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H1
Kinds of H1 Terms modified by H1 Selected AbstractsHistamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake statesACTA PHYSIOLOGICA, Issue 3 2010M. Hondo Abstract Aim:, The effect of orexin on wakefulness has been suggested to be largely mediated by activation of histaminergic neurones in the tuberomammillary nucleus (TMN) via orexin receptor-2 (OX2R). However, orexin receptors in other regions of the brain might also play important roles in maintenance of wakefulness. To dissect the role of the histaminergic system as a downstream mediator of the orexin system in the regulation of sleep/wake states without compensation by the orexin receptor-1 (OX1R) mediated pathways, we analysed the phenotype of Histamine-1 receptor (H1R) and OX1R double-deficient (H1R,/,;OX1R,/,) mice. These mice lack OX1R-mediated pathways in addition to deficiency of H1R, which is thought to be the most important system in downstream of OX2R. Methods:, We used H1R deficient (H1R,/,) mice, H1R,/,;OX1R,/, mice, OX1R and OX2R double-deficient (OX1R,/,;OX2R,/,) mice, and wild type controls. Rapid eye movement (REM) sleep, non-REM (NREM) sleep and awake states were determined by polygraphic electroencephalographic/electromyographic recording. Results:, No abnormality in sleep/wake states was observed in H1R,/, mice, consistent with previous studies. H1R,/,;OX1R,/, mice also showed a sleep/wake phenotype comparable to that of wild type mice, while OX1R,/,; OX2R,/, mice showed severe fragmentation of sleep/wake states. Conclusion:, Our observations showed that regulation of the sleep/wake states is completely achieved by OX2R-expressing neurones without involving H1R-mediated pathways. The maintenance of basal physiological sleep/wake states is fully achieved without both H1 and OX1 receptors. Downstream pathways of OX2R other than the histaminergic system might play an important role in the maintenance of sleep/wake states. [source] Lithium and KB-R7943 effects on mechanics and energetics of rat heart muscleACTA PHYSIOLOGICA, Issue 1 2002P. Bonazzola ABSTRACT The role of calcium influx on energy expenditure during cardiac contraction was studied. For this purpose, the described ability of lithium and KB-R 7943 (KBR) to diminish Ca entry through Na,Ca exchanger (Ponce-Hornos & Langer, J Mol Cell Cardiol 1980, 12, 1367, Satoh et al., Circulation 2000, 101, 1441) were used. In isolated contractions (contractions elicited after at least 5 min of rest) LiCl 45 mmol L,1 decreased pressure developed and pressure,time integral from 42.3 ± 2.7 and 14.5 ± 1.2 to 32.1 ± 3.4 mN mm,2 and 8.3 ± 0.9 mN mm,2 s, respectively. A similar effect was observed in regular contractions (at 0.16 Hz stimulation). The presence of KBR (5 ,mol L,1) in the perfusate induced a slight but not significant decrease in pressure developed and pressure,time integral in steady-state contractions. As it was previously described, the heat involved in a heart muscle contraction can be decomposed into several components (H1, H2, H3 and H4), but only one (H3) was associated with force generation. While H3 decreased with lithium in both types of contractions, H3/PtI ratio remained unaltered, indicating that the economy for pressure maintenance was unaffected. To further investigate the role of Ca entry on force development, a condition in which the contraction is mainly dependent on extracellular calcium was studied. An ,extra' stimulus applied 200 ms after the regular one in a muscle stimulated at 0.16 Hz induces a contraction with this characteristic (Marengo et al., Am J Physiol 1999, 276, H309). Lithium induced a strong decrease in pressure,time integral and H3 associated with this contraction (43 and 45%, respectively) with no change in H3/PtI ratio. Lithium also reduced (53%) an energy component (H2) associated with Ca cycling. The use of KBR showed qualitatively similar results [i.e. a 33% reduction in pressure,time integral associated with the extrasystole (ES) with no changes in H3/PtI ratio and a 30% reduction in the H2 component]. Li and KBR effects appear to be additive and in the presence of 45 mmol L,1 Li and 5 ,mol L,1 KBR the extrasystole was abolished in 77%. Lithium and KBR effects particularly for the extrasystole can be explained through the inhibition of Ca entry via Na,Ca exchange giving support to the participation of the Na,Ca exchanger in the Ca influx from the extracellular space. In addition, the results also suggest the possibility of an effect of Li on an additional Ca sensitive locus (different than the Na,Ca exchanger). In this connection, in isolated contractions lithium decreased the energy release fraction related to mitochondrial processes (H4) increasing the economy of the overall cardiac contraction. [source] Learning How and Learning What: Effects of Tacit and Codified Knowledge on Performance Improvement Following Technology AdoptionDECISION SCIENCES, Issue 2 2003Amy C. Edmondson ABSTRACT This paper examines effects of tacit and codified knowledge on performance improvement as organizations gain experience with a new technology. We draw from knowledge management and learning curve research to predict improvement rate heterogeneity across organizations. We first note that the same technology can present opportunities for improvement along more than one dimension, such as efficiency and breadth of use. We compare improvement for two dimensions: one in which the acquisition of codified knowledge leads to improvement and another in which improvement requires tacit knowledge. We hypothesize that improvement rates across organizations will be more heterogeneous for dimensions of performance that rely on tacit knowledge than for those that rely on codified knowledge (H1), and that group membership stability predicts improvement rates for dimensions relying on tacit knowledge (H2). We further hypothesize that when performance relies on codified knowledge, later adopters should improve more