reduced total integrated pulse power, particularly at high reduction factors. These benefits come at a modest increase in computational time. Magn Reson Med 58:598,604, 2007. © 2007 Wiley-Liss, Inc. [source] Player salary share and the distribution of player earningsMANAGERIAL AND DECISION ECONOMICS, Issue 2 2004Gerald W. Scully Veteran free agency in professional team sports has led to higher average player compensation, an increase in the share of league revenues going to players, and increased dispersion in player earnings. Tests on the distributions of player salaries in the last decade reject that they are the same in the early and later years. The variance in baseball player compensation is decomposed into share and marginal revenue product effects for 1990 and 1998, and it is found that both effects contributed to the increased variance in player salaries. A simulation of the effect of universal free agency in baseball suggests a modest increase in player salary share and a drop in compensation inequality among players. Copyright © 2004 John Wiley & Sons, Ltd. [source] Molecular phenotype of Fragile X syndrome: FMRP, FXRPs, and protein targetsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 3 2002Walter E. Kaufmann Abstract Fragile X syndrome (FraX) is one of the most prevalent genetic causes of mental retardation. FraX is associated with an unstable expansion of a polymorphism within the 5, untranslated region of the FMR1 gene. The main consequence of this mutation is a reduction in the levels of the gene product (FMRP). FMRP is an RNA-binding protein with multiple spliced variants (isoforms) and high levels of expression in a variety of tissues, including neurons. In the latter cells, it is localized not only to the perikaryon but also to dendrites and dendritic spines. FMRP belongs to a family of proteins that includes the Fragile X Related Proteins or FXRPs. FXRPs share high homology in their functional domains with FMRP, and also associate with mRNA and components of the protein synthesis apparatus. However, FXRPs do not have the same temporo-spatial pattern of distribution (and other properties) of FMRP. Immunochemical assays have confirmed that a functionally uncompensated FMRP deficit is the essence of the FraX molecular phenotype. Here, we report our preliminary study on FXRPs levels in leukocytes from FraX males. By immunoblotting, we found that a marked reduction in FMRP levels is associated with a modest increase in FXR1P and no changes in FXR2P levels. The consequences of this reduced FMRP expression on protein synthesis, in other words, the identification of FMRP targets, can be studied by different molecular approaches including protein interaction and proteomics methods. By two-dimensional gel electrophoresis, we showed that in FraX leukocytes there is a defect in acetylation that involves prominently the regulatory protein annexin-1. Extension of current studies of the molecular phenotype to more brain-relevant tissue samples, a wider range of proteomics-based methods, and correlative analyses of FMRP homologues and FMRP targets with multiple behavioral measures, will greatly expand our understanding of FraX pathogenesis and it will help to develop and monitor new therapeutic strategies. Microsc. Res. Tech. 57:135,144, 2002. © 2002 Wiley-Liss, Inc. [source] Training ACD/LogP with Experimental DataMOLECULAR INFORMATICS, Issue 7 2004Matthew Abstract The commercial physical property calculation software, ACD/Labs Physico-Chemical Laboratory, has the capability to accept experimental data for logP and pKa values which it can use to "train" its model to better predict un-represented structural classes. An attempt was made to produce a training set, called a "user database" by the software, based on Merck in-house data, which could be used to train the ACD/LogP model in order to achieve better predictivity on molecules of interest to Merck researchers. A user database consisting of a randomly selected 10% subset of the available Shake-Flask measured logP data was constructed and used to predict itself as well as the remaining 90% data set. The training produced a modest increase in accuracy of the model, with the R2 value of the prediction improving in the test set from 0.316 to 0.527. Narrowing the selection to a project-based, targeted subset of the in-house data in hopes of decreasing the diversity of the set, enhanced the coverage of the model but only produced an improvement in the R2 value from 0.350 to 0.537. Finally, training on a single, small representative of a structural class produced a sizable reduction in the bias of the prediction in a congeneric series of compounds, essentially confirming the original claim of the software