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Background Postpartum depression (PPD) is a major public health concern because it adversely affects maternal health and children's physical and mental development. The prevalence of PPD in Arab countries is higher than the worldwide prevalence. Additionally, refugee women are more likely to develop PPD than women in the general population, but little research of refugee women in Arab countries is available. The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) have provided primary health care to Palestine refugees since 1950 and began the Mental Health and Psychosocial (MHPSS) programme in Jordan in 2017 to enhance the psychosocial and social wellbeing of Palestine refugees. We assessed the prevalence of PPD and examined associated factors among Palestine refugee women living in Amman, Jordan. Methods This cross-sectional descriptive study was done between April 21 and May 21, 2018. Eligible participants were Palestine refugee mothers who had given birth 3–16 weeks previously and were attending any of five UNRWA health centres in Amman that were launching the MHPSS programme. Data were gathered in face-to-face structured interviews that included the Edinburgh Postpartum Depression Scale (EPDS) to assess PPD, the Maternal Social Support Scale to assess levels of perceived social support, and a structured questionnaire about sociodemographic, obstetric or paediatric, psychological, and social factors. Participants with scores greater than 12 in the EPDS were classified as having depressive symptoms. Logistic regression was used to identify factors associated with depressive symptoms. The study protocol was approved by the Department of Health, UNRWA Headquarters, Amman, Jordan, and Nagasaki University. Each participant provided written informed consent. Findings 251 women participated in the study, with a mean age of 27·2 years (range 18–42, SD 5·43). 123 (49%) women were classified as having PPD. Logistic regression showed that factors associated with PPD were perceived low levels of social support (adjusted odds ratio 3·76, 95% CI 1·92–10·93) and experiencing stressful life events (one event 3·92, 1·51–9·91; two events 5·77, 2·33–14·27; and three or more events 14·8, 5·23–41·89). Interpretation The prevalence of PPD among Palestine refugee women in Amman was higher than that reported in a previous study of the general childbearing population (women aged 18–45 years) in Irbid in Jordan (22%, Mohammad et al. Midwifery 2011; 27: e238–45) but similar to findings in the West Bank (47%, Quandil et al. BMC Pregnancy Childbirth 2016; 16: 375) and in Syrian refugee women in Jordan (49·6%, Mohammad et al. Res Nurs Health 2011; 41: 519–245). Our findings highlight the need to address this disorder in Palestine refugee mothers. Periodical PPD screening, raising awareness about PPD, providing information to husbands and families, and building a support system for mothers could alleviate the risk of PPD. Future studies should examine whether factors of antenatal depression, which were not assessed in this study, correlate with having PPD to clarify the need for early intervention in mothers. Funding Nagasaki University.

Metformin is widely used for the treatment of diabetes mellitus. Adenosine monophosphate-activated protein kinase (AMPK) is known to be activated by metformin and to inhibit the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the protein translational machinery and cell proliferation. We examined the effect of metformin on the suppression of colorectal carcinogenesis in chemical carcinogen-induced models. Seven-wk-old BALB/c mice were intraperitoneally (i.p.) injected with azoxymethane (AOM, 10 mg/kg) and then treated with or without metformin (250 mg/kg/d) for 6 wk (for the investigation of aberrant crypt foci [ACF] formation) or 32 wk (for polyp formation). We next investigated colonic epithelial proliferation using bromodeoxyuridine (BrdU) and the proliferating cell nuclear antigen (PCNA) labeling indices. Furthermore, to examine the indirect effect of metformin, the insulin resistance status and the serum lipid levels were assessed. Treatment with metformin significantly reduced ACF formation. The effect of metformin on colon polyp inhibition was relatively modest. No significant difference in body weight or glucose concentration was observed. The BrdU and PCNA indices decreased in mice treated with metformin. A Western blot analysis revealed that the phosphorylated mTOR, S6 kinase, and S6 protein levels in the colonic mucosa decreased significantly in mice treated with metformin. In conclusion, metformin suppresses colonic epithelial proliferation via the inhibition of the mTOR pathway through the activation of AMPK. As metformin is already used daily as an antidiabetic drug, it might be a safe and promising candidate for the chemoprevention of colorectal cancer.