quickly than earlier adopters (H3). All three hypotheses are supported in a study of 15 hospitals learning to use a new surgical technology. Implications for theory and practice are discussed. [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] Chiral separation of cetirizine by capillary electrophoresisELECTROPHORESIS, Issue 12 2006Ann Van Eeckhaut Abstract Chiral separation of cetirizine, a second-generation H1 -antagonist, was studied by CD-mediated CE. Several parameters, including pH, CD type, buffer concentration, type of co-ion, applied voltage and temperature, were investigated. The best conditions for chiral separation were obtained using a 75,mM triethanolamine-phosphate buffer (pH,2.5) containing 0.4,mg/mL heptakis(2,3-diacetyl-6-sulfato)-,-CD and 10%,ACN. Online UV detection was performed at 214,nm, a voltage of 20,kV was applied and the capillary was temperature controlled at 25°C by liquid cooling. Hydrodynamic injection was performed for 1,s. The method was validated for the quantification of levocetirizine in tablets and for enantiomeric purity testing of the drug substance. Selectivity, linearity, LOD and LOQ, precision and accuracy were evaluated for both methods. The amount of levocetirizine dihydrochloride in the commercially available tablets was quantified and was found to be within the specification limits of the claimed amount (5,mg). The amount of distomer in levocetirizine drug substance was found to be 0.87 ± 0.09%,w/w, which is in agreement with the certificate of analysis supplied by the company. [source] Stage-specific expression of Caenorhabditis elegans ribonuclease H1 enzymes with different substrate specificities and bivalent cation requirementsFEBS JOURNAL, Issue 2 2006Hiromi Kochiwa Ribonuclease H1 (RNase H1) is a widespread enzyme found in a range of organisms from viruses to humans. It is capable of degrading the RNA moiety of DNA,RNA hybrids and requires a bivalent ion for activity. In contrast with most eukaryotes, which have one gene encoding RNase H1, the activity of which depends on Mg2+ ions, Caenorhabditis elegans has four RNase H1-related genes, and one of them has an isoform produced by alternative splicing. However, little is known about the enzymatic features of the proteins encoded by these genes. To determine the differences between these enzymes, we compared the expression patterns of each RNase H1-related gene throughout the development of the nematode and the RNase H activities of their recombinant proteins. We found gene-specific expression patterns and different enzymatic features. In particular, besides the enzyme that displays the highest activity in the presence of Mg2+ ions, C. elegans has another enzyme that shows preference for Mn2+ ion as a cofactor. We characterized this Mn2+ -dependent RNase H1 for the first time in eukaryotes. These results suggest that there are at least two types of RNase H1 in C. elegans depending on the developmental stage of the organism. [source] Characterization of sequence variations in human histone H1.2 and H1.4 subtypesFEBS JOURNAL, Issue 14 2005Bettina Sarg In humans, eight types of histone H1 exist (H1.1,H1.5, H1°, H1t and H1oo), all consisting of a highly conserved globular domain and less conserved N- and C-terminal tails. Although the precise functions of these isoforms are not yet understood, and H1 subtypes have been found to be dispensable for mammalian development, it is now clear that specific functions may be assigned to certain individual H1 subtypes. Moreover, microsequence variations within the isoforms, such as polymorphisms or mutations, may have biological significance because of the high degree of sequence conservation of these proteins. This study used a hydrophilic interaction liquid chromatographic method to detect sequence variants within the subtypes. Two deviations from wild-type H1 sequences were found. In K562 erythroleukemic cells, alanine at position 17 in H1.2 was replaced by valine, and, in Raji B lymphoblastoid cells, lysine at position 173 in H1.4 was replaced by arginine. We confirmed these findings by DNA sequencing of the corresponding gene segments. In K562 cells, a homozygous GCC,GTC shift was found at codon 18, giving rise to H1.2 Ala17Val because the initial methionine is removed in H1 histones. Raji cells showed a heterozygous AAA,AGA codon change at position 174 in H1.4, corresponding to the Lys173Arg substitution. The allele frequency of these sequence variants in a normal Swedish population was found to be 6.8% for the H1.2 GCC,GTC shift, indicating that this is a relatively frequent polymorphism. The AAA,AGA codon change in H1.4 was detected only in Raji cells and was not present in a normal population or in six other cell lines derived from individuals suffering from Burkitt's lymphoma. The significance of these sequence variants is unclear, but increasing evidence indicates that minor sequence variations in linker histones may change their binding characteristics, influence chromatin remodeling, and specifically affect important cellular functions. [source] Self-assembled pearling structure of long duplex DNA with histone H1FEBS JOURNAL, Issue 9 2001Yuko Yoshikawa We report that complexes of giant DNA molecules with histone H1 proteins form a pearl necklace-like structure when the complexes are prepared by natural dilution from a high-salt solution (2 m NaCl) to a low-salt solution (0.2 m and 50 mm NaCl). We performed real-time observations on the conformational changes of individual T4 phage DNA (166 kb) molecules in bulk solution by fluorescence microscopy. To identify H1-binding regions on individual DNA molecules, we also performed immunofluorescence microscopic observations on the DNA,H1 complex spread on a glass surface. It was found that histone H1 binds DNA in a highly co-operative manner and is accompanied by local folding of the DNA. On the basis of the experimental observations and a theoretical simulation, we propose a self-assembling mechanism for the