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The predicted gastrointestinal tolerability of specific cyclooxygenase-2 inhibitors could be due to either a lack of 'topical' irritation and/or lack of effect on cyclooxygenase-1.Key pathophysiologic steps (in vitro and in vivo uncoupling, intestinal prostanoid levels (prostaglandin E, thromboxane B2, and 6-keto-prostaglandin F1alpha), intestinal permeability (51Cr-ethylenediaminetetraacetic acid), inflammation (faecal excretion of a granulocyte marker protein), and ulcer counts) in enteropathy induced by nonsteroidal anti-inflammatory drugs were assessed after administration of indomethacin, 10 mg/kg, and 15 (roughly equipotent), 30, and 60 mg/kg of the preferential cyclooxygenase-2 inhibitor nimesulide.Indomethacin uncoupled oxidative phosphorylation at lower concentrations than nimesulide in vitro. Indomethacin was associated with electron microscopy changes suggestive of uncoupling in 60%-70% of enterocytes examined, whereas nimesulide affected 10%-30% of enterocytes, depending on the dose. Indomethacin increased intestinal permeability and caused inflammation and ulcers with 71%-96% reductions in prostanoid levels. Nimesulide at 15 mg/kg caused no damage, whereas 30 and 60 mg/kg nimesulide were associated with significant decreases in mucosal prostanoids (46%-75%), but only the 60-mg/kg dose caused a transient increase in intestinal permeability. However, at none of the doses did nimesulide cause intestinal inflammation or ulcers.These results endorse the idea that selective cyclooxygenase-2 inhibitors may be associated with some gastrointestinal tolerance due to their selectivity for cyclooxygenase-2, inhibiting cyclooxygenase-1 at only very high doses, and reduced topical irritation.

Sleep is a complex process: the timing of sleep is regulated by two systems (the sleep homeostat and the circadian clock) and there are many potential functions of sleep. The aim of this thesis was to investigate: the impact of light on the regulation of sleep timing (study 1) and the role of sleep in emotional processing (study 2). Study 1 used natural variations in environmental light levels at different geographical locations, to examine the influence of daily light irradiance on sleep timing and chronotype using the Munich chronotype questionnaire (MCTQ). 6443 students were included in this study from six universities from the northern and southern hemispheres. Students in southern hemisphere cities had earlier sleep timings than those in the northern cities. Daily irradiance was higher in the southern hemisphere cities. The amount of time spent outside, age and sex, but not daily irradiance, influenced sleep timings. Study 2 explored the impact of an analogue traumatic event (trauma film) in students who were either sleep deprived or not sleep deprived on intrusive memories ("flashbacks"), sleep physiology and the impact of an increased risk of a mood disorder on this relationship. In this study the sleep deprived participants (n=19) reported fewer intrusive memories to the trauma film than those not sleep deprived (n=22). A change in sleep physiology was observed in the first sleep period following the trauma film, which was more pronounced in the sleep deprived group: increased levels of arousal, REM density and activity in the occipital region. Only three participants at-risk of a mood disorder completed study 2: their data are presented as case studies. In conclusion this research has demonstrated that differences in sleep timings exist between cities in the southern and northern hemispheres and has confirmed that many factors can influence sleep timing. It has also been demonstrated that following a highly emotional event not sleeping may have a beneficial effect, which has implications for the treatment of people after trauma.