Adiponectin is an adipose tissue-derived hormone. It is a key hormone that is responsible for insulin sensitization, and its circulating level is inversely associated with abdominal obesity. Recent studies have shown that a reduced plasma adiponectin level is significantly correlated with the risk of various kinds of cancers. Adiponectin may influence the cancer risk by modulating the metabolic environment indirectly. However several cancer cells express adiponectin receptors, suggesting that adiponectin also may modulate the cancer progression directly. Herein, we review the recent evidence concerning the molecular mechanisms linking adiponectin receptor signaling and cancer. Further studies are required to fully elucidate the molecular mechanisms of the adiponectin-mediated signaling pathway in cancer.

Background and aims: The molecular mechanisms underlying the promotion of colorectal carcinogenesis by a high-fat diet (HFD) remain unclear. We investigated the role of the insulin-signal pathway and the c-Jun N-terminal kinase (JNK) pathway, which reportedly play crucial roles in insulin resistance, during colorectal carcinogenesis in the presence of hyperinsulinaemia induced by a HFD. Methods: Azoxymethane-induced aberrant crypt foci formation and cell proliferation in the colonic epithelium were compared between mice fed a normal diet (ND) and mice fed a HFD. A western blot analysis was performed to elucidate the mechanism affecting colorectal carcinogenesis by a HFD. Results: The number of aberrant crypt foci and the colonic epithelial cell proliferative activity were significantly higher in the HFD group than in the ND group. While the plasma insulin level was significantly higher in the HFD group than in the ND group, a western blot analysis revealed the inactivation of Akt, which is located downstream of the insulin receptor, in the colonic epithelia of the HFD group. On the other hand, JNK activity was significantly higher in the HFD group than in the ND group. A JNK specific inhibitor significantly suppressed the increase in epithelial cell proliferation only under a HFD, but not under a ND. Conclusions: Colonic cell proliferation was promoted via the JNK pathway in the presence of a HFD but not in the presence of a ND. This novel mechanism may explain the involvement of the JNK pathway in the effect of dietary fat intake on colon carcinogenesis.

The antithrombotic effects of low-dose aspirin (LDA) are well established, and it is used for primary and secondary prevention of cardiovascular events. However, the small intestinal toxicity of LDA remains unclear. The aim of this study was to review the characteristics of small bowel injury in long-term LDA users with capsule endoscopy (CE). We retrospectively reviewed all chronic LDA users (>3 months) who underwent CE for suspected small bowel diseases from May 2004 to May 2008 at two medical centers. At our institutions, a total of 22 patients (13 males and 9 females, mean age 66.3 years) taking LDA underwent a CE examination. The indications for CE were obscure gastrointestinal bleeding in 21 patients and 1 patient who had abdominal pain. Twenty-one patients (95.5%) had some small bowel mucosal injury. Small bowel erosions were identified in 14 patients (63.6%). This enteropathy was characterized by multiple petechiae, loss of villi, erosions, and ulcers with round, irregular, and punched-out shapes. Two patients had circumferential ulcers with stricture. In most patients, small bowel lesions were multifocal and were evenly distributed in the small bowel. No patients failed to pass the capsule. This is the first CE report that has studied the characteristics of small bowel injury in chronic LDA users. CE is useful to diagnose small bowel enteropathy associated with LDA.

Background and Aims: Small intestinal toxicity of low-dose aspirin remains unclear. The purpose of this capsule endoscopy study was to assess the incidence of small bowel injury in healthy volunteers treated with short-term low-dose aspirin. Methods: Healthy subjects were randomly assigned to receive low-dose aspirin for 14 days (Aspirin group) or no drugs for 14 days (Control group). The two treatment occasions were separated by a washout period of at least 4 weeks. All subjects underwent capsule endoscopy at the end of each treatment period. Results: After 2 weeks of treatment, the percentages of subjects with small bowel pathology were 80% in the Aspirin group compared with 20% in the Control group (p = 0.023). The incidence of small bowel mucosal breaks in the Aspirin group was higher than that in the Control group, although the difference was not significant (30 vs. 0%; p = 0.210). Conclusions: This is the first pilot study using capsule endoscopy to report on the relation between small bowel injury and low-dose aspirin. Among the healthy subjects, the short-term administration of low-dose aspirin was associated with a mild mucosal inflammation of the small bowel.

