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71.
Narelle K. Hansell Arpana Agrawal John B. Whitfield Katherine I. Morley Scott D. Gordon Penelope A. Lind Michele L. Pergadia Grant W. Montgomery Pamela A. F. Madden Richard D. Todd† rew C. Heath Nicholas G. Martin 《Alcoholism, clinical and experimental research》2010,34(1):158-163
Background: We have previously identified suggestive linkage for alcohol consumption in a community-based sample of Australian adults. In this companion paper, we explore the strength of genetic linkage signals for alcohol dependence symptoms.
Methods: An alcohol dependence symptom score, based on DSM-IIIR and DSM-IV criteria, was examined. Twins and their nontwin siblings (1,654 males, 2,518 females), aged 21 to 81 years, were interviewed, with 803 individuals interviewed on 2 occasions, approximately 10 years apart. Linkage analyses were conducted on datasets compiled to maximize data collected at either the younger or the older age. In addition, linkage was compared between full samples and truncated samples that excluded the lightest drinkers (approximately 10% of the sample).
Results: Suggestive peaks on chromosome 5p (LODs >2.2) were found in a region previously identified in alcohol linkage studies using clinical populations. Linkage signal strength was found to vary between full and truncated samples and when samples differed only on the collection age for a sample subset.
Conclusions: The results support the finding that large community samples can be informative in the study of alcohol-related traits . 相似文献
Methods: An alcohol dependence symptom score, based on DSM-IIIR and DSM-IV criteria, was examined. Twins and their nontwin siblings (1,654 males, 2,518 females), aged 21 to 81 years, were interviewed, with 803 individuals interviewed on 2 occasions, approximately 10 years apart. Linkage analyses were conducted on datasets compiled to maximize data collected at either the younger or the older age. In addition, linkage was compared between full samples and truncated samples that excluded the lightest drinkers (approximately 10% of the sample).
Results: Suggestive peaks on chromosome 5p (LODs >2.2) were found in a region previously identified in alcohol linkage studies using clinical populations. Linkage signal strength was found to vary between full and truncated samples and when samples differed only on the collection age for a sample subset.
Conclusions: The results support the finding that large community samples can be informative in the study of alcohol-related traits . 相似文献
72.
Melissa J. Mulla rew G. Yu Ingrid Cardenas Seth Guller Britta Panda Vikki M. Abrahams 《American journal of reproductive immunology (New York, N.Y. : 1989)》2009,61(4):294-302
Problem: The cytoplasmic pattern recognition receptors, Nod1 and Nod2, are thought to be important for detecting intracellular bacteria. We have previously reported that first trimester trophoblast cells express Nod1 and Nod2, and that trophoblast Nod2 activation triggers an inflammatory response. The objectives of this study were to characterize the effects of Nod1 stimulation, and to determine the regulation of Nod1 and Nod2, in the trophoblast.
Method of Study: The effect of Nod1 activation on trophoblast cells was determined by analyzing the cytokine response following treatment with γ-D-glutamyl- meso -diaminopimelic acid (iE-DAP). The regulation of Nod1 and Nod2 expression by trophoblast cells was evaluated by RT-PCR.
Results: Treatment of trophoblast cells with iE-DAP significantly increased their production of cytokines and chemokines. In addition, Nod1 and Nod2 mRNA expression was upregulated following treatment of trophoblast cells with lipopolysaccharide (LPS), and this was significantly reduced by the presence of a NFκB inhibitor and a TLR4-dominant negative (DN).
Conclusion: This study demonstrates that LPS, through TLR4, increases trophoblast expression of Nod1 and Nod2 via the NFκB pathway; and that Nod1 is functional in the trophoblast. These findings suggest that extracellular recognition of bacterial LPS by TLR4 may prime the trophoblast in preparation for its cytoplasmic recognition of, and response to, bacterial peptides through the Nod proteins. 相似文献
Method of Study: The effect of Nod1 activation on trophoblast cells was determined by analyzing the cytokine response following treatment with γ-D-glutamyl- meso -diaminopimelic acid (iE-DAP). The regulation of Nod1 and Nod2 expression by trophoblast cells was evaluated by RT-PCR.
Results: Treatment of trophoblast cells with iE-DAP significantly increased their production of cytokines and chemokines. In addition, Nod1 and Nod2 mRNA expression was upregulated following treatment of trophoblast cells with lipopolysaccharide (LPS), and this was significantly reduced by the presence of a NFκB inhibitor and a TLR4-dominant negative (DN).
