The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

The 2018 ISDE achalasia guidelines

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Bradykinin system is involved in endometriosis-related pain through endothelin-1 production.

BACKGROUND: Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain. METHODS: Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1ß and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1ß and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited. RESULTS: The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1ß induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1ß and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist. CONCLUSIONS: The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain. SIGNIFICANCE: The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.

Comparison of spinal alignment, muscular strength, and quality of life between women with postmenopausal osteoporosis and healthy volunteers.

This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness. INTRODUCTION: Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers. METHODS: Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups. RESULTS: BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (p < 0.01). Both thoracic kyphosis and lumbar lordosis were significantly greater in the osteoporosis group than in the volunteer group (p < 0.01). With regard to QOL, the 36-Item Short-Form Health Survey (SF-36) subscale scores of role physical, bodily pain, general health, and role emotional were all significantly lower in the osteoporosis group than in the volunteer group (p < 0.05 each). SF-36 physical component summary (PCS) score was significantly lower in the osteoporosis group than in the volunteer group (p < 0.001). SF-36 PCS score correlated positively with thoracic kyphosis and negatively with BMI only in the osteoporosis group (p < 0.05 each). CONCLUSIONS: These results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness.

Optimal dose of ramosetron in female patients with irritable bowel syndrome with diarrhea: A randomized, placebo-controlled phase II study.

BACKGROUND: Previous studies showed that 5 µg of ramosetron, a serotonin (5-hydroxytryptamine: 5-HT)-3 receptor antagonist, is only effective in male patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D). We hypothesized that either dose 1.25, 2.5, or 5 µg of ramosetron would be effective in female patients with IBS-D. METHODS: This randomized, double-blind, placebo-controlled, phase II dose-finding exploratory trial included 409 female outpatients with IBS-D treated in Japan. They were administered oral placebo (n=102), or 1.25 µg (n=104), 2.5 µg (n=104), or 5 µg (n=99) of ramosetron once daily for 12 weeks after a 1-week baseline period. The primary endpoint was monthly responder rates of global improvement of IBS symptoms in the first month. Secondary endpoints included global improvement in the other months, abdominal pain/discomfort, weekly mean changes in the Bristol Stool Form Scale (BSFS), and IBS-QOL. KEY RESULTS: Middle dose (2.5 µg) of ramosetron significantly improved abdominal pain/discomfort at second month (62.5%, P=.002), third month (60.6%, P=.005), and the last evaluation point (63.5%, P=.002) and weekly BSFS (P<.05) except at Week 8, 11, and 12 than placebo. IBS-QOL did not change. Ramosetron induced more constipation than placebo. CONCLUSIONS & INFERENCES: The trial suggested that 2.5 µg of ramosetron is the most effective and least harmful option for treating female patients with IBS-D (Clinicaltrials.gov ID: NCT01274000).

Asia-Pacific consensus on the management of gastro-oesophageal reflux disease: an update focusing on refractory reflux disease and Barrett's oesophagus

"OBJECTIVE: Since the publication of the Asia-Pacific consensus on gastro-oesophageal reflux disease in 2008, there has been further scientific advancement in this field. This updated consensus focuses on proton pump inhibitor-refractory reflux disease and Barrett's oesophagus. METHODS: A steering committee identified three areas to address: (1) burden of disease and diagnosis of reflux disease; (2) proton pump inhibitor-refractory reflux disease; (3) Barrett's oesophagus. Three working groups formulated draft statements with supporting evidence. Discussions were done via email before a final face-to-face discussion. We used a Delphi consensus process, with a 70% agreement threshold, using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to categorise the quality of evidence and strength of recommendations. RESULTS: A total of 32 statements were proposed and 31 were accepted by consensus. A rise in the prevalence rates of gastro-oesophageal reflux disease in Asia was noted, with the majority being non-erosive reflux disease. Overweight and obesity contributed to the rise. Proton pump inhibitor-refractory reflux disease was recognised to be common. A distinction was made between refractory symptoms and refractory reflux disease, with clarification of the roles of endoscopy and functional testing summarised in two algorithms. The definition of Barrett's oesophagus was revised such that a minimum length of 1 cm was required and the presence of intestinal metaplasia no longer necessary. We recommended the use of standardised endoscopic reporting and advocated endoscopic therapy for confirmed dysplasia and early cancer. CONCLUSIONS: These guidelines standardise the management of patients with refractory gastro-oesophageal reflux disease and Barrett's oesophagus in the Asia-Pacific region."