It was recently observed that dehydration causes shrinkage of brain tissue and an associated increase in ventricular volume. Negative effects of dehydration on cognitive performance have been shown in some but not all studies, and it has also been reported that an increased perceived effort may be required following dehydration. However, the effects of dehydration on brain function are unknown. We investigated this question using functional magnetic resonance imaging (fMRI) in 10 healthy adolescents (mean age = 16.8, five females). Each subject completed a thermal exercise protocol and nonthermal exercise control condition in a cross‐over repeated measures design. Subjects lost more weight via perspiration in the thermal exercise versus the control condition (P < 0.0001), and lateral ventricle enlargement correlated with the reduction in body mass (r = 0.77, P = 0.01). Dehydration following the thermal exercise protocol led to a significantly stronger increase in fronto‐parietal blood‐oxygen‐level‐dependent (BOLD) response during an executive function task (Tower of London) than the control condition, whereas cerebral perfusion during rest was not affected. The increase in BOLD response after dehydration was not paralleled by a change in cognitive performance, suggesting an inefficient use of brain metabolic activity following dehydration. This pattern indicates that participants exerted a higher level of neuronal activity in order to achieve the same performance level. Given the limited availability of brain metabolic resources, these findings suggest that prolonged states of reduced water intake may adversely impact executive functions such as planning and visuo‐spatial processing. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Just as daily events are timed by living creatures through circadian rhythms, so seasonal events are timed through an internal calendar that signals birds to return to nesting grounds, salmon to spawn, plants to flower, squirrels to hibernate, kelp to stop growing. In this fascinating book, Russell G. Foster and Leon Kreitzman draw on remarkable recent scientific advances to explain how seasonal change affects organisms, and how plants and animals over countless generations have evolved exquisite sensitivities and adaptations to the seasons. The authors also highlight the impact of seasonal change on human health and well-being. They conclude with a discussion of the dangers posed when climate changes disrupt the seasonal rhythms on which so much life depends. © 2009 by Russell G. Foster and Leon Kreitzman.

The mechanisms by which the lifestyle risk factors obesity, physical inactivity, and low fiber intake predispose to colorectal cancer (CRC) are unclear. Chronic bowel inflammation predisposes to malignancy in cases of inflammatory bowel disease. Many lifestyle risk factors for CRC are associated with evidence of systemic inflammation as indicated by circulating levels of C-reactive protein (CRP), but it is unknown how this relates to inflammation at tissue level. Little is known about the degree of bowel inflammation in general population and the factors that affect it. Therefore, we aimed to assess the relation of levels of bowel inflammation in the general population and lifestyle risk factors for CRC, and to additionally assess whether these associations, if present, were attenuated by controlling for evidence of systemic inflammation. Average CRC risk subjects (320) of either sex aged 50-70 were recruited in South London. A stool sample was provided for calprotectin measurement (a marker of bowel inflammation), serum for CRP, and a detailed dietary and lifestyle questionnaire completed. There was a significant positive relationship between fecal calprotectin and increasing age (P = 0.002), obesity (P = 0.04), physical inactivity (P = 0.01), and an inverse relationship with fiber intake (P = 0.02) and vegetable consumption (P = 0.04). The relationship with obesity was attenuated by controlling for serum CRP. Fecal calprotectin levels are associated with lifestyle risk factors for colorectal cancer. Low-level asymptomatic bowel inflammation may be the link between lifestyle and the pathogenesis of CRC, and circulating proinflammatory cytokines may be part of the mechanism for this link.

Differentiating symptoms of irritable bowel syndrome (IBS) from those of organic intestinal disease is a familiar problem for physicians. The aim of this study was to assess the sensitivity, specificity, and odds ratios (ORs) of fecal calprotectin, small intestinal permeability, Rome I criteria, and laboratory markers of inflammation (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], blood count) in distinguishing organic from nonorganic intestinal disease.A total of 602 new referrals to a gastroenterology clinic who had symptoms suggestive of IBS or organic intestinal disease were studied for these parameters. All patients underwent invasive imaging (barium/endoscopic examination) and other investigations as appropriate, with physicians blinded to the results of fecal calprotectin and intestinal permeability.A total of 263 patients were diagnosed with organic disease and 339 with IBS. At 10 mg/L, the sensitivity and specificity of calprotectin for organic disease were 89% and 79%, respectively, and that of intestinal permeability for small intestinal disease were 63% and 87%, respectively. Sensitivity of positive Rome criteria for IBS was 85% with a specificity of 71%. An abnormal calprotectin test had an OR for disease of 27.8 (95% confidence interval [CI], 17.6-43.7; P0.0001) compared with ORs of 4.2 (95% CI, 2.9-6.1; P0.0001) and 3.2 (95% CI, 2.2-4.6; P0.0001) for elevated CRP and ESR values. An abnormal permeability test gave an OR of 8.9 (95% CI, 5.8-14.0; P0.0001) for small intestinal disease. The OR for IBS with positive Rome criteria was 13.3 (95% CI, 8.9-20.0).Fecal calprotectin, intestinal permeability, and positive Rome I criteria provide a safe and noninvasive means of helping differentiate between patients with organic and nonorganic intestinal disease.