Conclusion: This study demonstrates that LPS, through TLR4, increases trophoblast expression of Nod1 and Nod2 via the NFκB pathway; and that Nod1 is functional in the trophoblast. These findings suggest that extracellular recognition of bacterial LPS by TLR4 may prime the trophoblast in preparation for its cytoplasmic recognition of, and response to, bacterial peptides through the Nod proteins. 相似文献
73.
Maija I. Mednieks rew Szczepanski Brett Clark Arthur R. Hand 《International journal of experimental pathology》2009,90(4):412-422
Diabetes mellitus (DM) is a widespread disease with high morbidity and health care costs. An experimental animal model was employed, using morphological and biochemical methods, to investigate the effects of DM on the expression and compartmentation of salivary gland proteins. The distribution of proline-rich proteins (PRP), submandibular mucin (Muc10) and the regulatory (RI and RII) subunits of cyclic AMP-dependent protein kinase type I and type II was determined in the parotid and submandibular (SMG) glands of rats treated with streptozotocin. Quantitative immunocytochemistry of secretory granules in diabetic glands revealed decreases of 30% for PRP in both the parotid and SMG, and a 40% decrease in Muc10 in the SMG. Immunogold labelling showed that RII decreased in nuclei and the cytoplasm in diabetic acinar cells while labelling of secretory granules was similar in control and diabetic parotid. Electrophoresis and Western blotting of tissue extracts of two secretory proteins showed that the response to DM and insulin treatment was gland specific: PRP showed little change in the SMG, but decreased in the parotid in DM and was partially restored after insulin treatment. Photoaffinity labelling showed only RI present in the SMG and mainly RII in the parotid. The results of this and previous studies demonstrating highly specific changes in salivary protein expression indicate that the oral environment is significantly altered by DM, and that oral tissues and their function can be compromised. These findings may provide a basis for future studies to develop tests using saliva for diabetic status or progression in humans. 相似文献
74.
T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance 总被引:2,自引:1,他引:1
Robert J. Salmond rew Filby Ihjaaz Qureshi Stefano Caserta Rose Zamoyska 《Immunological reviews》2009,228(1):9-22
Summary: T-cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T-cell repertoire, while activation of naive peripheral T cells induces proliferation, gain of effector function, and, ultimately, long-lived T-cell memory. The T-cell immune response is initiated upon engagement of the T-cell receptor (TCR) and coreceptor, CD4 or CD8, by cognate antigen/major histocompatibility complexes presented by antigen-presenting cells. TCR/coreceptor engagement induces the activation of biochemical signaling pathways that, in combination with signals from costimulator molecules and cytokine receptors, direct the outcome of the response. Activation of the src- family kinases p56lck (Lck) and p59fyn (Fyn) is central to the initiation of TCR signaling pathways. This review focuses on our current understanding of the mechanisms by which these two proteins orchestrate T-cell function. 相似文献
75.
Alison D Bullock rew Hassell Wolfgang A Markham David W Wall & Andrew B Whitehouse 《Medical education》2009,43(6):516-520
Context UK doctors-in-training undergo assessments of their professional behaviours. From an analysis of multi-source feedback (MSF) data, we report how ratings of junior doctors (Foundation Programme [FP] doctors and senior house officers [SHOs]) differed by staff group.
Methods The MSF data were collected in 2003 and 2005 in hospitals in the West Midlands. Using a single-sided Team Assessment of Behaviour form, 1928 assessors evaluated 226 FP doctors and SHOs in four domains: professional relationship with patients; communication; team-working, and accessibility. The distribution of 'concerns' across the professional groups was explored using a random effects logistic regression model.
Results On average, each trainee received nine assessment forms from a range of staff, most commonly nurses. Although concerns were identified for the minority, ratings varied by staff group. Peers (other FP doctors or SHOs) and administrators or managers were four and three times, respectively, less likely to indicate concern. By contrast, consultants and sisters (senior nurses) were more likely to give concern ratings.
Conclusions Guidance on the selection of assessors in any MSF process should take into account findings that rating behaviour varies by staff group. 相似文献
Methods The MSF data were collected in 2003 and 2005 in hospitals in the West Midlands. Using a single-sided Team Assessment of Behaviour form, 1928 assessors evaluated 226 FP doctors and SHOs in four domains: professional relationship with patients; communication; team-working, and accessibility. The distribution of 'concerns' across the professional groups was explored using a random effects logistic regression model.
Results On average, each trainee received nine assessment forms from a range of staff, most commonly nurses. Although concerns were identified for the minority, ratings varied by staff group. Peers (other FP doctors or SHOs) and administrators or managers were four and three times, respectively, less likely to indicate concern. By contrast, consultants and sisters (senior nurses) were more likely to give concern ratings.