Purpose To determine the prevalence and progression of Barrett’s epithelium and associated risk factors in Japan. Methods The study population comprised 869 cases. Endoscopic Barrett’s epithelium was diagnosed based on the Prague C & M Criteria. The correlations of clinical factors with the prevalence and progression of endoscopic Barrett’s epithelium were examined. Results Endoscopic Barrett’s epithelium was diagnosed in 374 cases (43%), in the majority of which the diagnosis was short-segment Barrett’s esophagus. The progression of Barrett’s epithelium was identified in 47 cases. In univariate and multiple logistic regression analyses, aging, smoking habit, and erosive esophagitis were significantly associated with the prevalence of Barrett’s epithelium, whereas aging and erosive esophagitis, especially severe erosive esophagitis, were significant contributing factors to the progression of Barrett’s epithelium. Conclusions Forty-three percent of the total study population was diagnosed as having endoscopic Barrett’s epithelium. During the follow-up period, 12.6% of the cases with Barrett’s epithelium exhibited progression which was associated with aging and severe erosive esophagitis.

We report a rare case of adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM) in which parathyroid hormone-related protein (PTH-rP) was identified as the causative factor of hypercalcemia. A 72-year-old Japanese man was admitted to our institution complaining of fever and abdominal pain. Abdominal computed tomography demonstrated a large tumor in the body of the pancreas, with multiple liver metastases. Both serum calcium and PTH-rP levels were elevated. No accumulation was observed on bone scan with technetium-99. The patient died of pneumonia 3 months after admission. Autopsy demonstrated that the neoplasm in the pancreas showed an abrupt histological transition from adenocarcinoma to squamous cell carcinoma. PTH-rP was identified in the primary pancreatic tumor cells by immunohistochemical examination and a reverse-transcription polymerase chain reaction (RTPCR) method. We concluded that PTH-rP was the causative factor of the HHM, based on the laboratory data, immunohistochemical examination, and messenger RNA (mRNA) expression. This is a very rare report of adenosquamous cell carcinoma of the pancreas associated with HHM.

Life style-related diseases are associated with an increased risk of colorectal cancer (CRC). Recently, an association has been demonstrated between obesity and CRC. CRC has been associated with markers of insulin or glucose control, and insulin resistance might be the unifying mechanism by which several risk factors affect colorectal carcinogenesis. We evaluated the association between the number of aberrant crypt foci (ACF) and obesity, insulin resistance, hyperlipidemia, and other factors of life style-related disease. As a result, age, body mass index (BMI), waist circumference, and visceral fat obesity were significantly associated with the number of ACF. These results suggest that visceral fat obesity is an important target for CRC prevention. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily and is highly expressed in CRC. PPARγ ligand administration for 1 to 8 months significantly reduced the number of ACF in human subjects. PPARγ ligand is a promising candidate as a chemopreventive agent. Further investigation is needed to elucidate these mechanisms. Keywords:: life style-related disease, colorectal cancer, chemoprevention, aberrant crypt foci (ACF), peroxisome proliferator-activated receptor gamma (PPARγ)

Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg/day per body for 24 weeks), a synthetic ligand for PPARγ, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPARγ pathway in NASH and the therapeutic utility of a PPARγ ligand. Keywords:: life style-related disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), microarray, Gene Set Enrichment Analysis (GSEA), pioglitazone

The possible role of leptin in colorectal tumors has been investigated in previous studies; however, to date, the conclusions remain under debate. Therefore, we investigated the serum leptin levels in colorectal adenoma patients. In addition, expression of the leptin receptor, and the leptin receptor-mediated signaling pathways were investigated in biopsy specimens collected from human patients with colorectal adenoma. No significant difference in the mean serum leptin level was observed between the colorectal adenoma patients and the control subjects; however, increased expression and activation of the leptin receptor, as indicated by findings such as the phosphorylation of Tyr 1141, was observed in the colorectal adenoma tissues. In addition, activation of the JAK/STAT signaling pathway mediated by the leptin receptor and increased transcriptional regulation of downstream target molecules were observed in colorectal adenomas compared with the non-adenoma tissues. These results indicate STAT3-mediated leptin receptor signaling pathways may be activated in human colorectal adenomas. (Cancer Sci 2011; 102: 367–372)

The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 ± 6.45 before treatment versus 5.11 ± 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 ± 6.65 versus 7.56 ± 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer. Cancer Prev Res; 3(9); 1077–83. ©2010 AACR.