Improvement of spinal alignment and quality of life after corrective surgery for spinal kyphosis in patients with osteoporosis: a comparative study with non-operated patients.

UNLABELLED: This study evaluated changes in spinal alignment and quality of life (QOL) after corrective spinal surgery for patients with postmenopausal osteoporosis and spinal kyphosis. Spinal global alignment and QOL were significantly improved after corrective spinal surgery but did not reach the level of non-operated controls. INTRODUCTION: With the increased aging of society, the demand for corrective spinal instrumentation for spinal kyphosis in osteoporotic patients is increasing. However, previous studies have not focused on the improvement of quality of life (QOL) after corrective spinal surgery in patients with osteoporosis, compared to non-operated control patients. The purposes of this study were thus to evaluate changes in spinal alignment and QOL after corrective spinal instrumentation for patients with osteoporosis and spinal kyphosis and to compare these results with non-operated patients. METHODS: Participants comprised 39 patients with postmenopausal osteoporosis ≥50 years old who underwent corrective spinal surgery using multilevel posterior lumbar interbody fusion (PLIF) for symptomatic thoracolumbar or lumbar kyphosis, and 82 age-matched patients with postmenopausal osteoporosis without prevalent vertebral fractures. Spinopelvic parameters were evaluated with standing lateral spine radiography, and QOL was evaluated with the Japanese Osteoporosis QOL Questionnaire (JOQOL), SF-36, and Roland-Morris Disability Questionnaire (RDQ). RESULTS: Lumbar kyphosis angle, sagittal vertical axis, and pelvic tilt were significantly improved postoperatively. QOL evaluated with all three questionnaires also significantly improved after 6 months postoperatively, particularly in domain and subscale scores for pain and general/mental health. However, these radiographic parameters, total JOQOL score, SF-36 physical component summary score, and RDQ score were significantly inferior compared with non-operated controls. CONCLUSIONS: The results indicate that spinal global alignment and QOL were significantly improved after corrective spinal surgery using multilevel PLIF for patients with osteoporosis and spinal kyphosis but did not reach the level of non-operated controls.

Randomised clinical trial: rabeprazole improves symptoms in patients with functional dyspepsia in Japan.

BACKGROUND: The efficacy of proton pump inhibitors (PPIs) for treating functional dyspepsia (FD) is not well established. AIM: This study, named the SAMURAI study, aimed to assess the efficacy and dose-response relationship of rabeprazole in Japanese patients with FD in a multicentre, double-blinded, randomised, placebo-controlled trial. METHODS: Investigated FD was diagnosed using the Rome III criteria. Subjects who did not respond to 1 week of single-blind placebo treatment in a run-in period were randomly assigned to 8 weeks of double-blind treatment with rabeprazole 10 mg, 20 mg, 40 mg or placebo, once daily. Dyspeptic symptoms were assessed by a dyspepsia symptom questionnaire (7-point Likert scale) and symptom diary. RESULTS: Of 392 subjects entered into the run-in period, 338 were randomly assigned. Although there was no significant difference between placebo and rabeprazole groups in complete symptom relief for four major dyspeptic symptoms, the satisfactory symptom relief of rabeprazole 20 mg was significantly higher than placebo according to the dyspepsia symptom questionnaire (45.3% vs. 28.2%, P = 0.027) and the symptom diary assessment (48.7% vs. 30.0%, P = 0.016). The efficacy was not influenced by syndrome type or Helicobacter pylori status. No statistically significant differences in the incidence of adverse events were seen among treatment groups. CONCLUSIONS: Rabeprazole 20 mg once daily but not 10 or 40 mg significantly provides satisfactory symptom relief for functional dyspepsia (ClinicalTrials.gov, Number NCT01089543).

Association of spinal curve deformity and back extensor strength in elderly women with osteoporosis in Japan and the United States.