Conclusions Guidance on the selection of assessors in any MSF process should take into account findings that rating behaviour varies by staff group. 相似文献
76.
77.
Maria P. Arolfo David H. Overstreet Lina Yao Peidong Fan rew J. Lawrence Guoxin Tao Wing-Ming Keung Bert L. Vallee M. Foster Olive Justin T. Gass Emanuel Rubin Helen Anni Clyde W. Hodge Joyce Besheer Jeff Zablocki Kwan Leung Brent K. Blackburn Louis G. Lange Ivan Diamond 《Alcoholism, clinical and experimental research》2009,33(11):1935-1944
Background: Inherited human aldehyde dehydrogenase 2 (ALDH‐2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH‐2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH‐2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH‐2 inhibitor might affect other metabolic factors involved in regulating drinking. Methods: Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co‐crystal structure of ALDH‐2 and daidzin. We tested the efficacy of a highly selective reversible ALDH‐2 inhibitor, CVT‐10216, in models of moderate and high alcohol drinking rats. We studied 2‐bottle choice and deprivation‐induced drinking paradigms in Fawn Hooded (FH) rats, operant self‐administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue‐induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. Results: CVT‐10216 increases acetaldehyde after alcohol gavage and inhibits 2‐bottle choice alcohol intake in heavy drinking rodents, including deprivation‐induced drinking. Moreover, CVT‐10216 also prevents operant self‐administration and eliminates cue‐induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT‐10216 prevents alcohol‐induced increases in NAc DA without changing basal levels. CVT‐10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. Conclusion: Our findings suggest that selective reversible ALDH‐2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics. 相似文献
78.
Mu Yang rew M. Clarke Jacqueline N. Crawley 《The European journal of neuroscience》2009,29(8):1663-1677
The BTBR T+tf/J (BTBR) strain is an inbred strain of mice that displays prominent social deficits and repetitive behaviors analogous to the defining symptoms of autism, along with complete congenital agenesis of the corpus callosum (CC). The BTBR strain is genetically distant from the widely used C57BL/6J (B6) strain, which exhibits high levels of sociability, a low level of repetitive behaviors, and an intact CC. Emerging evidence implicates compromised interhemispherical connectivity in some cases of autism. We investigated the hypothesis that the disconnection of CC fiber tracts contributes to behavioral traits in mice that are relevant to the behavioral symptoms of autism. Surgical lesion of the CC in B6 mice at postnatal day 7 had no effect on juvenile play and adult social approaches, and did not elevate repetitive self-grooming. In addition, LP/J, the strain that is genetically closest to the BTBR strain but has an intact CC, displayed juvenile play deficits and repetitive self-grooming similar to those seen in BTBR mice. These corroborative results offer evidence against the hypothesis that the CC disconnection is a primary cause of low sociability and a high level of repetitive behaviors in inbred mice. Our findings indicate that genes mediating other aspects of neurodevelopment, including those whose mutations underlie more subtle disruptions in white matter pathways and connectivity, are more likely to contribute to the aberrant behavioral phenotypes in the BTBR mouse model of autism. 相似文献
79.
Putting out the fire: coordinated suppression of the innate and adaptive immune systems by SOCS1 and SOCS3 proteins 总被引:1,自引:0,他引:1
Ioannis D. Dimitriou Liliana Clemenza rew J. Scotter Grace Chen Fiona M. Guerra Robert Rottapel 《Immunological reviews》2008,224(1):265-283
Summary: The mounting of an effective immune response requires the coordinated function of both the innate and the adaptive arm of the immune system. Cells from both types of immunity respond to antigenic stimuli through a variety of surface and intracellular receptors and produce cytokines that tightly orchestrate the inflammatory response. The operation of feedback control mechanisms that regulate the duration and the amplitude of antigenic and cytokine receptor signaling is therefore required to prevent hyper-activation of the immune system that could lead to tissue destruction or autoimmunity. Suppressor of cytokine signaling (SOCS) proteins have been identified as a negative feedback loop to cytokine signaling. Recently, the generation of genetically engineered mouse models permitted the evaluation of their function in different processes of the immune responses. In this article, we review new insights into the modular structure of SOCS proteins and the function of SOCS1 and SOCS3 to negatively regulate activation and/or differentiation pathways in macrophages, dendritic cells, and T lymphocytes. Thus, SOCS family proteins are components of an emerging immunoregulatory mechanism that maintains the coordinated balance of both innate and adaptive immune responses. 相似文献
80.