pearling structure. [source] Divalent metal cation binding properties of human prothymosin ,FEBS JOURNAL, Issue 15 2000Nina V. Chichkova The divalent cation binding properties of human prothymosin ,, an abundant nuclear protein involved in cell proliferation, were evaluated. By using prothymosin , retardation on a weak cation chelating resin charged with various divalent cations, specific binding of Zn2+ ions by prothymosin , was observed. This finding was further confirmed by the equilibrium dialysis analysis which demonstrated that, within the micromolar range of Zn2+ concentrations, prothymosin , could bind up to three zinc ions in the presence of 100 mm NaCl and up to 13 zinc ions in the absence of NaCl. Equilibrium dialysis analysis also revealed that prothymosin , could bind Ca2+, although the parameters of Ca2+ binding by prothymosin , were less pronounced than those of Zn2+ binding in terms of the number of metal ions bound, the KD values, and the resistance of the bound metal ions to 100 mm NaCl. The effects of Zn2+ and Ca2+ on the interaction of prothymosin , with its putative partners, Rev of HIV type 1 and histone H1, were examined. We demonstrated that Rev binds prothymosin ,, and that prothymosin , binding to Rev but not to histone H1 was significantly enhanced in the presence of zinc and calcium ions. Our data suggest that the modes of prothymosin , interaction with Rev and histone H1 are distinct and that the observed zinc and calcium-binding properties of prothymosin , might be functionally relevant. [source] Histone modifications and chromatin dynamics: a focus on filamentous fungiFEMS MICROBIOLOGY REVIEWS, Issue 3 2008Gerald Brosch Abstract The readout of the genetic information of eukaryotic organisms is significantly regulated by modifications of DNA and chromatin proteins. Chromatin alterations induce genome-wide and local changes in gene expression and affect a variety of processes in response to internal and external signals during growth, differentiation, development, in metabolic processes, diseases, and abiotic and biotic stresses. This review aims at summarizing the roles of histone H1 and the acetylation and methylation of histones in filamentous fungi and links this knowledge to the huge body of data from other systems. Filamentous fungi show a wide range of morphologies and have developed a complex network of genes that enables them to use a great variety of substrates. This fact, together with the possibility of simple and quick genetic manipulation, highlights these organisms as model systems for the investigation of gene regulation. However, little is still known about regulation at the chromatin level in filamentous fungi. Understanding the role of chromatin in transcriptional regulation would be of utmost importance with respect to the impact of filamentous fungi in human diseases and agriculture. The synthesis of compounds (antibiotics, immunosuppressants, toxins, and compounds with adverse effects) is also likely to be regulated at the chromatin level. [source] Stereoselective renal tubular secretion of levocetirizine and dextrocetirizine, the two enantiomers of the H1 -antihistamine cetirizineFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2008M. Strolin Benedetti Abstract Competition for uptake and/or efflux transporters can be responsible for drug interactions. Cetirizine is mainly eliminated unchanged in urine through both glomerular filtration and tubular secretion. The aim of this study was to investigate whether the eutomer, levocetirizine, and the distomer, dextrocetirizine, have a similar tubular secretion. The renal clearance associated with tubular secretion was calculated from the renal clearance of levocetirizine and dextrocetirizine obtained in a study in healthy volunteers. The values of the unbound fraction in plasma were obtained in an in vitro study of the binding of 14C-cetirizine and 14C-levocetirizine to human plasma proteins using equilibrium dialysis and chiral high-performance liquid chromatography (HPLC) with on-line liquid scintillation counting. The unbound fraction was 0.074 for levocetirizine and 0.141 for dextrocetirizine. The tubular secretion of dextrocetirizine (44.5 mL/min) is higher than that of levocetirizine (23.1 mL/min), which may have consequences for drug interactions at the renal level. The higher tubular secretion for dextrocetirizine may be due to the higher free fraction available for secretion or to a higher affinity for (a) renal transporter(s) mediating the secretion pathway. [source] DPPA4 modulates chromatin structure via association with DNA and core histone H3 in mouse embryonic stem cellsGENES TO CELLS, Issue 4 2010Hisaharu Masaki Developmental pluripotency associated 4 (DPPA4) is one of the uncharacterized genes that is highly expressed in embryonic stem (ES) cells. DPPA4 is associated with active chromatin and involved in the pluripotency of mouse ES cells. However, the biological function of DPPA4 remains poorly understood. In this study, we performed fluorescence recovery after photobleaching (FRAP) analysis to examine the dynamics of DPPA4 in ES cells. FRAP analysis showed that the mobility of DPPA4 is similar to that of histone H1. In addition, biochemical analysis with purified proteins and immunoprecipitation analysis showed that DPPA4 directly binds to both DNA and core histone H3. The analysis using truncated proteins indicated that DPPA4 is associated with DNA via the N-terminal region and histone H3 via the C-terminal region. In vitro assembled chromatin showed resistance to micrococcal nuclease (MNase) digestion in the presence of DPPA4. Moreover, MNase assay and FRAP analysis with the truncated proteins implies that DPPA4 binding to both DNA and histone H3 is necessary for the chromatin structure resistant to MNase and for the proper localization of DPPA4 in ES cell nuclei. These results suggest that DPPA4 modulates the chromatin structure in association with DNA and histone H3 in ES cells. [source] The