UNLABELLED: The difference in the shape of sagittal spinal curvature and distribution of vertebral fractures in women of comparable age with osteoporosis from Japan and the United States with different cultures and lifestyles was identified. Back extensor strength was significantly associated with lumbar lordosis in Akita group, indicating the potential importance of strengthening the back extensor. INTRODUCTION: The purpose of the study was to assess the association of osteoporotic spinal deformities with back strength in elderly women in Japan and the United States. METHODS: Subjects diagnosed with osteoporosis were selected to participate prospectively. In both groups, we measured the angles of thoracic kyphosis and lumbar lordosis with plain lateral radiographs and back extensor strength. The number of vertebral fractures and the ratio of lumbar fractures to thoracic fractures are also evaluated. The level of participants' daily activities was assessed with use of comparable tests in Akita (quality-of-life score) and Minnesota (physical activity score). RESULTS: A total of 102 Japanese women residing in Akita, Japan (Akita group), and 104 white women evaluated in Rochester, MN, USA (Minnesota group), participated in this study. The angle of thoracic kyphosis and lumbar lordosis was higher in the Minnesota group than in the Akita group. The ratio of lumbar fractures to thoracic fractures was higher in the Akita group than in the Minnesota group. In the Akita group, multiple regression analysis revealed that the angle of lumbar lordosis correlated significantly with back extensor strength. CONCLUSIONS: We identified the difference in the shape of sagittal spinal curvature and distribution of vertebral fractures in women of comparable age with osteoporosis from two geographic areas of the world with different cultures and lifestyles. Back extensor strength was significantly associated with lumbar lordosis in Akita group, indicating the potential importance of strengthening the back extensor for improving or maintaining lumbar lordosis.

A long-term study of acotiamide in patients with functional dyspepsia: results from an open-label phase III trial in Japan on efficacy, safety and pattern of administration.

BACKGROUND: This long-term 48-week study of acotiamide was carried out to investigate the efficacy, safety and administration pattern in patients with functional dyspepsia (FD). METHODS: This was a multicenter, open-label, single-arm, long-term phase III study in which patients with FD were given acotiamide, 100 mg t.i.d., for 48 weeks. The two major efficacy endpoints were global overall treatment efficacy (OTE) and the elimination rate of three cardinal symptoms (i.e. postprandial fullness, early satiation and upper abdominal bloating), which were evaluated weekly and daily by the patients, respectively. The long-term administration patterns were investigated by following the patients based on cessation and readministration criteria. RESULTS: Efficacy was analyzed in 405 patients. The OTE improvement rate was 26.1% at week 1 and increased with time. It was 60.6% at week 8 and subsequently maintained. Similarly, the symptom elimination rate increased up to week 8. Many patients who met the cessation criterion achieved remission of FD symptoms after experiencing dose interruption and readministration. The incidence rate of adverse drug reactions was 11.5% and most of the adverse drug reactions were mild in severity except increased ALT in 1 patient. CONCLUSION: FD symptoms were controlled by intermittent administration of acotiamide even in patients with relapsing FD.

Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study.

BACKGROUND: Lubiprostone is a prostone analog with a novel mechanism of action involving type-2 chloride channel activation. The aim of this work was to perform a dose-finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. METHODS: A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n=42) or 16µg (n=41), 32µg (n=43), or 48µg (n=44) of lubiprostone daily for 2weeks. KEY RESULTS: There was a statistically significant and dose-dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5±0.4; 16µg: 2.3±0.4, 32µg: 3.5±0.5; and 48µg: 6.8±1.1, per week, mean±SE; P<0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P<0.0001). The primary endpoint in patients with IBS treated with 48µg of lubiprostone was significantly better than those given placebo (P=0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. CONCLUSIONS & INFERENCES: Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose-dependent manner with a good safety profile and tolerability in a Japanese population.

Randomised clinical trial: a multicentre, double-blind, placebo-controlled study on the efficacy and safety of rabeprazole 5 mg or 10 mg once daily in patients with non-erosive reflux disease.

BACKGROUND: The efficacy of rabeprazole 5 mg/day for patients with non-erosive reflux disease (NERD) has not been reported in the literature. AIM: To evaluate the efficacy of rabeprazole 5 mg and 10 mg/day in Japanese NERD patients. The influence of baseline characteristics as well as genetic background on efficacy was also analysed. METHODS: Subjects were grade M (minimal changes) NERD patients. Two hundred and eighty-eight of these subjects, who were nonresponders to open label antacid therapy, entered in a 4-week, double-blind treatment (placebo, rabeprazole 5 mg or 10 mg/day). RESULTS: Complete heartburn relief rates were 21% in placebo, 34% in rabeprazole 5 mg and 44% in rabeprazole 10 mg (5 mg vs. placebo P = 0.074, 10 mg vs. placebo P = 0.001). Rabeprazole 5 mg was significantly more effective than placebo in elderly patients and in patients with low heartburn frequency or without hiatal hernia. The efficacy of rabeprazole 10 mg was not influenced by age, BMI, hiatal hernia, Helicobacter pylori infection, frequency and severity of heartburn or CYP2C19 genotypes. CONCLUSIONS: Rabeprazole 5 mg was effective in a subgroup of Japanese NERD patients. Rabeprazole 10 mg provided more potent heartburn relief than 5 mg and was less fragile to baseline characteristics.