BACKGROUND AND AIMS—Testing for faecal occult blood has become an accepted technique of non-invasive screening for colorectal neoplasia but lack of sensitivity remains a problem. The aim of this study was to compare the sensitivity and specificity of faecal calprotectin and faecal occult blood in patients with colorectal cancer and colonic polyps. METHODS—Faecal calprotectin and occult blood were assessed in 62 patients with colorectal carcinoma and 233 patients referred for colonoscopy. The range of normality for faecal calprotectin (0.5-10.5 mg/l) was determined from 96 healthy subjects. RESULTS—Median faecal calprotectin concentration in the 62 patients with colorectal carcinoma (101 mg/l, 95% confidence interval (CI) 57-133) differed significantly from normal (2.3 mg/l, 95% CI 1.6-5.0) with 90% of patients having elevated levels (normal

Background—Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent “topical” action and by inhibiting cyclooxygenase.Aims—To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol.Methods—The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats.Results—All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B2 concentrations following (R)-flurbiprofen) while racemic and (S)- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF1α concentrations by 73–95%). Intestinal inflammation was significantly greater following administration of (S)-flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or (R)-flurbiprofen while both racemic and (S)-flurbiprofen caused numerous ulcers.Conclusions—Dinitrophenol and (R)-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.

1 The behaviour of five salmonella serotypes in minced chicken breast (pH 5.8) and leg muscle (pH 6.4) held at 1 °C, -2 °C, -5 °C and -20 °C was studied with and without the addition of 0.35% polyphosphate (Puron 604). 2 In the absence of polyphosphate, survival of the test organisms was greater in breast than in leg muscle at all four temperatures, but was greatest at -20 °C in both types of muscle and least at -2 °C and -5 °C, just above and below the freezing point of the muscle. 3 Addition of polyphosphate increased the death rate of the salmonellae in breast muscle held at -2 °C and to a lesser extent at -20 °C but had little or no effect in leg muscle or in breast held at 1 °C or -5 °C.

Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug–induced enteropathy is controversial, but it is thought that cyclooxygenase-1 (COX-1) inhibition is of pivotal importance. We compared small intestinal function and morphology in untreated wild-type, COX-1– and COX-2–deficient mice and the effect of indomethacin, selective COX-1 (SC-560), and COX-2 (celecoxib) inhibition. Methods: Intestinal permeability (51CrEDTA), inflammation (fecal granulocyte marker protein), prostaglandin E2 (PGE2) levels, and macroscopic and microscopic appearances were assessed at baseline and after the drugs. Results: COX-1−/− animals were normal except for a 97% decrease in intestinal PGE2 levels. COX-1+/+ and COX-1−/− animals reacted in a similar way to indomethacin. However, celecoxib, having caused no damage in COX-1+/+ animals, caused small bowel ulcers in COX-1−/− animals. Selective inhibition of COX-1 decreased intestinal PGE2 levels in COX-2+/+ and COX-2−/− animals by 95%–97%, but caused only small bowel ulcers in the latter group. Dual inhibition of COX-1 and COX-2 in wild-type animals resulted in similar small bowel damage. Between 40% and 50% of untreated COX-2−/− animals had increased intestinal permeability and inflammation. Some had ileal ulcers that were distinctively different from indomethacin-induced ulcers. Furthermore, long-term celecoxib administration in wild-type animals was associated with similar damage as in the COX-2−/− mice. Conclusions: COX-1 deficiency or inhibition and short-term COX-2 inhibition are compatible with normal small intestinal integrity. Dual inhibition of the COX enzymes leads to damage similar to that seen with indomethacin. Long-term COX-2 deficiency or inhibition is associated with significant intestinal pathology despite normal intestinal PGE2 levels, suggesting a role for COX-2 in the maintenance of small intestinal integrity in the mouse. GASTROENTEROLOGY 2002;122:1913-1923