Toshihiro Konagaya

Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease

Regulatory neuropeptides are widely distributed in the gastrointestinal tract, where they play an important role in motility, secretion, and immune and inflammatory responses. In this study, the rectal mucosal content of somatostatin (SOM), substance P (SP), β-endorphin (BE), and thyrotropin-releasing hormone (TRH) was measured by radioimmunoassay in 56 patients with ulcerative colitis (UC), 15 patients with Crohns disease (CD), 15 patients with acute infectious colitis (AIC), and 11 controls, who showed no inflammation of the rectal mucosa, nor abnormal bowel movements. The content of immunoreactive (ir)-SOM was decreased in UC patients, especially in those with persistent disease activity, while the levels of ir-SP, BE, and TRH were increased in such patients. Some changes of ir-peptide levels were also observed in CD and AIC patients. The changes in neuropeptide levels were analyzed in relation to histological grades of inflammation in UC patients, grades 4–5 showing the most significant changes. The levels of ir-SOM, SP, BE, and TRH showed no significant change in chronic persistent UC when measured 6–12 months after the initial examination. In contrast, in patients with remitting intermittent UC, the levels of SP and BE decreased during remission. Abnormal intestinal neuropeptide content may be implicated in the continued mucosal immune and inflammatory responses that are manifested in patients with inflammatory bowel disease.

Associations among positive mood, brain, and cardiovascular activities in an affectively positive situation.

It is hypothesized that experiencing positive emotions such as pleasure leads to a perception of the body being in a positive state. This study demonstrated associations among positive mood, brain, and cardiovascular activities by simultaneously recording these activities when positive emotions were evoked in participants watching films revolving around a love story. Heart rate variability analysis revealed increased parasympathetic nervous activity while watching the film. The following brain regions were significantly activated in the positive condition relative to the control condition: medial prefrontal cortex, thalamus, superior temporal gyrus, inferior frontal gyrus, and cerebellum. Further, covariate analyses indicated that these brain regions were temporally associated with subjective positive mood. Activities of brain regions considered to be related to interoceptive awareness, such as the insular cortex, anterior cingulate cortex, amygdala, and orbitofrontal cortex, were also temporally associated with the cardiovascular change. These results suggest that while an individual experiences positive emotions, activities of the central nervous system and cardiovascular system may be interrelated, and the brain may perceive the body to be in a positive state.

Mucosal Chemokine Activity in helicobacter pylori Infection

We examined secretion, mRNA expression, and histologic localization of interleukin-8 (IL-*) and growth-related gene product-alpha (GRO alpha) in the Helicobacter pylori-infected gastric antral mucosa. Antral biopsies were obtained from an area of endoscopically intact mucosa. Significantly higher levels of IL-8 and GRO alpha were secreted in organ cultures from patients with H. pylori infection, and their elevation was prominent in patients with duodenal ulcer. There was a significant association between these alpha-chemokine levels and histologic grades of activity, inflammation, and H. pylori density. In fresh antral biopsies, IL-8 and GRO alpha mRNA expression was detected more frequently in H. pylori-infected patients compared with those without infection. Immunofluorescence microscopy showed localization of IL-8 and GRO alpha proteins in gastric epithelial cells and infiltrating CD68+ macrophages. In the chemotaxis assay, a significant positive correlation was found between neutrophil migration induced by the organ culture supernatants and their contents of IL-8 and GRO alpha. After H. pylori eradication, a significant decrease was observed in IL-8 and GRO alpha levels detected in organ cultures. In conclusion, mucosal alpha-chemokine activity correlates well with histologic severity of H. pylori-associated antral gastritis and can be used to predict the effects of H. pylori eradication therapy.

Helicobacter pylori and gut hormones

Helicobacter pylori infection has been found to decrease the expression of antral somatostatin and to increase the release of the acid-stimulating hormone gastrin. The reversal of these changes in gut hormones by the eradication of H. pylori, and in-vivo and in-vitro studies in animals either infected with H. pylori or exposed to H. pylori-related materials may support the somatostatin-gastrin link theory in the pathophysiology of H. pylori infection. The following mechanisms have been proposed to explain the H. pylori infection-associated changes in gut hormones; (1) ammonia produced by H. pylori and monochloramine, (2) effect on somatostatin receptor subtype-2, (3) action of lipopolysaccharide from H. pylori on somatostatin receptor, (4) inflammatory cells and mediators, and (5) bacterial strain diversity. H. pylori infection can alter gastric acid secretion in both directions. The elevated acid secretion in patients with duodenal ulcer is decreased by H. pylori eradication, and is accompanied by the normalization of gut hormones in patients whose H. pylori-induced gastritis is limited to the antrum with hyperacidity. Corpus gastritis and the subsequent development of mucosal atrophy induced by H. pylori result in decreased acid secretion, although the mechanism underlying H. pylori-induced atrophy in some subjects remains unclear. Hypoacidity enhances corpus atrophy and increases gastrin secretion, mediated via a physiological suppression of somatostatin release, features that are also observed in H. pylori infection. Therefore, the capacity of acid secretion and distribution of gastritis or atrophy should be taken into consideration when we discuss the affect of H. pylori on gut hormones.