developers. These improvements came with an increase in time and machine load to perform the calculation relative to the size of the training set. [source] The white dwarf in AE Aqr brakes harderMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2006Christopher W. Mauche ABSTRACT Taking advantage of the very precise de Jager et al. optical white dwarf orbit and spin ephemerides; ASCA, XMM,Newton and Chandra X-ray observations spread over 10 yr; and a cumulative 27-yr baseline, we have found that in recent years the white dwarf in AE Aqr is spinning down at a rate that is slightly faster than predicted by the de Jager et al. spin ephemeris. At the present time, the observed period evolution is consistent with either a cubic term in the spin ephemeris with , which is inconsistent in sign and magnitude with magnetic dipole radiation losses, or an additional quadratic term with , which is consistent with a modest increase in the accretion torques spinning down the white dwarf. Regular monitoring, in the optical, ultraviolet and/or X-rays, is required to track the evolution of the spin period of the white dwarf in AE Aqr. [source] Meat Consumption and Colorectal Cancer: A Review of Epidemiologic EvidenceNUTRITION REVIEWS, Issue 2 2001Drs. Teresa Norat Ph.D This article reviews the epidemiologic evidence on colorectal cancer risk and meat consumption from 32 case-control and 13 cohort studies published in English from 1970 to 1999 and retrieved from the Medline database. The results support the hypothesis that meat consumption is associated with a modest increase in colorectal cancer risk. This association, however, seems to have been more consistently found for red meat and processed meat. The studies on cooking methods and meat "doneness" are not consistent and the evidence is not conclusive. [source] Clay-reinforced epoxy nanocompositesPOLYMER INTERNATIONAL, Issue 9 2003D Ratna Abstract Epoxy/clay nanocomposites were prepared using a conventional diglycidyl ether of bisphenol A (DGEBA) epoxy, cured with diethyltoluene diamine (DETDA). The nanocomposites were characterized by dynamic mechanical analysis. A modest increase in glass transition temperature and significant increase in storage modulus were achieved as a result of incorporation of clay. The formation of nanocomposite was confirmed by wide-angle X-ray analysis. The higher impact strength of the nanocomposite compared the DGEBA matrix was explained in terms of with the morphology observed by SEM. © 2003 Society of Chemical Industry [source] Host and non-host pathogens elicit different jasmonate/ethylene responses in ArabidopsisTHE PLANT JOURNAL, Issue 5 2004Laurent Zimmerli Summary Arabidopsis does not support the growth and asexual reproduction of the barley pathogen, Blumeria graminis f. sp. hordei Bgh). A majority of germlings fail to penetrate the epidermal cell wall and papillae. To gain additional insight into this interaction, we determined whether the salicylic acid (SA) or jasmonate (JA)/ethylene (ET) defence pathways played a role in blocking barley powdery mildew infections. Only the eds1 mutant and NahG transgenics supported a modest increase in penetration success by the barley powdery mildew. We also compared the global gene expression patterns of Arabidopsis inoculated with the non-host barley powdery mildew to those inoculated with a virulent, host powdery mildew, Erysiphe cichoracearum. Genes repressed by inoculations with non-host and host powdery mildews relative to non-inoculated control plants accounted for two-thirds of the differentially expressed genes. A majority of these genes encoded components of photosynthesis and general metabolism. Consistent with this observation, Arabidopsis growth was inhibited following inoculation with Bgh, suggesting a shift in resource allocation from growth to defence. A number of defence-associated genes were induced during both interactions. These genes likely are components of basal defence responses, which do not effectively block host powdery mildew infections. In addition, genes encoding defensins, anti-microbial peptides whose expression is under the control of the JA/ET signalling pathway, were induced exclusively by non-host pathogens. Ectopic activation of JA/ET signalling protected Arabidopsis against two biotrophic host pathogens. Taken together, these data suggest that biotrophic host pathogens must either suppress or fail to elicit the JA/ET signal transduction pathway. [source] Are common symptoms in childhood associated with chronic widespread body pain in adulthood?: Results from the 1958 british birth cohort studyARTHRITIS & RHEUMATISM, Issue 5 2007Gareth T. Jones Objective Studies have shown that common symptoms in childhood predict the onset