Introduction Standard endoscopic mucosal resection or endoscopic submucosal dissection is a procedure for patients with minute cancers, complicated with esophageal varices that puts them at high risk of bleeding. Case presentation We present the case of a 77-year-old Japanese man with alcoholic cirrhosis who underwent a routine endoscopy examination as a screening procedure for esophageal varices and was incidentally diagnosed as having minute cancer of the esophagogastric junction with esophageal varices. Endoscopic ultrasonography findings suggested that the minute cancer was a non-invasive carcinoma (carcinoma in situ) and a 2 mm in diameter blood vessel, feeding the esophageal varices, pierced the lesion. Following the examination, we carried out endoscopic treatment of the minute cancer and esophageal varices. Endoscopic variceal ligation was performed using a pneumo-activated device (Sumitomo Bakelite, Tokyo, Japan). Two years after the treatment, during the follow-up endoscopic examination on the patient, recurrence of carcinoma was not detected endoscopically or histologically. Conclusion Endoscopic therapy using an endoscopic variceal ligation device for minute cancer of the esophagogastric junction, complicated with esophageal varices, may be an acceptable and easily applicable method.

Hepatic mitochondrial beta-oxidation is considered to play a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine whether there were differences between patients with NASH and healthy controls in a breath test with 13C-octanoate, a medium-chain fatty acid.The subjects were 8 patients (5 men, 3 women, median age 46.5 years) with histologically proven NASH and 6 healthy controls (5 men, 1 women, and median age 27.8 years). The 13C breath test was performed for 4 hours using the BreathID system with a 100 mL of water containing 100 mg 13C-octanoate.There were no significant differences between NASH patients and controls about all breath test parameters.NASH-mediated changes in breath test parameters after ingestion of 13C-octanoate were not observed in our study. The present study findings suggest the possible preservation of 13C-octanoate metabolism (mitochondrial beta-oxidation) in patients with NASH.

The aim of this study was to evaluate the risk factors of perforation during endoscopic submucosal dissection (ESD).ESD was performed using a Flex knife in 64 patients with a total of 67 gastric tumors. Perforation occurred at the sites of a total of 4 lesions (5.9% [4/67]) for which conservative treatment had been effective. We evaluated several possible risk factors for perforation following ESD, such as tumor size, the location of the lesion, the operation time, and other clinical factors.All the perforations occurred in the posterior wall of the gastric upper or middle body. In an analysis adjusted for age and sex, the tumor size (odds ratio (OR), 1.017; 95% confidence interval (CI), 1.004-1.030), the location of the lesion in an upper region (OR, 10.64; 95%CI, 1.160-10.00) and the operation time (OR, 1.017; 95%CI, 1.013-1.295) were significantly associated with the incidence of perforation. All perforations were transient, resolving within 7 days, and did not require surgical treatment.A large tumor size, the location of the lesion in an upper region, and a long operation time are risk factors for perforation following ESD.

The ideal medication for treatment of acid related diseases should have a rapid onset of action to promote hemostasis. The aim of our study was to investigate the inhibitory effects on gastric acid secretion after single intravenous administrations of lansoprazole 30 mg and famotidine 20 mg.Twelve Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after single intravenous administration of lansoprazole 30 mg or famotidine 20 mg.The average pH during the 4-hour period after administration of famotidine was higher than after lansoprazole (median: 5.15 versus 3.55, respectively; p = 0.0376). During the 4-hour study period, famotidine 20 mg provided a longer duration of pH3, 3.5, 4, 5, 6 and 7, compared to lansoprazole 30 mg (median: 73.6% versus 57.0%; p = 0.0414, 66.8% versus 47.8%; p = 0.0281, 60.8% versus 38.8%; p = 0.0150, 55.7% versus 29.7%; p = 0.0281, 45.0% versus 23.1%; p = 0.0414 and 23.9% versus 3.65%; p = 0.0076).In Helicobacter pylori-negative healthy male subjects, an intravenous dose of famotidine 20 mg more rapidly increases intragastric pH than lansoprazole 30 mg.

Background The association between obesity and the risk of Barrett's esophagus (BE) is unclear. Furthermore, the association between visceral obesity and the risk of BE is entirely unknown. Methods We conducted a retrospective study in 163 patients with non-alcoholic fatty liver disease (NAFLD) who underwent both endoscopy and abdominal CT at an interval of less than a year at our institution. BE was endoscopically diagnosed based on the Prague C & M Criteria. The surface areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were calculated from CT images at the level of the umbilicus. The correlations between the BMI, VAT, and SAT and the risk of BE were examined by univariate and multivariate analyses. Results Sixty-nine of the 163 study participants (42.3%) were diagnosed to have endoscopic BE, which was classified as short-segment BE (SSBE) in almost all of the cases. There were no significant differences in the age or gender distribution between the groups with and without BE. According to the results of the univariate analysis, VAT was significantly associated with the risk of BE; the BMI tended to be higher in the group with BE than in the group without BE, but this relation did not reach statistical significance. VAT was independently associated with the risk of BE even after adjustment for the BMI. Conclusion In Japanese patients with NAFLD, obesity tended to be associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal visceral adiposity.

