bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dexamethasone and cardiac potassium currents in the diabetic rat
Authors: Shimoni Yakhin 
Published: July 2005

Experiments were designed to compare effects of dexamethasone on transient (Ipeak) and sustained (Isus) K+ currents in control and diabetic rat myocytes. Ventricular myocytes were isolated from control or type 1 streptozotocin (STZ)‐induced diabetic male and female rats. Currents were measured using whole‐cell voltage‐clamp methods.
Incubation of cells from control males or females with 100 nM dexamethasone (5–9 h) significantly (P<0.005) augmented Isus (by 28–31%). Ipeak was unchanged. Isus augmentation was abolished by cycloheximide or cytochalasin D, but not by inhibition of protein kinases A or C. Inhibition of tyrosine kinases by genistein (but not its inactive analog genistin) prevented the increase of Isus by dexamethasone. In marked contrast, dexamethasone had a significantly (P<0.015) smaller effect on Isus (11% increase) in cells from male STZ‐diabetic rats, as compared to control cells. However, Isus augmentation in cells from female STZ‐diabetic rats was normal (31% increase). In ovariectomized‐diabetic rats, Isus was unchanged by dexamethasone. The reduced effect in diabetic males might be due to preactivation of tyrosine kinases linking dexamethasone to current modulation.
In conclusion, type I diabetes is associated with gender‐specific changes in sensitivity of K+ currents to glucocorticoids, linked to alterations in tyrosine‐phosphorylated proteins.

British Journal of Pharmacology (2005) 146, 280–287. doi:10.1038/sj.bjp.0706314
Studies on the effect of MDMA (‘ecstasy’) on the body temperature of rats housed at different ambient room temperatures
Authors: Green A Richard , O'Shea Esther , Saadat Kathryn S , Elliott J Martin , Colado M Isabel 
Published: July 2005

3,4‐Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (Ta) conditions (20°C), but hypothermia when in cool conditions (Ta17°C). We have now investigated some of the mechanisms involved.
MDMA (5 mg kg−1 i.p.) produced a rapid decrease in rectal temperature in rats at Ta 15°C. This response was blocked by pretreatment with the dopamine D2 receptor antagonist remoxipride (10 mg kg−1 i.p.), but unaltered by pretreatment with the D1 antagonist SCH23390 (1.1 mg kg−1 i.p.).
MDMA (5 mg kg−1) did not alter the tail temperature of rats at Ta 15°C, but decreased the tail temperature of rats at Ta 30°C.
A neurotoxic dose of MDMA (three doses of 5 mg kg−1 given 3 h apart) decreased cortical and hippocampal 5‐HT content by approximately 30% 7 days later. This lesion did not influence the rise in tail temperature when rats were moved from Ta 20°C to 30°C compared to nonlesioned controls, but did result in a lower tail temperature than that of controls when they were returned to Ta 24°C.
Acute administration of MDMA (5 mg kg−1) to MDMA‐lesioned rats produced a sustained decrease in tail temperature in rats housed at Ta 30°C compared to nonlesioned controls.
These data suggest that the thermoregulatory problems previously observed in MDMA‐lesioned rats housed at Ta 30°C result, partially, from their inability to lose heat by vasodilation of the tail, a major heat‐loss organ in this species.

British Journal of Pharmacology (2005) 146, 306–312. doi:10.1038/sj.bjp.0706318
Induction of cytochrome P450 1A by cow milk‐based formula: a comparative study between human milk and formula
Authors: Xu Haibo , Rajesan Ratheishan , Harper Patricia , Kim Richard B , Lonnerdal Bo , Yang Mingdong , Uematsu Satoko , Hutson Janine , Watson‐MacDonell Jo , Ito Shinya 
Published: July 2005