of chronic widespread pain in the short term. However, it is unknown whether this association persists into adulthood. The aim of the current study was to examine, prospectively, whether children with common symptoms experience an increased risk of chronic widespread pain as adults. Methods Information on vomiting/bilious attacks, abdominal pain, and headaches/migraine was collected on 10,453 7-year-old children, by maternal report. Similar data were gathered when the children were ages 11 years and 16 years. Body pain at age 45 years was assessed by postal questionnaire. Poisson regression was used to examine chronic widespread pain in relation to childhood symptom reporting. Results Of the 10,453 subjects on whom data were obtained when they were children, 7,470 participated at age 45 years (71.5%). Children with multiple symptoms at age 7 years experienced a 50% increased risk of chronic widespread pain (relative risk 1.5 [95% confidence interval 1.03, 2.3]). This relationship persisted after adjustment for sex, recent psychological distress, and childhood and current socioeconomic status, and after excluding children with major illnesses that might have explained early symptom reporting. A similar relationship with symptoms at ages 11 and 16 years was observed, although this was not associated with additional risk compared with that found with the presence of symptoms at age 7 years. However, despite a modest increase in risk, the presence of multiple symptoms at early ages was uncommon (<1.5%), and therefore, the associated population attributable risk was low (<1%). Conclusion Multiple common symptoms in childhood are associated with an increased risk of chronic widespread pain in adulthood. However, the magnitude of this increased risk is modest, and reports of multiple symptoms in childhood are uncommon. Thus the "early pain pathway" phenomenon is applicable only to a small proportion of individuals with chronic widespread pain. [source] Public health needs a strong, well-planned advocacy programAUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH, Issue 5 2006Mike Daube Public health is the poor relation in the health system and attracted little additional funding from the 2006 Budget. A modest increase in the allocation to prevention would enable significant advances to be made across a wide range of public health activity and research areas. PHAA should take the lead in developing a planned and sustained advocacy program. [source] ELF magnetic fields increase amino acid uptake into Vicia faba L. Roots and Alter Ion movement across the plasma membraneBIOELECTROMAGNETICS, Issue 5 2002B.C. Stange Abstract Vicia faba seedlings, subjected to a 10 µT 50 Hz square wave magnetic field for 40 min together with a radioactive pulse, showed a marked increase in amino acid uptake into intact roots. A more modest increase was observed with a 100 µT 50 Hz square wave. An increase in media conductivity at low field intensities from 10 µT 50 Hz square wave, 100 µT 50 Hz sine wave, and 100 µT 60 Hz square wave fields, indicated an alteration in the movement of ions across the plasma membrane, most likely due to an increase in net outflow of ions from the root cells. Similarly, marked elevation in media pH, indicating increased alkalinity, was observed at 10 and 100µT for both square and sine waves at both 50 and 60 Hz. Our data would indicate that low magnetic field intensities of 10 and 100 µT at 50 or 60 Hz can alter membrane transport processes in root tips. Bioelectromagnetics 23:347,354, 2002. © 2002 Wiley-Liss, Inc. [source] Noninvasive measurement of dissolved oxygen in shake flasksBIOTECHNOLOGY & BIOENGINEERING, Issue 5 2002Leah Tolosa Abstract Shake flasks are ubiquitous in cell culture and fermentation. However, conventional devices for measuring oxygen concentrations are impractical in these systems. Thus, there is no definitive information on the oxygen supply of growing cells. Here we report the noninvasive, nonintrusive monitoring of dissolved oxygen (DO) in shake flasks using a low-cost optical sensor. The oxygen-sensitive element is a thin, luminescent patch affixed to the inside bottom of the flask. The sensitivity and accuracy of this device is maximal up to 60% DO, within the range that is critical to cell culture applications. By measuring actual oxygen levels every 1 or 5 min throughout the course of yeast and E. coli fermentations, we found that a modest increase in shaker speed and a decrease in culture volume slowed the onset of oxygen limitation and reduced its duration. This is the first time that in situ oxygen limitation is reported in shake flasks. The same data is unattainable with a Clark type electrode because the presence of the intrusive probe itself changes the actual conditions. Available fiber optic oxygen sensors require cumbersome external connections and recalibration when autoclaved. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 594,597, 2002. [source] Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinomaCANCER, Issue 1 2010Robert R. McWilliams MD Abstract BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are common in white persons and are associated with pancreatic disease. The purpose of this case-control study was to determine whether CFTR mutations confer a higher risk of pancreatic cancer. METHODS: In a case-control study, the authors compared the rates of 39 common cystic fibrosis-associated CFTR mutations between 949 white patients with pancreatic adenocarcinoma and 13,340 white controls from a clinical laboratory database for prenatal testing for CFTR mutations. The main outcome measure was the CFTR mutation frequency in patients and controls. RESULTS: Overall, 50 (5.3%) of 949 patients with pancreatic cancer carried a common CFTR mutation versus 510 (3.8%) of 13,340 controls (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.04-1.89; P = .027). Among patients who were younger when their disease was diagnosed (<60 years), the carrier frequency was higher than in controls (OR, 1.82; 95% CI, 1.14-2.94; P = .011). In patient-only analyses, the presence of a mutation was associated with younger age (median 62 vs 67 years; P = .034). In subgroups, the difference was seen only among ever-smokers (60 vs 65 years, P = .028). Subsequent sequencing analysis of the CFTR gene detected 8 (16%) compound heterozygotes among the 50 patients initially detected to have 1 mutation. CONCLUSIONS: Carrying a disease-associated mutation in CFTR is associated with a modest increase in risk for pancreatic cancer. Those affected appear to be diagnosed at a younger age, especially among smokers. Clinical evidence of antecedent pancreatitis was uncommon among both carriers and noncarriers of CFTR mutations. Cancer 2010. © 2010 American Cancer Society. [source] Changes associated with the development of resistance to imatinib (STI571) in two leukemia cell lines expressing p210 Bcr/Abl protein,CANCER, Issue 7 2004Barbara Scappini M.D. Abstract BACKGROUND Although various mechanisms have been recognized as being associated with the development of resistance to imatinib mesylate in vitro and in clinical situations, their relative significance and contributions remain poorly understood, as is the sequence of events leading to the selection of the resistant phenotype. Experimental in vitro systems involving well defined cell lines and conditions can be used to some advantage to answer specific questions and to develop in vitro models of imatinib resistance that would reflect its potential heterogeneity. METHODS Two cell lines, KBM5 and KBM7, which expressed p210 Bcr/Abl and which differed in their inherent sensitivity to imatinib, the number of copies of the BCR/ABL fusion gene, and the activation of apoptotic pathways, were grown in vitro in the presence of increasing concentrations of imatinib. The resistant cells were analyzed for cell cycle progression, apoptotic response after exposure to imatinib, expression of Bcr/Abl, tyrosine kinase activity, and the presence of mutations within the adenosine triphosphate (ATP) coding domain of BCR/ABL. At various levels of resistance, the cells were transferred into drug-free media, and the stability of the resistant phenotype was determined in the absence of the drug. RESULTS In KBM7 cells, the development of resistance was characterized by loss of apoptotic response to the drug, amplification of BCR/ABL, increased levels of expression of p210 Bcr/Abl, and decreased inhibition of Bcr/Abl tyrosine kinase (TK) activity by imatinib. No mutations within the ATP-binding domain of Bcr/Abl were identified, and resistance remained stable in the absence of the drug. In KBM5 cells, which previously were found to be characterized by the acquisition of a single C-T mutation at ABL nucleotide 944 (T315I) at high levels of resistance, this same mutation was detected at an intermediate level, but not at a low level, of resistance. The response of KBM5 cells to imatinib was characterized by a low level of apoptotic response, a marginal increase in BCR/ABL copy number, a modest increase in p210 expression, and a highly imatinib-resistant Bcr/Abl TK. Partial reversal of resistance was observed in highly resistant KBM5-STI571R1.0 cells, which continued to display the C-T mutation. In KBM5 cells with an intermediate level of resistance, the T315I mutation was no longer detectable upon their reversal to the sensitive phenotype. CONCLUSIONS BCR/ABL amplification with subsequent