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. METHODS: Nine healthy volunteers (five males, four females) participated in the study. The counterbalanced regimen consisted of a 2-week period of oral administration of 7.5 g day(-1) rikkunshito, then a 2-week period without treatment. Fundic sensorimotor function was examined using a gastric barostat twice on the day after each period. Virtual reality stress was imposed during the measurements of gastric tone and electrocardiogram. KEY RESULTS: Stress induced a significant increase in heart rate (P = 0.041), gastric volume (P = 0.008), and phasic volume events (P = 0.049) and a decrease in sensory (P = 0.038), discomfort (P = 0.011), and pain (P = 0.041) thresholds of the stomach. Rikkunshito significantly reduced epigastric fullness (P = 0.037) and perceived stress (P = 0.034) following stimulation of the pain threshold, regardless of stress without the drug. Stress reduced gastric volume at the sensory threshold and increased anxiety at the discomfort threshold, and these responses were significantly inhibited by rikkunshito (P = 0.026, P = 0.022, respectively). CONCLUSIONS & INFERENCES: These findings suggest that rikkunshito may improve symptoms and impaired gastric accommodation under distention stimuli of the proximal stomach superimposed by stress.

Unsedated transnasal ultrathin esophagogastroduodenoscopy may provide better diagnostic performance in gastroesophageal reflux disease.

Transnasal ultrathin esophagogastroduodenoscopy (N-EGD) with less gagging reflexes under non-sedation is likely suitable for the diagnosis of gastroesophageal reflux disease (GERD), however, N-EGD might have drawbacks, including its low image resolution. Limited information is available regarding the diagnosability of N-EGD for GERD. We compared the utility and gagging reflexes of three different endoscopies, including N-EGD, ultrathin transoral EGD (UTO-EGD) and conventional oral EGD (CO-EGD), in the diagnosis of GERD. We performed screening endoscopy in 1580 patients (N-EGD n=727, UTO-EGD n=599, CO-EGD n=254) and compared the frequency distributions of the severity of reflux esophagitis, hiatus hernia, and Barrett's epithelium to estimate the diagnostic performance of each endoscopy. We also analyzed patients' tolerability of endoscopy by the subjective evaluation of gagging reflexes. In the diagnosis of reflux esophagitis and Barrett's epithelium, there was no significant difference in the frequency distributions of the severity of the diseases among three EGDs. However, the incidence of Barrett's epithelium was higher than that in the previous nationwide survey of GERD in Japan. The evaluated size of hiatus hernia was smaller in N-EGD than in two other peroral endoscopies. The size of hiatus hernia correlated significantly with severity of gagging reflexes that was also lowest when diagnosed with N-EGD. N-EGD had an equivalent performance in the diagnosis of reflux esophagitis and Barrett's epithelium compared with CO-EGD. Enlargement of hiatus hernia induced by gagging reflexes was minimal in N-EGD, resulting in its better performance in the diagnosis of Barrett's epithelium.

Clinical trial: dose-dependent therapeutic efficacy of acotiamide hydrochloride (Z-338) in patients with functional dyspepsia - 100 mg t.i.d. is an optimal dosage.

BACKGROUND: Acotiamide is a selective acetylcholinesterase inhibitor and enhances the actions of cholinergic neurons localized in the stomach. METHODS: The present two studies were conducted to examine the optimal dosage of acotiamide hydrochloride (Z-338) in patients with functional dyspepsia (FD) in Japan. KEY RESULTS: The improvement rate of 'subjects global assessment of overall treatment efficacy (OTE)' at the final evaluation was approximately 10% higher in the acotiamide 100 mg group than that in the placebo group with good reproducibility though there was no significant differences at primary endpoint. The elimination rate of postprandial fullness in the acotiamide 100 mg group was significantly higher compared to placebo group. In addition, the post hoc analysis showed that in patients whose main complaints are meal-related symptoms such as postprandial fullness, upper abdominal bloating and/or early satiety, the improvement rate of 'OTE' at final evaluation in acotiamide 100 mg group was significantly superior to that in the placebo group. CONCLUSIONS & INFERENCES: These results suggest that acotiamide possesses efficacy on FD and more specifically its meal-related symptoms of FD.

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.

Spinal curvature and postural balance in patients with osteoporosis.