The goal of this study was to investigate Cystatin SN, a cysteine protease inhibitor, as a novel tumor marker for colorectal cancer (CRC). Gene expression profiles of mRNA from normal tissues and cancer cell lines were performed. Twenty-eight monoclonal antibodies for Cystatin SN were generated and serum Cystatin SN was quantified using ELISA in sera from 159 patients with CRC and 40 healthy controls. Cystatin SN was highly expressed in colon cancer cells. Employing a receiver-operating characteristic curve, we obtained an area under the curve of 0.708 for Cystatin SN, 0.819 for carcinoembryonic antigen (CEA) and 0.703 for carbohydrate antigen 19-9 (CA19-9). The combination assay of Cystatin SN, CEA and CA19-9 showed 62.9% sensitivity and 90.0% specificity. Especially, the sensitivity of the combination assay in stages I and II detection, in which stages curative operation would be possible, was improved over that of the assay testing only for CEA and CA19-9 (from 37.5 to 42.5% in stage I, from 49.0 to 60.8% in stage II). Furthermore, Western blot analysis revealed that Cystatin SN was increased in the urine from patients with CRC. Our results suggest the possibility of utilizing this novel tumor marker that can be tested in urine samples. These observations suggest that Cystatin SN in combination with CEA and CA19-9 is a useful tumor marker for detecting early stage CRC and that it is a unique urinary excretory protein, suggesting that Cystatin SN might be a novel candidate for use in mass screening for CRC.

In contrast to Western countries where erosive esophagitis (EE) is more prevalent in males, there is a high incidence of EE in elderly females in Japan. We aimed to examine the gender differences in the age-stratified prevalence of EE and Barrett's epithelium.The study population comprised 869 cases (463 men and 406 women) who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. EE was graded according to the Los Angeles Classification. Barrett's epithelium was diagnosed based on the Prague CM Criteria.In contrast to the decrease of the proportion of EE with aging in males, that in females remained constant. The results suggest that the suppressive effect of the increased gastric mucosal atrophy associated with aging was wiped out by the age-related effect of the increased incidence of hiatal hernia. The proportions of Barrett's epithelium in both males and females increased with aging.In Japan, the prevalence of elderly females complicated with hiatal hernia, which was partly due to osteoporosis and kyphosis, may affect the proportion of EE and probably Barrett's epithelium.

Background We aimed to estimate whether the macroscopic extent of gastric mucosal atrophy is associated with a risk for esophageal squamous cell carcinoma using a case-control study in Japanese subjects, a population known to have a high prevalence of CagA-positive H. pylori infection. Methods Two hundred and fifty-three patients who were diagnosed as having esophageal squamous cell carcinoma, and 253 sex- and age-matched controls were enrolled in the present study. The macroscopic extent of gastric mucosal atrophy was evaluated based on the Kimura and Takemoto Classification. A conditional logistic regression model with adjustment for potential confounding factors was used to assess the associations. Results Body gastritis, defined endoscopically, was independently associated with an increased risk for esophageal squamous cell carcinoma. Conclusion Our findings suggest that macroscopic body gastritis may be a risk factor for esophageal squamous cell carcinoma in Japan. Further studies are needed to confirm these findings.