overexpression of Bcr/Abl protein, loss of apoptotic response, or point mutation of the ATP-binding site of BCR/ABL was associated alternatively with the acquisition of the resistant phenotype, supporting the notion that multiple mechanisms are involved in the induction of resistance to imatinib. The initial number of BCR/ABL copies itself was not related directly to the degree of resistance. The reversibility of the resistance may be complete, partial, or irreversible, depending on the mechanism(s) involved and the degree of resistance. Both cell lines serve as models for further elucidation of various aspects of imatinib-resistance mechanisms. Cancer 2004;100:1459,71. © 2004 American Cancer Society. [source] Genetic polymorphisms of cyclooxygenase-2 and colorectal adenoma risk: The Self Defense Forces Health StudyCANCER SCIENCE, Issue 3 2008Naoyuki Ueda Cyclooxygenase (COX) is a key enzyme in the formation of prostaglandins, and an inducible isoform of COX, COX-2, has been implicated in colorectal carcinogenesis. This study investigated the relation of COX-2 polymorphisms (,1195G>A, ,765G>C and 8160A>G) to colorectal adenomas in a case,control study of male officials in the Self Defense Forces (SDF). The study subjects were 455 cases of colorectal adenoma and 1052 controls with no polyps who underwent total colonoscopy. Genotypes were determined using the polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP) method with genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index (BMI), cigarette smoking, and alcohol intake. A statistically non-significant decrease in the risk of colorectal adenomas was observed for the AA versus GG genotype of ,1195G>A polymorphism and for the GC versus GG genotype of ,765G>C polymorphism. None had the ,765CC genotype in either the case or control groups. No effect modification of overweight, smoking or alcohol use was observed for either ,1195G>A or ,765G>C polymorphism. The variant allele of the 8160A>G polymorphism was extremely rare. A haplotype of ,1195G, ,765G and 8160A alleles was associated with a modest increase in the risk (adjusted odds ratio [OR] 1.38, 95% confidence interval [CI] 0.99,1.91), and the increase was more evident for distal adenomas (adjusted OR 1.57, 95% CI 1.04,2.38). Another haplotype of ,1195A, ,765C and 8160A alleles showed an adjusted OR of 0.22 (95% CI 0.06,0.88). These findings add to evidence for the role of COX-2 in colorectal carcinogenesis and warrant further studies focusing on haplotypes. (Cancer Sci 2008; 99: 576,581) [source] Strategies for improving the diagnostic specificity of the frequency doubling perimeterACTA OPHTHALMOLOGICA, Issue 1 2005Govert P. Heeg Abstract. Purpose:,To evaluate various strategies designed to improve the specificity of the interpretation of results obtained with the frequency doubling technology perimeter (FDT) used in the full-threshold mode. Methods:,Three different strategies were compared using data from 452 glaucoma patients and 237 healthy subjects: combining several FDT parameters from a single test, combining the FDT test with a GDx test, and confirming an abnormal FDT test result with a repeat test. Results:,Confirming an abnormal FDT test result with a repeat test yielded a specificity increase of 0.10, from 0.80 to 0.90, at the expense of some loss of sensitivity for early but not for moderate or severe glaucoma. Combining several FDT parameters from a single test and combining FDT with GDx did not yield any noticeable increase in diagnostic performance. Conclusions:,A modest increase in FDT diagnostic performance can be obtained by the confirmation of an abnormal test result with a repeat test. [source] Oral antidiabetic treatment in patients with coronary disease: Time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-upCLINICAL CARDIOLOGY, Issue 2 2001Enriqe Z. Fisman M.D. Abstract Background: A sulfonylurea ,usually glyburide,plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. Hypothesis: This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long-term follow-up period. Methods: The study sample comprised 2,275 diabetic patients, aged 45,74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition. 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). Results: The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%). 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20,1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02,1.45) and HR 1.26 (95% CI 0.81,1.96), respectively. Conclusions: We conclude that after a 7.7-year follow-up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time-related mortality was markedly increased when a combined glyburide/metformin treatment was used. [source] | |||||||||||||||||||||||||||||||||||||