absence of ribonuclease H1 or H2 alters the sensitivity of Saccharomyces cerevisiae to hydroxyurea, caffeine and ethyl methanesulphonate: implications for roles of RNases H in DNA replication and repairGENES TO CELLS, Issue 10 2000Arulvathani Arudchandran Background RNA of RNA-DNA hybrids can be degraded by ribonucleases H present in all organisms including the eukaryote Saccharomyces cerevisiae. Determination of the number and roles of the RNases H in eukaryotes is quite feasible in S. cerevisiae. Results Two S. cerevisiae RNases H, related to Escherichia coli RNase HI and HII, are not required for growth under normal conditions, yet, compared with wild-type cells, a double-deletion strain has an increased sensitivity to hydroxyurea (HU) and is hypersensitive to caffeine and ethyl methanesulphonate (EMS). In the absence of RNase H1, RNase H2 activity increases, and cells are sensitive to EMS but not HU and are more tolerant of caffeine; the latter requires RNase H2 activity. Cells missing only RNase H2 exhibit increased sensitive to HU and EMS but not caffeine Conclusions Mutant phenotypes infer that some RNA-DNA hybrids are recognized by both RNases H1 and H2, while other hybrids appear to be recognized only by RNase H2. Undegraded RNA-DNA hybrids have an effect when DNA synthesis is impaired, DNA damage occurs or the cell cycle is perturbed by exposure to caffeine suggesting a role in DNA replication/repair that can be either beneficial or detrimental to cell viability. [source] Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinizationHISTOPATHOLOGY, Issue 6 2006D E Burstein Aims :,To examine invasive head and neck squamous carcinomas for expression of GLUT1, a glucose transporter and marker of increased glucose uptake, glycolytic metabolism and response to tissue hypoxia; p63, a p53 homologue that is a marker of the undifferentiated proliferative basaloid phenotype; and phospho-histone H1, a marker of activation of the cell cycle-promoting cyclin-dependent kinases 1 and 2. Methods :,Routinely processed slides from 34 invasive squamous carcinomas, including 25 with intraepithelial components, were immunostained with anti-GLUT1 (Chemicon), anti-p63 (4A4, Santa Cruz), and antiphospho-histone H1 (monoclonal 12D11). Results :,In keratinizing carcinomas, all three markers were most commonly immunodetected peripherally, with loss of expression in central keratinized zones. In contrast, in non-keratinizing carcinomas, p63 and phospho-histone H1 expression was most commonly observed throughout tumour nests and anti-GLUT1 stained in a pattern suggestive of hypoxia-induced expression (,antistromal' staining), in which cells at the tumour,stromal interface were GLUT1, and cells in central, perinecrotic zones showed progressive induction of GLUT1. Intraepithelial components also displayed basal and ,antibasal' GLUT1 staining patterns, homologous to the pro- and antistromal patterns in invasive carcinoma; basal patterns in intraepithelial lesions appeared to be more predictive of keratinizing invasive carcinoma and antibasal intraepithelial staining more predictive of non-keratinizing poorly differentiated carcinomas. Conclusions :,Keratinizing and non-keratinizing squamous carcinomas differ in expression patterns of GLUT1, p63 and phospho-histone H1. In the former, all three markers were typically suppressed in conjunction with keratinization; in the latter, GLUT1 expression was more likely to occur in a hypoxia-inducible pattern and expression of p63 and phospho-histone H1 was unsuppressed. GLUT1 expression patterns in intraepithelial lesions may be predictive of the differentiation status of the associated invasive carcinoma. [source] Relational Uncertainty and Message Production Within Courtship: Features of Date Request MessagesHUMAN COMMUNICATION RESEARCH, Issue 3 2006Leanne K. Knobloch This paper theorizes about how relational uncertainty may predict features of date request messages within courtship. It reports a study in which 248 individuals role-played leaving a date request voice mail message for their partner. Relational uncertainty was negatively associated with the fluency (H1), affiliativeness (H2), relationship focus (H3), explicitness (H4), and perceived effectiveness (H5) of messages. Also as expected, relational uncertainty was negatively associated with people's perceptions of the effectiveness of their messages after covarying the judgments of independent observers (H6). Relational uncertainty continued to predict features of messages when length of romantic interest was covaried (RQ1). The paper concludes by discussing the implications of the results for understanding the link between relational uncertainty and message production. [source] Lack of effects between rupatadine 10,mg and placebo on actual driving performance of healthy volunteersHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2007Eric Vuurman Abstract Introduction Rupatadine fumarate is a potent, selective, histamine H1 -receptor antagonist and PAF inhibitor with demonstrated efficacy for the relief of allergic rhinitis. Rupatadine does not easily cross the blood,brain barrier and is believed to be non-sedating at therapeutic doses. Consequently, rupatadine should show no impairment on car driving. Objective This study compared the acute effects of rupatadine, relative to placebo and hydroxyzine (as an active control), on healthy subjects' driving performance. Methods Twenty subjects received a single dose of rupatadine 10,mg, hydroxyzine 50,mg, or placebo in each period of this randomized, double-blind, three-way crossover study. Two hours postdosing, subjects operated a specially instrumented vehicle in tests designed to measure their driving ability. Before and after the driving tests ratings of sedation were recorded. Results There was no significant difference between rupatadine and placebo in the primary outcome variable: standard deviation of lateral position (SDLP); however, hydroxyzine treatment significantly