During the treatment of neonatal apnea, formula‐fed infants, compared to breastfed infants, show nearly three‐fold increase in clearance of caffeine, a substrate of cytochrome P450 1A (CYP1A) and in part CYP3A4. However, human milk is known to contain higher concentrations of environmental pollutants than infant formula, which are potent CYP1A inducers. To gain insight into the mechanism underlying this apparent contradiction, we characterized CYP1A and CYP3A4 induction by human milk and cow milk‐based infant formula.
The mRNA and protein expression of CYP1A1/1A2 were significantly induced by cow milk‐based formula, but not by human milk, in HepG2 cells.
Luciferase reporter assay demonstrated that cow milk‐based formula but not human milk activated aryl hydrocarbon receptor (AhR) significantly. The cotreatment of 3,4‐dimethoxyflavone, an AhR antagonist, abolished the formula‐induced CYP1A expression. In addition, AhR activation by dibenzo[a,h]anthracene, a potent AhR agonist, was significantly suppressed by infant formula and even more by human milk.
In contrast, CYP3A4 mRNA expression was only mildly induced by formula and human milk. Consistently, neither formula nor human milk substantially activated pregnane X receptor (PXR).
Effects of whey and soy protein‐based formulas on the AhR–CYP1A and the PXR–CYP3A4 pathways were similar to those of cow milk‐based formula.
In conclusion, infant formula, but not human milk, enhances in vitro CYP1A expression via an AhR‐mediated pathway, providing a potential mechanistic basis for the increased caffeine elimination in formula‐fed infants.

British Journal of Pharmacology (2005) 146, 296–305. doi:10.1038/sj.bjp.0706319
Worldwide Genetic Variation at the 3′‐UTR Region of theLDLRGene: Possible Influence of Natural Selection
Authors: Fagundes N. J. R. , Salzano F. M. , Batzer M. A. , Deininger P. L. , Bonatto S. L. 
Published: July 2005

SummaryThe low density lipoprotein receptor gene (LDLR) contains manyAluinsertions, and is especiallyAlu‐rich at its 3′‐untranslated region (3′‐UTR). Previous studies suggested that theLDLR3′‐UTR could regulate gene expression by the stabilization of its mRNA. Given the fasterAluevolutionary rate, and wondering about its consequences in a possibly regulatory locus, we have studied ∼800 bp of 222 chromosomes from individuals of African, Asian, Caucasian and Amerind ancestry, to better understand the evolution of the worldwide genetic diversity at this locus. Twenty‐one polymorphic sites, distributed in 15 haplotypes, were found. High genetic diversity was observed, concentrated in oneAluinsertion (AluU), which also shows a fast evolutionary rate. Genetic diversity is similar in all populations except Amerinds, suggesting a bottleneck during the peopling of the American continent. Three haplotype clusters (A, B, C) are distinguished, cluster A being the most recently formed (∼500,000 years ago). No clear geographic structure emerges from the haplotype network, the globalFst(0.079) being lower than the average for the human genome. When ancestral population growth is taken into account, neutrality statistics are higher than expected, possibly suggesting the action of balancing selection worldwide.
Family‐Based Association Tests for Different Family Structures Using Pooled DNA
Authors: Zou Guohua , Zhao Hongyu 
Published: July 2005

SummaryDNA pooling is a cost‐effective strategy for genomewise association studies to identify disease genes. In the context of family‐based association studies, Risch & Teng (1998) mainly considered families of identical structures to detect associations between genetic markers and disease, and suggested possible approaches to incorporating different family types without a thorough study of their properties. However, families collected in real genetic studies often have different structures and, more importantly, the informativeness of each family structure depends on the disease model which is generally unknown. So there is a need to develop and investigate statistical methods to combine information from diverse family types. In this article, we propose a general strategy to incorporate different family types by assigning each family an “optimal” weight in association tests. In addition, we consider measurement errors in our analysis. When we evaluate our approach under different disease models and measurement errors, we find that our weighting scheme may lead to a substantial reduction in sample size required over the approach suggested by Risch & Teng (1998), and measurement errors may have significant impact on the required sample size when the error rates are not negligible.
Genetic Polymorphisms and Haplotypes of the Human Cardiac Sodium Channel α Subunit Gene (SCN5A) in Japanese and their Association with Arrhythmia
Authors: Maekawa K. , Saito Y. , Ozawa S. , Adachi‐Akahane S. , Kawamoto M. , Komamura K. , Shimizu W. , Ueno K. , Kamakura S. , Kamatani N. , Kitakaze M. , Sawada J. 
Published: July 2005

