Hormonal and genetic regulation of Helicobacter hepaticus-induced intestinal inflammation

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from PDF of title page (University of Missouri--Columbia, viewed on March 11, 2011).Vita.Thesis advisor: Craig L. Franklin."December 2010"Ph. D. University of Missouri-Columbia 2010.Inflammatory Bowel Diseases (IBDs) affect millions of people worldwide and are characterized by a chronic intestinal inflammation resulting from a dysregulated immune response to environmental stimuli in genetically susceptible individuals. Utilizing a mouse model of IBD, the studies presented herein investigated 1) the role for estrogen and estrogen receptors in disease development 2) genetic factors contributing to differential disease susceptibility 3) differences in bacterial flora between susceptible and resistant mice. Infection of the A/J mouse strain with the bacterium Helicobacter hepaticus results in acute over-expression of proinflammatory cytokines followed 2-3 months later by chronic cecal inflammation that is more severe in females than in males. Studies in these mice investigating the role for estrogen and estrogen receptors have revealed that selective signaling through estrogen receptor [beta] is immunomodulatory and decreases intestinal inflammation. Helicobacter hepaticus infected A/J mice develop intestinal inflammation, but infected C57BL/6 mice do not. Our investigations into the genetic factors responsible for Helicobacter hepaticus-induced intestinal inflammation have identified two major quantitative trait loci (QTL) on chromosome 3 and 17 associated with disease susceptibility. We also show that the microbial flora between these two mouse strains differs and can impact disease susceptibility. Together the work presented herein a further understanding into the role of hormones in controlling inflammation and insight into the genetic and bacterial factors associated with disease susceptibility.Includes bibliographical references

Corticotropin-releasing factor receptors couple to multiple g-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning

Corticotropin-releasing factor (CRF) exerts a key neuroregulatory control on stress responses in various regions of the mammalian brain, including the hippocampus. Using hippocampal slices, extracts, and whole animals, we investigated the effects of human/rat CRF (h/rCRF) on hippocampal neuronal excitability and hippocampus-dependent learning in two mouse inbred strains, BALB/c and C57BL/6N. Intracellular recordings from slices revealed that application of h/rCRF increased the neuronal activity in both mouse inbred strains. Inhibition of protein kinase C (PKC) by bisindolylmaleimide I (BIS-I) prevented the h/rCRF effect only in hippocampal slices from BALB/c mice but not in slices from C57BL/6N mice. Inhibition of cAMP-dependent protein kinase (PKA) by H-89 abolished the h/rCRF effect in slices from C57BL/6N mice, with no effect in slices from BALB/c mice. Accordingly, h/rCRF elevated PKA activity in hippocampal slices from C57BL/6N mice but increased only PKC activity in the hippocampus of BALB/c mice. These differences in h/rCRF signal transduction were also observed in hippocampal membrane suspensions from both mouse strains. In BALB/c mice, hippocampal CRF receptors coupled to Gq/11 during stimulation by h/rCRF, whereas they coupled to Gs, Gq/11, and Gi in C57BL/6N mice. As expected on the basis of the slice experiments, h/rCRF improved context-dependent fear conditioning of BALB/c mice in behavioral experiments, and BIS-I prevented this effect. However, although h/rCRF increased neuronal spiking in slices from C57BL/6N mice, it did not enhance conditioned fear. These results indicate that the CRF system activates different intracellular signaling pathways in mouse hippocampus and may have distinct effects on associative learning depending on the mouse strain investigated

Measuring Burden of Diseases in a Rapidly Developing Economy: State of Qatar National Burden of Diseases in Qatar

Abstract Background: The Global Burden of Disease (GBD) study has provided a conceptual and methodological framework to quantify and compare the health of populations. Aim: The objective of the study was to assess the national burden of disease in the population of Qatar using the disability-adjusted life year (DALYs) as a measure of disability. Methods: We adapted the methodology described by the World Health Organization for conducting burden of disease to calculate years of life lost due to premature mortality (YLL), years lived with disability (YLD) and disability adjusted life years (DALYs). The study was conducted during the period from November 2011 to October 2012. Results: The study findings revealed that ischemic heart disease (11.8%) and road traffic accidents (10.3%) were the two leading causes of burden of diseases in Qatar in 2010. The burden of diseases among men (222.04) was found three times more than of women's (71.85). Of the total DALYs, 72.7% was due to non fatal health outcomes and 27.3% was due to premature death. For men, chronic diseases like ischemic heart disease (15.7%) and road traffic accidents (13.7%) accounted great burden and an important source of lost years of healthy life. For women, birth asphyxia and birth trauma (12.6%) and abortion (4.6%) were the two leading causes of disease burden. Conclusion: The results of the study have shown that the national health priority areas should cover cardiovascular diseases, road traffic accidents and mental health. The burden of diseases among men was three times of women's

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction

Background: This study was designed to investigate the association of the 894G>T polymorphism in the eNOS gene with risk of acute myocardial infarction (AMI), extent of coronary artery disease (CAD) on coronary angiography, and in-hospital mortality after AMI. Methods: We studied 1602 consecutive patients who were enrolled in the GEMIG study. The control group was comprised by 727 individuals, who were randomly selected from the general adult population. Results: The prevalence of the Asp298 variant of eNOS was not found to be significantly and independently associated with risk of AMI (RR = 1.08, 95%CI = 0.77–1.51, P = 0.663), extent of CAD on angiography (OR = 1.18, 95%CI = 0.63–2.23, P = 0.605) and in-hospital mortality (RR = 1.08, 95%CI = 0.29–4.04, P = 0.908). Conclusion: In contrast to previous reports, homozygosity for the Asp298 variant of the 894G>T polymorphism in the eNOS gene was not found to be associated with risk of AMI, extent of CAD and in-hospital mortality after AM

Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts

Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia

Emotional Intelligence Buffers the Effects of Negative Emotions on Job Burnout in Nursing

The study was designed to examine whether trait emotional intelligence would moderate the impact of negative emotions at work on job burnout. A total of 188 female nurses participated in this study and completed measures of trait affectivity, emotional intelligence, anger and sadness at work, and burnout. The results revealed significant and positive relationships between both types of negative emotions and burnout above and beyond demographics and the nurses’ trait affectivity. Importantly, the study demonstrated that trait emotional intelligence buffers the effects of negative emotions on burnout. Specifically, anger- and sadness-related emotions predicted greater burnout among nurses with low trait emotional intelligence but not among nurses with high trait emotional intelligence. These results suggest that emotional intelligence training could be implemented to prevent the adverse effect of negative emotions felt at work on job burnout

The consultant contract:Marriage or divorce?

At the birth of the new millennium Britain's Labour government published a 10-year plan for modernising the National Health Service (NHS), placing great emphasis on new ways of working. As part of this process, and following extensive negotiation, general practitioners and hospital consultants were offered new contracts in 2003. This process highlighted the issues academic clinicians and managers face in dealing with the tensions inherent in delivering the tripartite mission of teaching, research and clinical service. Following a retrospective review of clinical academic appraisals, this paper considers new strategies for strengthening the relationship across the university and NHS interface and how this novel and strategic approach might be adopted in future health policy. These findings can be helpful for both UK colleagues and for a broader international audience by providing a pragmatic approach to increasing collaboration across the higher education and health service sectors