increased SDLP (p,<,0.001 for both comparisons). Objective (Stanford sleepiness scale) and subjective sedation ratings (Visual Analogue Scales) showed similar results: subjects reported negative effects after hydroxyzine but not after rupatadine. Conclusion Rupatadine 10,mg is not sedating and does not impair driving performance. Copyright © 2007 John Wiley & Sons, Ltd. [source] Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteersHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2006Manuel J. Barbanoj Abstract Introduction The Central Nervous System (CNS) impairment induced by moderate alcohol (ALC) ingestion may be enhanced if other drugs are taken simultaneously. Rupatadine (RUP) is a new H1 -antihistamine which also inhibits platelet activating factor (PAF) release in inflammatory reactions. Objective The main aim of the study was to assess the effects of ALC 0.8,g/Kg on RUP (10,mg and 20,mg) CNS effects. An evaluation of alcohol and RUP pharmacokinetics was also attained. Methods Eighteen healthy young volunteers of both sexes participated in a phase I, randomised, crossover, double-blind, placebo-controlled study. At 2-week intervals they received six treatments: (a) placebo (PLA), (b) ALC alone and ALC in combination with: (c) hydroxyzine 25,mg (HYD), (d) cetirizine 10,mg (CET), (e) RUP 10,mg or (f) RUP 20,mg. At baseline and several times thereafter, seven psychomotor performance tests (finger tapping, fine motoric skills, nystagmus, temporal estimation, critical-flicker-fusion frequency, ,d2' cancellation, simple reaction) and eleven subjective self-reports (drunkenness, sleepiness, alertness, clumsiness, anger, inattentiveness, efficiency, happiness, hostility, interest and extraversion) were carried out. Two-way (treatment, time) ANOVAs for repeated measures to each variable together with a multivariate non-parametric approach were applied. Plasma concentrations of alcohol, and of RUP and its metabolites, were quantified by validated immunofluorescence and LC/MS/MS methods, respectively. Plasma-time curves for all compounds were analysed by means of model-independent methods. Results The combination of alcohol with HYD, CET and RUP 20,mg produced more cognitive and psychomotor impairment as compared to alcohol alone, being the combination of alcohol and HYD the one which induced the greatest deterioration. The combination of alcohol and RUP 10,mg could not be differentiated from ALC alone. Subjective self-reports reflect effects on metacognition after the combination of alcohol with HYD and CET i.e. the increased objective impairment observed was not subjectively perceived by the subjects. No significant differences were obtained when comparing alcohol plasma concentrations assessed after the treatments evaluated. RUP showed a lineal kinetic relationship after 10 and 20,mg with a higher exposition to both metabolites assayed. Conclusions Present results showed that single oral doses of rupatadine 10,mg in combination with alcohol do not produce more cognitive and psychomotor impairment than alcohol alone. Higher doses of rupatadine, in combination with alcohol, may induce cognitive and psychomotor deterioration as hydroxyzine and cetirizine at therapeutic doses. Copyright © 2006 John Wiley & Sons, Ltd. [source] An analysis of alternative conceptual models relating hyporheic exchange flow to diel fluctuations in discharge during baseflow recessionHYDROLOGICAL PROCESSES, Issue 6 2010Steven M. Wondzell Abstract Diel fluctuations in stream flow during baseflow have been observed in many streams and are typically attributed to water losses from evapotranspiration (ET). However, there is no widely transferable conceptual model that explains how ET results in diel fluctuations in streamflow at the watershed outlet. For fluctuations to occur, two factors must be present: (1) some process must generate the fluctuations and transfer them to the stream channel, and (2) fluctuations must be accumulated and transported down the stream network in such a way that they arrive at a stream gauge as a coherent signal. We have previously shown how stream flow velocity affects the transport of diel fluctuations in discharge through a stream network. Here, we examined how riparian ET and hyporheic exchange flows generate diel fluctuations in discharge. We hypothesized that ET would cause a slight drawdown of riparian aquifers during the day, slightly increasing head gradients away from the stream and slightly reducing head gradients back to the stream. Thus, slightly more water would flow into the hyporheic zone than is returned to the stream, gradually reducing stream discharge. The process would be reversed at night. Using stream-tracer experiments and riparian water-level data, we tested two hypotheses related to this conceptual model,that the amplitude (H1) and time lag (H2) of diel aquifer drawdown would be constant over the summer. Neither hypothesis was supported by our data. We conclude that the processes that link watershed ET with streams include both local- and watershed-scale effects. Conceptual models attempting to explain diel fluctuations need to include the combined effects of ET on lateral inputs and hyporheic exchange flows, the redistribution of water within riparian aquifers, and the transport of ET signals from the whole stream network to the stream gauge. Copyright © 2009 John Wiley & Sons, Ltd. [source] Variation and infectivity neutralization in influenzaIMMUNOLOGY, Issue 1 2006Marcel Knossow Summary Worldwide epidemics of influenza are caused by viruses that normally infect other species, particularly waterfowl, and that contain haemagglutinin membrane glycoproteins (HAs) to which the human population has no immunity. Anti-HA immunoglobulins neutralize influenza virus infectivity. In this review we outline structural differences that distinguish the HAs of the 16 antigenic subtypes (H1,16) found in viruses from avian species. We also describe structural changes in HA required for