Mucosal macrophage inflammatory protein‐1α activity in Helicobacter pylori infection

Mucosal chemokines are considered to be important in the pathogenesis of Helicobacter pylori‐associated gastritis. The aims of this study are to examine the levels of macrophage inflammatory protein‐1α (MIP‐1α) in organ cultures, the expression of MIP‐1α mRNA and the cellular source of MIP‐1α, using the antral mucosal specimens obtained from H. pylori‐positive and ‐negative patients. Enzyme‐linked immunosorbent assay was used to measure the levels of MIP‐1α in organ cultures of mucosal tissues and cell cultures of fractionated mucosal cells. The expression of MIP‐1α mRNA and protein was analysed in fresh biopsy tissues with reverse transcriptase–polymerase chain reaction (RT‐PCR) and double immunofluorescence microscopy, respectively. The mucosal specimens obtained from H. pylori‐positive patients exhibited significantly higher values of MIP‐1α activity in organ cultures with increased numbers of CD68+ macrophages, myeloperoxidase+ neutrophils and mononuclear cells in the lamina propria compared with those from H. pylori‐negative patients. The RT‐PCR analysis detected MIP‐1α mRNA in more than 50% of the specimens with H. pylori infection, but not in those without infection. In cell cultures, the macrophage fraction contained substantially higher amounts of MIP‐1α on a per cell basis than the lymphocyte fraction and MIP‐1α activity was not detected in cultures of gastric epithelial cells. This observation was also confirmed by a double immunofluorescence microscopic study in which most (> 90%) MIP‐1α‐positive infiltrating cells were CD68+ macrophages. This study indicates that synthesis and secretion of MIP‐1α are increased in H. pylori‐infected antral mucosa and that mucosal macrophages are the main cell type responsible for this phenomenon.

Inhibitory effect of oxytocin on accelerated colonic motility induced by water-avoidance stress in rats

Abstract  Recent studies have indicated that brain and gut activities are interrelated and exposure to several stressors, such as water‐avoidance stress, stimulates the motor function of the gut through corticotropin‐releasing factor (CRF)‐signalling pathways in the brain. Central oxytocin is known to attenuate stress responses, including CRF expression in the brain. Here, we examined whether central oxytocin attenuated the acceleration of colonic motility induced by water‐avoidance stress. A force transducer was attached to the distal colon of male rat, and the colonic motility and faecal pellet output were recorded while the rats were exposed to water‐avoidance stress. Intracerebroventricular (i.c.v.) injections of oxytocin (5, 50 and 500 pmol) and the oxytocin receptor antagonist tocinoic acid (25 μg) were administered before exposure to water‐avoidance stress, and the effect of oxytocin on colonic motor function was determined. Centrally administered oxytocin inhibited the accelerated colonic motility induced by water‐avoidance stress. The effective dose ranged between 5 and 50 pmol on i.c.v. injection. Oxytocin also decreased the number of CRF‐positive cells in the paraventricular nucleus and corticosterone release. The inhibitory effect of oxytocin on accelerated colonic motility was blocked by pretreatment with oxytocin receptor antagonist. Furthermore, centrally administered tocinoic acid enhanced the acceleration of colonic motility. These results suggested that endogenous central oxytocin may contribute to the regulation of colonic function and inhibit the brain CRF‐signalling pathways targeting the gut, resulting in the inhibition of stress‐induced colonic contractions.

Interactions among gastric somatostatin, interleukin-8 and mucosal inflammation in Helicobacter pylori-positive peptic ulcer patients.

Background. To investigate whether Helicobacter pylori infection, but not drugs, affects gastric somatostatin, interleukin‐8 (IL‐8), histological inflammation through eradication therapy, and interactions among these parameters.

Polymorphism of the serotonin transporter gene modulates brain and physiological responses to acute stress in Japanese men

A short (S) variant, compared to a long (L) variant, of the promoter region of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been related to emotional hyper-reactivity. We tested whether the 5HTTLPR could modulate acute stress responses in the brain and, the cardiovascular and neuroendocrine systems. Ten Japanese male participants carrying double copies of the S alleles and 10 Japanese males carrying S and L alleles conducted a mental arithmetic task, and their regional cerebral blood flow by 15O positron emission tomography and cardiovascular and neuroendocrine parameters were measured. During the acute stress task, the participants with the SS alleles showed stronger reactivity in blood pressure and secretion of epinephrine, compared to the participants with the SL and LL alleles. Furthermore, the SS carriers showed greater activation in stress-related brain regions such as the hypothalamus, cerebellum, midbrain, and pulvinar compared to the SL and LL carriers during the acute stress task. The present findings indicated that the S allele of the 5HTTLPR is associated with greater brain and physiological reactivity to acute stress in Japanese men.

Comparison between in vivo and in vitro chemokine production in Helicobacter pylori infection.

Background: Enhanced gastric mucosal chemokine activity has been demonstrated in patients with Helicobacter pylori infection. However, little is known about the mechanisms involved in this phenomenon.

Psychological and physiological responses accompanying positive emotions elicited on seeing favorite persons

Positive emotions are evoked on seeing ones favorite person. To investigate the psychological and physiological responses accompanying these positive emotions, we simultaneously recorded various parameters such as the mood state, heart rate, skin conductance level (SCL), serum levels of catecholamines, and proportions of T cells and natural killer (NK) cells among the lymphocytes while participants viewed films featuring their favorite persons. The participants reported that they felt better and invigorated; in addition, SCL and proportion of NK cells in peripheral blood increased significantly, and these physiological changes were positively correlated. These results suggest that positive emotions elicited on seeing a favorite person may lead to psychological and physiological activation and, more importantly, may promote health. A cheerful heart is good medicine, but a crushed spirit dries up the bone (Proverbs 17 : 22; New International Version)