SummaryGenetic variations in cardiac ion channels have been implicated not only as the causes of inherited arrhythmic syndromes, but also as genetic risk factors for some acquired arrhythmias. To elucidate the potential roles of genetic polymorphisms of the α subunit of the voltage‐gated sodium channel type V (SCN5A) in cardiac rhythm disturbance, the entire SCN5A coding exons and their flanking introns were sequenced in 166 Japanese arrhythmic patients and 232 healthy controls. We detected 69 genetic variations, including 54 novel ones. Out of the 12 novel nonsynonymous single nucleotide polymorphisms (SNPs), p.Leu1988Arg was found at a frequency of 0.015. The other 11 SNPs were rare (0.001), with 6 found in arrhythmic patients and 5 in healthy controls. The frequency of a novel intronic SNP, c.703+130G>A, was significantly higher in the patients than in the controls, suggesting this SNP is associated with an unknown risk factor for arrhythmia. Following linkage disequilibrium analysis, the haplotype structure of SCN5A was inferred using high‐frequency SNPs. The frequency of the haplotype harbouring both p.Leu1988Arg and the common SNP p.His558Arg (haplotype GG) was significantly lower in the patients than in the controls. This finding suggests that this haplotype (GG) might have been positively selected in the controls because of its protective effect against arrhythmias. This study provides fundamental information necessary to elucidate the effect of genetic variations in SCN5A on channel function and cardiac rhythm in Japanese, and probably in the Asian population.
Score Statistic to Test for Genetic Correlation for Proband‐Family Design
Authors: El Galta R. , Van Duijn C. M. , Van Houwelingen J. C. , Houwing‐Duistermaat J. J. 
Published: July 2005

SummaryIn genetic epidemiological studies informative families are often oversampled to increase the power of a study. For a proband‐family design, where relatives of probands are sampled, we derive the score statistic to test for clustering of binary and quantitative traits within families due to genetic factors. The derived score statistic is robust to ascertainment scheme. We considered correlation due to unspecified genetic effects and/or due to sharing alleles identical by descent (IBD) at observed marker locations in a candidate region. A simulation study was carried out to study the distribution of the statistic under the null hypothesis in small data‐sets. To illustrate the score statistic, data from 33 families with type 2 diabetes mellitus (DM2) were analyzed. In addition to the binary outcome DM2 we also analyzed the quantitative outcome, body mass index (BMI). For both traits familial aggregation was highly significant. For DM2, also including IBD sharing at marker D3S3681 as a cause of correlation gave an even more significant result, which suggests the presence of a trait gene linked to this marker. We conclude that for the proband‐family design the score statistic is a powerful and robust tool for detecting clustering of outcomes.
Polymorphic Alu Insertions and their Associations with MHC Class I Alleles and Haplotypes in the Northeastern Thais
Authors: Dunn D. S. , Romphruk A. V. , Leelayuwat C. , Bellgard M. , Kulski J. K. 
Published: July 2005

SummaryPolymorphic Alu insertions (POALINs) are known to contribute to the strong polymorphic nature of the Major Histocompatibility Complex (MHC). Previous population studies on MHC POALINs were limited to only Australian Caucasians and Japanese. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA‐A and ‐B associations, and the three and four locus alpha block POALIN haplotype frequencies in the Northeastern (NE) Thai population. Of the five POALINs, the lowest frequency was 0.018 for AluyHF and the highest frequency was 0.292 for AluyHJ and AluyHG. The strongest positive associations between the POALINs and HLA class I alleles was between AluyMICB and HLA‐B*57, AluyHJ and HLA‐A*24 and HLA‐A*01, and AluyHG and HLA‐A*02, supporting previous findings in Caucasians and Japanese. Single POALIN haplotypes were found more frequently than multiple POALIN haplotypes. However, of the seven different POALIN haplotypes within the MHC alpha block, there were only two significant differences between the NE Thais, Caucasians and Japanese. This study confirms that the MHC POALINs are in linkage disequilibrium with HLA‐A and –B alleles and that there are significant frequency differences for some of the POALINs when compared between NE Thai, Caucasians and Japanese.
The role of dendritic cells in shaping the immune response
Authors: Howard C. J. , Charleston B. , Stephens S. A. , Sopp P. , Hope J. C. 
Published: July 2005