the effective transfer to humans of viruses containing three of them, H1, H2 and H3, in the 1918 (Spanish), the 1957 (Asian) and the 1968 (Hong Kong) pandemics, respectively. In addition, we consider changes that may be required before the current avian H5 viruses could pass from human to human. [source] High-frequency haplotypes in the X chromosome locus TLR8 are associated with both CD and UC in femalesINFLAMMATORY BOWEL DISEASES, Issue 3 2009Masayuki Saruta MD Abstract Background: TNF-, and IL-1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15/NOD2. Recently, Toll-like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD. Methods: Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes. Results: Both "risk (H4)" and "protective (H1)" TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls (P = 0.02). Fifty-nine percent of CD females had H1 compared with 72% of controls (P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4,0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0,2.2. Thus, the risk for IBD was 4,5 times higher in females with 1 risk haplotype than with the protective/protective diplotype. Conclusions: TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well. (Inflamm Bowel Dis 2008) [source] IL23R haplotypes provide a large population attributable risk for Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2008Kent D. Taylor PhD Abstract Background: The IL-23 pathway plays a pivotal role in the development of chronic mucosal inflammation seen in the inflammatory bowel diseases. Multiple studies have now established the contribution of the interleukin 23 receptor gene (IL23R) to Crohn's disease (CD) risk in general and of the IL23R R381Q variant in particular. The aim of this work was to estimate the total contribution of this gene to CD risk test using a haplotype approach. Methods: In all, 763 CD subjects and 254 controls were genotyped for single nucleotide polymorphisms in the IL23R gene using Illumina and ABI methods. Haplotypes were assigned using PHASEv2 and tested for association with CD by chi-square and permutation. Results: Haplotypes with both increased and decreased risk for CD were observed in 2 of the 4 observed blocks (Block 2 H1: 55.4% control, 64% CD, P = 0.019; H2: 64.5% control, 54.4% CD, P = 0.006; Block 3 H1: 55.8% control, 64.4% CD, P = 0.013; H2: 47.0% control, 36.6% CD, P = 0.001). The population attributable risk for these haplotypes was substantially larger than that estimated for the IL23R R381Q variant (Block 2 H1 and block 3 H1 ,20%, compared with ,4% for Block 3 H6, containing the variant). Conclusions: These observations suggest that IL23R makes a substantial contribution to CD susceptibility, larger than that estimated from the population frequency of the R381Q variant. These observations also support the expectation that finding "hits" from genomewide association studies will be but an important chapter in the story of unraveling the genetic contribution to CD, rather than the final chapter that brings clarity to all the plot twists of a complicated story. (Inflamm Bowel Dis 2008) [source] Serologic survey of swine workers for exposure to H2N3 swine influenza AINFLUENZA AND OTHER RESPIRATORY VIRUSES, Issue 3 2010Amanda Beaudoin Please cite this paper as: Beaudoin et al. (2010) Serologic survey of swine workers for exposure to H2N3 swine influenza A. Influenza and Other Respiratory Viruses 4(3), 163,170. Background, Of the 16 influenza A hemagglutinin (H) subtypes, only H1, H2 and H3 viruses have been shown to cause sustained human infection. Whereas H1 and H3 viruses currently circulate seasonally in humans, H2 viruses have not been identified in humans since 1968. In 2006, an H2N3 influenza virus was isolated from ill swine in the United States. Objective, To assess the potential for zoonotic influenza transmission, the current study looked for serologic evidence of H2 influenza infection among workers at two swine facilities, some exposed and some unexposed to H2N3-positive pigs. Methods, The sera were assessed for antibodies to swine H2 influenza and currently circulating seasonal human influenza A subtypes H1N1 and H3N2. Workers were interviewed to obtain details such as age, influenza vaccination history, experiences of influenza-like-illness, and use of personal protective equipment and hygiene when working with pigs. Exposure and risk factors for positive antibody titers were compared for exposed and unexposed individuals as well as for H2 antibody-positive and H2 antibody-negative individuals. Results, Blood was taken from 27 swine workers, of whom four had positive H2 antibody titers (,1:40). Three of the positive employees were born before 1968 and one had an unknown birth date. Only one of these workers had been exposed to H2N3-positive pigs, and he was born in 1949. Conclusions, These data do not support the hypothesis that swine workers were infected with the emergent swine H2N3 influenza A virus. [source] Bridging domain methods for coupled atomistic,continuum models with L2 or H1 couplingsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 11 2009P.