Tomotaka Shoji

Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

Background and aims: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of α-helical CRH (αhCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients. Methods: Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of αhCRH (10 μg/kg). Results: ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of αhCRH. Administration of αhCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. αhCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by αhCRH. Conclusion: Peripheral administration of αhCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

Epidemiology of esophageal cancer: Orient to Occident. Effects of chronology, geography and ethnicity

Esophageal adenocarcinoma (EAC) has been rapidly increasing in Western countries during the past half century, especially in white men. Esophageal squamous cell carcinoma (ESCC) used to be the dominant type of esophageal malignancy both in Western and Asian countries. The rapid increase of EAC in Western countries has occurred in parallel with an increased prevalence of gastroesophageal reflux disease (GERD) and its major determinant, obesity. Such an increase in EAC has not yet been observed in Asia, despite a recent increase in prevalence of GERD. In this mini‐review, we analyze possible factors influencing such east–west (‘Orient to Occident’) differences, particularly possible roles of ethnicity and environmental factors, such as Helicobacter pylori infection and nutritional factors, and how these might interact with socioeconomic differences. Development of Barretts esophagus and esophageal adenocarcinoma appears to be strongly affected by ethnic factors, with populations resident at the west end of the Eurasian continent, such as Anglo‐Celtics, being more prone to both conditions. On the other hand, ethnic groups from the eastern and southern ends of Eurasia, such as Chinese, Koreans and Japanese, and Africans might be more prone to developing esophageal squamous cell carcinoma. Future trends will also be discussed.

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

BACKGROUND AND AIMS Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. METHODS We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. RESULTS Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). CONCLUSION These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Neural Basis of Impaired Cognitive Flexibility in Patients with Anorexia Nervosa

Background Impaired cognitive flexibility in anorexia nervosa (AN) causes clinical problems and makes the disease hard to treat, but its neural basis has yet to be fully elucidated. The purpose of this study was to evaluate the brain activity of individuals with AN while performing a task requiring cognitive flexibility on the Wisconsin Card Sorting Test (WCST), which is one of the most frequently used neurocognitive measures of cognitive flexibility and problem-solving ability. Methods Participants were 15 female AN patients and 15 age- and intelligence quotient-matched healthy control women. Participants completed the WCST while their brain activity was measured by functional magnetic resonance imaging during the task. Brain activation in response to set shifting error feedback and the correlation between such brain activity and set shifting performance were analyzed. Results The correct rate on the WCST was significantly poorer for AN patients than for controls. Patients showed poorer activity in the right ventrolateral prefrontal cortex and bilateral parahippocampal cortex on set shifting than controls. Controls showed a positive correlation between correct rate and ventrolateral prefrontal activity in response to set shifting whereas patients did not. Conclusion These findings suggest dysfunction of the ventrolateral prefrontal cortex and parahippocampal cortex as a cause of impaired cognitive flexibility in AN patients.

Effect of rikkunshito on gastric sensorimotor function under distention

Background  The herbal medicine rikkunshito is effective for the treatment of gastrointestinal symptoms in patients with functional dyspepsia. Although some basic studies on the effects of rikkunshito have been reported in rats, its effects on human gastric function have not yet been clarified. Psychosocial stress induces visceral hypersensitivity and elements of rikkunshito may reasonably affect or suppress this process. We conducted a study to verify the hypothesis that rikkunshito improves stress‐induced gastric hypersensitivity and/or changes in gastric wall tone.

The features of adolescent irritable bowel syndrome in Japan.

Objective and Background:  The onset of IBS is in adolescence in many cases. However, the features of adolescent IBS were generally lacking. The objective of this research was to know the features of adolescent IBS in Japan.

Primary care in the treatment of functional gastrointestinal symptoms in Japan: prescription preferences and impression of results.

Background : Functional gastrointestinal (GI) disorders are common in primary care. However, proper pharmacological approaches have not yet been established. The reason for a lack of proper approaches may be attributable to the lack in clarity of their pathogenesis and pathophysiology. Meta‐analysis of pharmacological approaches to functional GI disorders failed to identify the solid cluster of patients’ symptoms.