SUMMARY: Postural deformity might represent another risk factor for postural instability and falls. Relation between spinal curvatures and postural sway were evaluated. Lumbar (not thoracic) kyphosis and spinal inclination have a statistical correlation with postural sway. Postural deformity with lumber kyphosis may represent as a risk factor for falls. INTRODUCTION: Postural instability has been considered as a risk factor for falls and osteoporotic fractures. Previous studies have demonstrated that several factors display significant relationships with postural instability. Postural deformity might represent another risk factor for postural instability and falls. This study evaluates the influence of spinal curvature on postural instability in patients with osteoporosis. METHODS: Subjects comprised 93 patients with a mean age of 70 years. Angles of thoracic and lumbar kyphosis and spinal inclination that reflected a forward stooped posture were evaluated using a computer-assisted device. Sway and postural instability were evaluated using a computerized stabilometer showing seven parameters. Relationships among parameters of postural deformity and postural balance were analyzed using Pearson's correlation coefficients. RESULTS: No significant correlations were observed between any parameters of postural balance and angle of thoracic kyphosis. However, all parameters showed significant positive correlations with angle of lumbar kyphosis (r = 0.251-0.334; p < 0.05-0.001). Moreover, lumbar kyphosis, but not thoracic kyphosis, showed a positive correlation with spinal inclination (r = 0.692, p < 0.001), and all parameters of postural balance showed significant positive correlations with spinal inclination (r = 0.417-0.551, p < 0.001). CONCLUSION: Lumbar kyphosis, but not thoracic kyphosis, affecting spinal inclination and postural balance may represent a risk factor for falls.

A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT3) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT3 receptor antagonists has gender difference is uncertain. METHODS: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT3 receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 microg, 103 subjects: 5 microg, and 101 subjects: 10 microg) and administered the study drug once daily. RESULTS: The monthly responder rates of 'Patient-reported global assessment of relief of irritable bowel syndrome symptoms' in the 5- and 10-microg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 microg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 microg. CONCLUSION: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

Effect of low-intensity back exercise on quality of life and back extensor strength in patients with osteoporosis: a randomized controlled trial.

UNLABELLED: Randomized controlled study in 80 postmenopausal women with osteoporosis was conducted to investigate the effect of a home-based, simple, low-intensity exercise. Low-intensity back-strengthening exercise was effective in improving the quality of life and back extensor strength. INTRODUCTION AND HYPOTHESIS: Back-strengthening exercise is effective in increasing back extensor strength and decreasing risk of vertebral fractures. We hypothesized that a home-based, simple, low-intensity exercise could enhance back extensor strength and improve the quality of life and/or spinal range of motion in postmenopausal women in a short-term follow-up. METHODS: Eighty postmenopausal women with osteoporosis were randomly assigned to a control group (n = 38) or an exercise group (n = 42). Subjects were instructed to lift their upper trunk from a prone position antigravity and maintain the neutral position. Isometric back extensor strength, spinal range of motion, and scores for quality of life were evaluated at baseline and 4 months. RESULTS: Back extensor strength significantly increased both in the exercise group (26%) and in the control group (11%). Scores for quality of life increased in the exercise group (7%), whereas it remained unchanged in the control group (0%). There was a significant difference in quality of life score between the groups (p = 0.012). CONCLUSIONS: Low-intensity back-strengthening exercise was effective in improving the quality of life and back extensor strength in patients with osteoporosis.

Effect of alpha-helical CRH on quantitative electroencephalogram in patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) may have a higher tone of corticotropin-releasing hormone (CRH) in the brain. We tested our hypothesis that peripheral administration of CRH antagonist, alpha-helical CRH(9-41) (alphahCRH), improves decreased alpha power spectra and increased beta power spectra of electroencephalogram (EEG) in IBS patients. A barostat bag was inserted to the descending colon of 10 normal controls and 10 IBS patients. The EEG power spectra and topography were measured during baseline period and colonic distention period with the administration of saline followed by the administration of 10 microg kg(-1) of alphahCRH. IBS patients showed a significantly lower alpha power percentage and a higher beta power percentage than normal controls during baseline. Colonic distention induced a decrease in the alpha power percentage and an increase in the beta power percentage in both groups without difference between groups. After the administration of alphahCRH, changes in the EEG power spectra in response to colonic distention were blunted and the differences in the EEG power spectra between IBS patients and controls vanished. Peripheral administration of alphahCRH almost normalized EEG activities in IBS patients. Our data strongly suggest that CRH plays an important role in IBS.