-A. Guidault Abstract A bridging domain method for coupled atomistic,continuum models is proposed that enables to compare various coupling terms. The approach does not require the finite element mesh to match the lattice spacing of the atomic model. It is based on an overlapping domain decomposition method that makes use of Lagrange multipliers and weight functions in the coupling zone in order to distribute the energy between the two competing models. Two couplings are investigated. The L2 coupling enforces the continuity of displacements between the two models directly. The H1 coupling involves the definition of a strain measure. For this purpose, a moving least-square interpolant of the atomic displacement is defined. The choice of the weight functions is studied. Patch tests and a graphene sheet with a crack are studied. It is shown that both continuous and discontinuous weight functions can be used with the H1 coupling whereas the L2 coupling requires continuous weight functions. For the examples developed herein, the L2 coupling produces less error in the zone of interest. The flexibility of the H1 coupling with constant weight function may be beneficial but the results may be affected depending on the topology of the bridging zone. Copyright © 2008 John Wiley & Sons, Ltd. [source] Hierarchic finite element bases on unstructured tetrahedral meshesINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 14 2003Mark Ainsworth Abstract The problem of constructing hierarchic bases for finite element discretization of the spaces H1, H(curl), H(div) and L2 on tetrahedral elements is addressed. A simple and efficient approach to ensuring conformity of the approximations across element interfaces is described. Hierarchic bases of arbitrary polynomial order are presented. It is shown how these may be used to construct finite element approximations of arbitrary, non-uniform, local order approximation on unstructured meshes of curvilinear tetrahedral elements. Copyright © 2003 John Wiley & Sons, Ltd. [source] Climate predictability and breeding phenology in red deer: timing and synchrony of rutting and calving in Norway and FranceJOURNAL OF ANIMAL ECOLOGY, Issue 4 2005L. E. LOE Summary 1Timing and synchrony of reproduction are regarded as crucially important factors for fitness in seasonal environments. Natural selection has probably favoured temperate and arctic female herbivores that match reproduction with onset of plant growth in spring. However, breeding synchrony may also be affected by variation in phenotypic quality of females in a population, because females in poor body condition have been found to delay ovulation and subsequent calving. 2We compared breeding phenology, i.e. the timing and synchrony of rutting (roaring, sexual aggregation) and calving of red deer (Cervus elaphus L.) in France (latitude: 49°N) and Norway (latitude: 63°N). We hypothesized (H1) that calving and rutting were later at the site with latest onset of plant growth. 3We further quantified overall environmental predictability as the sum of annual constancy and seasonality and tested three different (not mutually exclusive) hypotheses about breeding synchrony: (H2a) the population experiencing most seasonal plant phenology should show the highest breeding synchrony; (H2b) overall predictability of plant phenology should determine breeding synchrony; and (H2c) breeding should be more synchronized in the population with lowest female body weight variation within age classes because they ovulate more synchronously. 4Calving and rutting, as well as onset of plant phenology, were later in Norway than in France, complying with the first hypothesis. Plant growth in spring was overall more predictable and also more seasonal in Norway than France. Hence we expected higher breeding synchrony in Norway than in France according to H2a and H2b. Variance in female body weight was slightly higher in France than in Norway, which should also cause more synchronized breeding in Norway than in France (H2c). Contrary to all predictions, variance in rutting and calving dates was around two times higher in Norway than in France. 5We suggest two alternative explanations of breeding synchrony. A more variable topography in Norway can make optimal birth date more variable on a local scale than in France, thereby maintaining a higher genetic variance for calving date in Norwegian red deer. Further, population age structure may play a role, as ovulation varies according to female age. Clearly, processes of breeding synchrony are far more complex than previously realized. [source] Programming the genome in embryonic and somatic stem cellsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2007Philippe Collas ,,Introduction ,,Epigenetic makeup of embryonic stem cells: keeping chromatin loose -,DNA methylation and gene expression -,CpG methylation profiles in mouse ESCs -,CpG methylation patterns in human ESCs -,Both active and inactive histone modification marks on developmentally regulated genes in ESCs suggest transcriptional activation potential -,A regulatory role of histone H1 in gene expression in embryonic stem cells? -,Polycomb group proteins impose a transcriptional brake on lineage-priming genes ,,The epigenetic makeup of mesenchymal stem cells reflects restricted differentiation potential -,CpG methylation patterns on lineage-specific promoters in adipose stem cells -,CpG content affects the relationship between promoter DNA methylation and transcriptional activity -,Bivalent histone modifications on potentially active genes? ,,Linking DNA methylation to histone modifications, chromatin packaging and (re)organization of the nuclear compartment ,,Perspectives: towards remodelling the stem cell epigenome? Abstract In opposition to terminally differentiated cells, stem cells can self-renew and give rise to multiple cell types. Embryonic stem cells retain the ability of the inner cell mass of blastocysts to differentiate into all cell types of the body and have acquired in culture unlimited self-renewal capacity. Somatic stem cells are found in many adult tissues, have an extensive but finite lifespan and can differentiate into a more restricted array of cell types. A growing body of evidence indicates that multi-lineage differentiation ability of stem cells can be defined by the potential for expression of lineage-specification genes. Gene expression, or as emphasized here, potential for gene expression, is largely controlled by epigenetic modifications of DNA and chromatin on genomic regulatory and coding regions. These modifications modulate chromatin organization not only on specific genes but also at the level of the whole nucleus; they can also affect timing of DNA replication. This review highlights how mechanisms by which genes are poised for transcription in undifferentiated stem cells are being uncovered through primarily