Performance evaluation of the small-animal PET scanner ClairvivoPET using NEMA NU 4-2008 Standards

The aim of this study was to evaluate the performance of ClairvivoPET using NEMA NU4 standards. The ClairvivoPET incorporates a LYSO dual depth-of-interaction detector system with 151 mm axial field of view (FOV). Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated using NEMA NU4-2008 standards. Normal mouse imaging was also performed for 10 min after intravenous injection of (18)F(-)-NaF. Data were compared with 19 other preclinical PET scanners. Spatial resolution measured using full width at half maximum on FBP-ramp reconstructed images was 2.16 mm at radial offset 5 mm of the axial centre FOV. The maximum absolute sensitivity for a point source at the FOV centre was 8.72%. Peak noise equivalent counting rate (NECR) was 415 kcps at 14.6 MBq ml(-1). The uniformity with the image-quality phantom was 4.62%. Spillover ratios in the images of air and water filled chambers were 0.19 and 0.06, respectively. Our results were comparable with the 19 other preclinical PET scanners based on NEMA NU4 standards, with excellent sensitivity because of the large FOV. The ClairvivoPET with iterative reconstruction algorithm also provided sufficient visualization of the mouse spine. The high sensitivity and resolution of the ClairvivoPET scanner provided high quality images for preclinical studies.

1101 Impact of Serotonin-3 Receptor Gene Polymorphism On Brain Activation By Rectal Distention in Human

Background& Aims: Visceral perception of functional dyspepsia (FD) is based on the braingut interaction via various neurotransmission pathways. Peripheral or central serotonergic abnormalities are associated with the pathophysiology of functional gastrointestinal disorders or psychiatric depression and anxiety. To examine the roles of the cerebral serotonin (5HT) neurotransmission systems in visceral perception of FD patients, we examined both 5HT transporter (5-HTT) binding potential in the brain and the correlation between differences between patients and controls in 5-HTT binding potential and abdominal symptoms. Methods: Patients with FD diagnosed according to the Rome III criteria (N=9, female: 6, age range 25-61 yrs) were recruited for this study. There were 9 healthy controls (female: 3, age range 36-76 yrs). To measure 5-HTT binding potential with region-of-interest data in areas of the thalamus, putamen, caudate, amygdala, midbrain, and cerebellum (as a reference region), positron emission tomography (PET) with [11C]N,N-dimethyl-2-(2-amino4-cyanophenylthio) benzylamine ([11C]DASB), which binds specifically to 5-HTT, was performed. We used the Multi-linear Reference Tissue Mode method within the standard software package of PMOD Technologies for analysis of [11C]DASB with reference to the co-registered MRI images. Clinical symptoms were evaluated on the Gastrointestinal Symptoms Rating Scale (GSRS) including subscales for abdominal pain and indigestion. Depression and anxiety were evaluated on the Self-Rating Depression Scale and the State-Trait Anxiety Inventory. Results: All scores for abdominal pain, indigestion, depression, and anxiety were higher for FD patients than for controls (p<0.01). In FD patients, the binding potential of [11C]DASB in the midbrain (p=0.001) and amygdala (p=0.065) was higher than in the corresponding areas in controls, while there were no differences between the groups in the thalamus, putamen, or caudate. Binding potential of [11C]DASB in the midbrain was correlated with total GSRS (p=0.018, r=0.572), indigestion (p=0.021, r=0.565), and abdominal pain (p=0.091, r=0.420) scores, while in the amygdala it was correlated with total GSRS (p=0.080, r=0.426), indigestion (p=0.057, r=0.469), depression (p=0.091, r=0.413), and anxiety (p=0.096, r=0.406) scores. Conclusion: These findings suggest that in FD patients there are disorders of central 5-HT neurotransmission, especially in the midbrain and amygdala, which are correlated with their visceral symptoms and psychological characteristics.

When and How Should We Study Colonic Motility

The colon has an autonomic activity owing to the concerted actions of the interstitial cells of Cajal, the enteric nervous system (especially myentric plexus and submucosal plexus), and smooth muscle