AbstractDendritic cells are central to the initiation of primary immune responses. They are the only antigen-presenting cell capable of stimulating naive T cells, and hence they are pivotal in the generation of adaptive immunity. Dendritic cells also interact with and influence the response of cells of the innate immune system. The manner in which dendritic cells influence the responses in cells of both the innate and adaptive immune systems has consequences for the bias of the adaptive response that mediates immunity to infection after vaccination or infection. It also provides an opportunity to intervene and to influence the response, allowing ways of developing appropriate vaccination strategies. Mouse and human studies have identified myeloid, lymphoid and plasmacytoid dendritic cells. Studies in domesticated animals with agents of specific infectious diseases have confirmed the applicability of certain of the generic models developed from mice or fromin vitrostudies on human cells.In vivoandex vivostudies in cattle have demonstrated the existence of a number of subpopulations of myeloid dendritic cells. These cells differ in their ability to stimulate T cells and in the cytokines that they produce, observations clearly having important implications for the bias of the T-cell response. Dendritic cells also interact with the innate immune system, inducing responses that potentially bias the subsequent adaptive response.
Genetic variation and responses to vaccines
Authors: Glass Elizabeth J. 
Published: July 2005

AbstractDisease is a major source of economic loss to the livestock industry. Understanding the role of genetic factors in immune responsiveness and disease resistance should provide new approaches to the control of disease through development of safe synthetic subunit vaccines and breeding for disease resistance. The major histocompatibility complex (MHC) has been an important candidate locus for immune responsiveness studies. However, it is clear that other loci play an important role. Identifying these and quantifying the relative importance of MHC and non-MHC genes should result in new insights into host–pathogen interactions, and information that can be exploited by vaccine designers. The rapidly increasing information available about the bovine genome and the identification of polymorphisms in immune-related genes will offer potential candidates that control immune responses to vaccines. The bovine MHC,BoLA, encodes two distinct isotypes of class II molecules, DR and DQ, and in about half the common haplotypes theDQgenes are duplicated and expressed. DQ molecules are composed of two polymorphic chains whereas DR consists of one polymorphic and one non-polymorphic chain. Although, it is clear that MHC polymorphism is related to immune responsiveness, it is less clear how different allelic and locus products influence the outcome of an immune response in terms of generating protective immunity in outbred animals. A peptide derived from foot-and-mouth disease virus (FMDV) was used as a probe for BoLA class II function. Both DR and DQ are involved in antigen presentation. In an analysis of T-cell clones specific for the peptide, distinct biases to particular restriction elements were observed. In addition inter-haplotype pairings of DQA and DQB molecules produced functional molecules, which greatly increases the numbers of possible restriction elements, compared with the number of genes, particularly in cattle with duplicatedDQgenes. In a vaccine trial with several peptides derived from FMDV,BoLAclass IIDRB3polymorphisms were correlated with both protection and non-protection. Although variation in immune responsiveness to the FMDV peptide between different individuals is partly explainable byBoLAclass II alleles, other genetic factors play an important role. In a quantitative trait locus project, employing a second-generation cross between Charolais and Holstein cattle, significant sire and breed effects were also observed in T-cell, cytokine and antibody responses to the FMDV peptide. These results suggest that both MHC and non-MHC genes play a role in regulating bovine immune traits of relevance to vaccine design. Identifying these genes and quantifying their relative contributions is the subject of further studies.
Advances in mucosal vaccination
Authors: Meeusen Els N. T. , Scheerlinck Jean-Pierre Y. , Wattegedera Sean , Entrican Gary 
Published: July 2005

AbstractPathogens that enter the body via mucosal surfaces face unique defense mechanisms that combine the innate barrier provided by the mucus layer with an adaptive response typified by the production and transepithelial secretion of pathogen-specific IgA. Both the measurement and induction of mucosal responses pose significant challenges for experimental and practical application and may need to be adapted to the species under study. In particular, for livestock, immunization procedures developed in small rodent models are not always effective in large animals or compatible with management practices. This paper reviews the latest advances in our understanding of the processes that lead to secretory IgA responses and how this relates to the development of mucosal immunization procedures and adjuvants for veterinary vaccines. In addition, it highlights the complex interactions that can take place between the pathogen and the host's immune response, with specific reference toChlamydia/Chlamydophilainfections in sheep.
Vaccination against classical swine fever virus: limitations and new strategies
Authors: Greiser-Wilke Irene , Moennig Volker 
Published: July 2005