the mapping of DNA methylation, histone modifications and transcription factor binding throughout the genome. The combinatorial association of epigenetic marks on developmentally regulated and lineage-specifying genes in undifferentiated cells seems to define a pluripotent state. [source] Topoisomerase inhibitor induced dephosphorylation of H1 and H3 histones as a consequence of cell cycle arrestJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Nicole Happel Abstract Posttranslational modifications of histones have an integral function in the structural and functional organization of chromatin. Several changes in the modification state of histones could be observed after induction of apoptosis with topoisomerase inhibitors and other inducers. Most of these studies include the analysis of the state of phosphorylation of histones, and the results are to some extent controversial, depending on cell lines and agents used. In the present study we compared the kinetics of the dephosphorylation of H1 and H3 histones with apoptosis markers after treatment of leukemic cell lines with topoisomerase inhibitors. In parallel, we determined cell cycle parameters in detail. Dephosphorylation of both histone classes started within 1 h of induction, and no direct correlation with timing and intensity of the investigated apoptotic features could be observed. In contrast, we show that the effect of topoisomerase inhibitors on the state of H1 and H3 phosphorylation is not directly related to apoptosis, but reflects the changes in the cell cycle distribution of cells treated with these inducers. © 2005 Wiley-Liss, Inc. [source] Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease GJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Piotr Widlak Abstract Toward the end of the 20th and beginning of the 21st centuries, clever in vitro biochemical complementation experiments and genetic screens from the laboratories of Xiaodong Wang, Shigekazu Nagata, and Ding Xue led to the discovery of two major apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G). Both endonucleases attack chromatin to yield 3,-hydroxyl groups and 5,-phosphate residues, first at the level of 50,300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non-apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45) [also called inhibitor of CAD (ICAD-L)] and a 40 kD latent nuclease subunit (DFF40/CAD). Apoptotic activation of caspase-3 or -7 results in the cleavage of DFF45/ICAD and release of active DFF40/CAD nuclease. DFF40's nuclease activity is further activated by specific chromosomal proteins, such as histone H1, HMGB1/2, and topoisomerase II. DFF is regulated by multiple pre- and post-activation fail-safe steps, which include the requirements for DFF45/ICAD, Hsp70, and Hsp40 proteins to mediate appropriate folding during translation to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitors (DFF45/35; ICAD-S/L). By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF). Understanding further regulatory check-points involved in safeguarding non-apoptotic cells against accidental activation of these nucleases remain as future challenges, as well as designing ways to selectively activate these nucleases in tumor cells. © 2005 Wiley-Liss, Inc. [source] G-protein coupled receptors: SAR analyses of neurotransmitters and antagonistsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2004C. L. Kuo MS Summary Background:, From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (, - and , -), dopaminergic, serotoninergic (5-HT1,5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective:, The aim of the present study is to examine the structure,activity relationships of agents acting on G-protein coupled receptors. Method:, Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results:, The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and , as independent variables. Conclusion:, It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors. [source] Fourier transformation of arterial Doppler waveforms of the lower extremityJOURNAL OF CLINICAL ULTRASOUND, Issue 6 2004Hong Gi Lee MD Abstract Purpose Although it is well known that the normal, triphasic pulsatile arterial Doppler waveform changes in shape as flow is impaired, interpretation of the waveform has largely been subjective. We aimed to describe the Doppler waveforms of the lower extremity objectively using Fourier transformation. Methods Sixty-eight zero-crossing detector arterial recordings from 25 lower extremities were grouped as follows: group 1, no ischemic symptoms with an ankle-brachial index (ABI) > 0.9 (n = 17, 8 limbs); group 2, no ischemic symptoms with ABI < 0.9 (n = 18, 5 limbs); group 3, symptoms of claudication (n = 19, 7 limbs); group 4, rest pain or tissue loss (n = 14, 5 limbs). The waveforms were Fourier transformed and their amplitudes and phases were compared up to the third harmonic (H3). Results Amplitudes of both the fundamental (H1) and second harmonic (H2) were predominant in group 1. In contrast, amplitudes of the H2 and H3 decreased with altered flow (p < 0.0001 for group 1 versus others). The phases of the H1 and H2 were delayed with altered flow (p < 0.05 for group 1 versus others). Phases of the H1 were different between group 2 and 4 (p < 0.05). The difference of phase between the H3 and H1 was shortened with altered flow (p < 0.05 for group 1 or 2 versus group 4). Multivariate analysis revealed that the relative amplitudes of the H2 and H3, the phases of the H1 and H2, and the relative phase of the H3 were significant discriminators among the groups. Conclusion Abnormal waveforms could be characterized by the predominant amplitude of the H1, phase delay of the H1 and H2, and shortening of the relative phase of the H3. These parameters may be useful in the evaluation of Doppler waveforms in patients with peripheral arterial disease. © 2004 Wiley Periodicals, Inc. J Clin Ultrasound 32:277,285, 2004 [source] | ||||||||||||||||||||||||||||||||||||||||||||||