Toll-Like Receptor mRNA Expression Is Selectively Increased in the Colonic Mucosa of Two Animal Models Relevant to Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is largely viewed as a stress-related disorder caused by aberrant brain-gut– immune communication and altered gastrointestinal (GI) homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs) are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stressinduced IBS-like symptoms. Methodology/Principal Findings: In this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensivity; the stress-sensitive Wistar-Kyoto (WKY) rat and the maternally separated (MS) rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains. Conclusions: These data suggest that both early life stress (MS) and a genetic predisposition (WKY) to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS

Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge

BackgroundThe corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation.MethodsTransgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions.ResultsMice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei.ConclusionsChronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders

Housing conditions affect rat responses to two types of ambiguity in a reward-reward discrimination cognitive bias task

Decision-making under ambiguity in cognitive bias tasks is a promising new indicator of affective valence in animals. Rat studies support the hypothesis that animals in a negative affective state evaluate ambiguous cues negatively. Prior automated operant go/go judgement bias tasks have involved training rats that an auditory cue of one frequency predicts a Reward and a cue of a different frequency predicts a Punisher (RP task), and then measuring whether ambiguous cues of intermediate frequency are judged as predicting reward ('optimism') or punishment ('pessimism'). We investigated whether an automated Reward-Reward (RR) task yielded similar results to, and was faster to train than, RP tasks. We also introduced a new ambiguity test (simultaneous presentation of the two training cues) alongside the standard single ambiguous cue test. Half of the rats experienced an unpredictable housing treatment (UHT) designed to induce a negative state. Control rats were relatively 'pessimistic', whilst UHT rats were quicker, but no less accurate, in their responses in the RR test, and showed less anxiety-like behaviour in independent tests. A possible reason for these findings is that rats adapted to and were stimulated by UHT, whilst control rats in a predictable environment were more sensitive to novelty and change. Responses in the new ambiguity test correlated positively with those in single ambiguous cue tests, and may provide a measure of attention bias. The RR task was quicker to train than previous automated RP tasks. Together, they could be used to disentangle how reward and punishment processes underpin affect-induced cognitive biases. © 2014 The Authors

The point-prevalence of alcohol use disorders and binge drinking in an Irish general hospital.

There is a paucity of data concerning the prevalence of alcohol use disorders and binge drinking in the general hospital adult population in Ireland. The authors examined the point-prevalence of alcohol use disorders and of binge drinking in the adult inpatient population of the acute wards of an Irish university teaching hospital. The secondary aim was to examine gender, age, and patient group (medical/surgical) as risk factors. The authors administered the Alcohol Use Disorders Identification Test (AUDIT) to all consenting patients (n=126) on the acute adult medical and surgical wards over one day. 76% of all inpatients on the acute medical and surgical wards were interviewed (n=126) using the AUDIT. Of the subjects 28% screened positive for an alcohol use disorder. Of these 91% were identified as binge drinkers. A further 8% of the subjects screened positive for binge drinking but were not identified as having an alcohol use disorder. Overall, 36% of the subjects screened positive for either an alcohol use disorder and/or for binge drinking using the AUDIT. Male gender and under 65s were risk factors for both alcohol use disorders and binge drinking. The high point-prevalences of alcohol use disorders and binge drinking in hospital inpatients in particular are a cause for concern as they may have illness complicated by or secondary to undiagnosed alcohol excess. As this population is an easily accessible group for screening, and clinical and economic evidence supports intervention, we recommend screening all acute hospital admissions for alcohol use disorders and binge drinking, followed by appropriate management

Learning and Approximation Algorithms for problems motivated by Evolutionary Trees

vi Chapter 1 Introduction 1 1.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Biological Background . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.2.1 Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2.2 Models and Methods . . . . . . . . . . . . . . . . . . . . . . 7 1.3 Learning in the General Markov Model . . . . . . . . . . . . . . . 15 1.3.1 The Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 1.3.2 Learning Problems for Evolutionary Trees . . . . . . . . . 19 1.4 Layout of the thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Chapter 2 Learning Two-State Markov Evolutionary Trees 28 2.1 Previous research . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.1.1 The General Idea . . . . . . . . . . . . . . . . . . . . . . . . 28 2.1.2 Previous work on learning the distribution . . . . . . . . . 34 2.1.3 Previous work on finding the topology . . . . . . . . . . . . 39 ii 2.1.4 Re..

An Assessment of the state of tourism in Venice -- a quantitative estimate and characterization of excursionist tourists.

This project, conducted by Worcester Polytechnic Institute in conjunction with the Azienda di Promozione Turistica, aims to assess the state of tourism in Venice. It continued the research begun in 1999 by a WPI team, to actually count visitors coming to Venice for the day without spending the night, using a sophisticated methodology of visual identification. From the summer data collected, a full year estimate was made of 7.5 million excursionists. Additionally, a pilot face-to-face sample survey was conducted to characterize the excursionists by overnight plans, demographics, spending, and involvement in the celebration of Jubilee 2000

Use of bicyclic esters or amides for the treatment of diseases responsive to enhanced potassium channel activity

No description supplie

Use of bicyclic esters or amides for the treatment of diseases responsive to enhanced potassium channel activity

No description supplie