AbstractThe most widely used vaccines for the control of classical swine fever (CSF) in countries where it is endemic are live attenuated virus strains, which are highly efficacious, inducing virtually complete protection against challenge with pathogenic virus. In the European Union (EU), the combination of prophylactic mass vaccination and culling of infected pigs in endemic regions has made it possible to almost eradicate the disease. However, it is not possible to discriminate between infected and vaccinated animals, thus hampering disease control measures that rely on serology. Therefore, vaccination was banned at the end of 1990 before the internal common market was established in the EU. Vaccination is allowed only in severe emergencies. In addition, there are strict restrictions on the international trade in pig products from countries using vaccination. To circumvent these problems, marker vaccines which allow differentiation of infected from vaccinated animals (DIVA) have been developed. There are several approaches, ranging from protective peptides, single expressed proteins, naked DNA and chimeric viruses. To date, two subunit vaccines based on the E2 glycoprotein are commercially available and have been tested extensively for their efficacy. The accompanying discriminatory tests are based on an ELISA detecting another viral glycoprotein, the Erns. The subunit vaccines were found to be less efficacious than live attenuated vaccines. In addition, the currently available discriminatory tests do not provide high enough specificity and sensitivity. Although there is an urgent need for more advanced marker vaccines and better discriminatory tests, the development of new DIVA vaccines against CSF is hampered by the small market potential for these products.
Complexities of the pathogenesis ofMannheimia haemolyticaandHaemophilus somnusinfections: challenges and potential opportunities for prevention?
Authors: Czuprynski Charles J. , Leite Fabio , Sylte Matt , Kuckleburg C. , Schultz Ron , Inzana Tom , Behling-Kelly Erica , Corbeil Lynette 
Published: July 2005

AbstractProgress in producing improved vaccines against bacterial diseases of cattle is limited by an incomplete understanding of the pathogenesis of these agents. Our group has been involved in investigations of two members of the family Pasteurellaceae,Mannheimia haemolyticaandHaemophilus somnus, which illustrate some of the complexities that must be confronted. Susceptibility toM. haemolyticais greatly increased during active viral respiratory infection, resulting in rapid onset of a severe and even lethal pleuropneumonia. Despite years of investigation, understanding of the mechanisms underlying this viral–bacterial synergism is incomplete. We have investigated the hypothesis that active viral infection increases the susceptibility of bovine leukocytes to theM. haemolyticaleukotoxin by increasing the expression of or activating the β2integrin CD11a/CD18 (LFA-1) on the leukocyte surface.In vitroexposure to proinflammatory cytokines (i.e. interleukin-1β, tumor necrosis factor-α and interferon-γ) increases LFA-1 expression on bovine leukocytes, which in turn correlates with increased binding and responsiveness to the leukotoxin. Alveolar macrophages and peripheral blood leukocytes from cattle with active bovine herpesvirus-1 (BVH-1) infection are more susceptible to the lethal effects of the leukotoxinex vivothan leukocytes from uninfected cattle. Likewise,in vitroincubation of bovine leukocytes with bovine herpesvirus 1 (BHV-1) potentiates LFA-1 expression and makes the cells more responsive to leukotoxin. A striking characteristic ofH. somnusinfection is its propensity to cause vasculitis. We have shown thatH. somnusand its lipo-oligosaccharide (LOS) trigger caspase activation and apoptosis in bovine endothelial cellsin vitro. This effect is associated with the production of reactive oxygen and nitrogen intermediates, and is amplified in the presence of platelets. The adverse effects ofH. somnusLOS are mediated in part by activation of endothelial cell purinergic receptors such as P2X7. Further dissection of the pathways that lead to endothelial cell damage in response toH. somnusmight help in the development of new preventive or therapeutic regimens. A more thorough understanding ofM. haemolyticaandH. somnusvirulence factors and their interactions with the host might identify new targets for prevention of bovine respiratory disease.