In human subjects, aberrant crypt foci (ACF) can be classified as dysplastic or non-dysplastic using magnifying colonoscopy. Dysplastic ACF are thought to be a biomarker for the risk of colorectal cancer (CRC). Hyperinsulinemia and insulin-like growth factor-1 (IGF-1) have also been reported to be associated with an increased risk of CRC. To clarify this association, we investigated the relationship between diabetes risk, IGF-1 and the number of dysplastic ACF. Assessment of the number of dysplastic ACF in the entire colorectum is technically difficult, and we imaged the lower rectum only. Blood collections were taken in the morning on the day of colonoscopy. A total of 512 ACF were counted in 84 male participants, and a correlation was demonstrated to exist between age, body mass index (BMI), fasting blood sugar (FBS), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), plasma leptin levels, plasma IGF-1 levels and the number of dysplastic ACF. A significant association between plasma IGF-1 levels and the number of dysplastic ACF was still demonstrable after adjustment for age, BMI, FBS, insulin, HOMA-IR and plasma leptin levels. Our findings suggest that increased plasma leptin and IGF-1 levels, hyper-insulinemia and insulin resistance may promote the growth of dysplastic ACF. The results of multiple regression analysis revealed that increased plasma IGF-1 levels are associated with the number of dysplastic ACF present, and may be an independent risk factor for CRC. In conclusion, elevated plasma IGF-1 may promote the growth of dysplastic ACF and play a key role in colon carcinogenesis in male individuals.

Adiponectin is a peptide hormone secreted by adipose tissue. It is a key hormone responsible for insulin sensitization, and its circulating level is inversely associated with abdominal obesity. Recent studies have shown that a reduced plasma adiponectin level is significantly correlated with the risk of various cancers. However, there are few studies regarding the association of adiponectin and colorectal cancer. To address this issue, we investigated the effect of adiponectin on colorectal cancer cells. Three colorectal cancer cell lines express both AdipoR1 and AdipoR2 receptors. MTT assay revealed that adiponectin inhibited human colorectal cancer cell growth. Furthermore, Western blot analysis revealed that adiponectin activated adenosine monophosphate-activated protein kinase (AMPK) and suppressed mammalian target of rapamycin (mTOR) pathways. Selective AMPK inhibitor compound C abrogated the inhibitory effect of adiponectin on cell growth. Our results clearly demonstrate the novel findings that adiponectin inhibits colorectal cancer cell growth via activation of AMPK, thereby down-regulating the mTOR pathway.

The aim of this study was to determine whether there was a correlation between body positions and gastric emptying, using a novel non-invasive technique for measuring gastric emptying with a continuous real time 13C breath test (BreathID system).Ten healthy male volunteers participated in this randomized, two-way crossover study. On both occasions, the 13C breath test was performed for 4 hours using the BreathID system with a liquid meal (200 kcal per 200 mL) containing 100 mg 13C-acetic acid. Subjects were randomly assigned to sit comfortable (the sitting position) or to lie supine (the lying position).In the lying position, T 1/2 and T lag were significantly delayed. The gastric emptying coefficient was also decreased in lying position.This study showed that gastric emptying following a liquid meal was significantly delayed in the lying position compared to the sitting position, suggesting the potential use of these findings in the clinical setting for patients receiving enteral nutrition via the stomach.

Barrett's epithelium is currently believed to be related to acid gastroesophageal reflux. The aim was to determine the role of pancreatic-biliary reflux in the genesis of Barrett's epithelium.The study population comprised 1055 cases (606 men and 449 women; median age, 67 years) who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The study population was composed of 869 cases with intact stomachs and 186 cases with distal-gastrectomies. The presence and the progression of Barrett's epithelium were diagnosed based on the Prague CM Criteria. The correlations of clinical factors, including distal-gastrectomy, with the presence and the progression of Barrett's epithelium were examined.The study demonstrated that 42.2% of the total population was diagnosed to have Barrett's epithelium and, in 12.6% of the cases with Barrett's epithelium, the progression of Barrett's epithelium was observed during the median 72 month followup. A distal gastrectomy was not significantly correlated with either the incidence or progression of Barrett's epithelium.This lack of association between gastric surgery and Barrett's epithelium suggests that pancreatic-biliary reflux with limited acid is not sufficient for the genesis of Barrett's epithelium.

Although peroxisome proliferator-activated receptor γ (PPARγ) is strongly expressed in the intestinal epithelium, the role of PPARγ in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARγ inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated ApcMin/+ mice and carcinogen-induced colon cancer model C57BL/6 mice with T0070907 and counted the number of spontaneous polyps and aberrant crypt foci and observed cell proliferation and β-catenin protein in the colon epithelium. To investigate its mechanism, the changes of β-catenin/TCF (T cell factor) transcriptional activity and location of β-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of ApcMin/+ mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARγ inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the β-catenin protein in the colon epithelium. In vitro, cell proliferation was promoted, but it was inhibited by the transfection of dominant-negative Tcf4. T0070907 increased β-catenin/TCF transcriptional activity and β-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARγ antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. β-Catenin contributes to the promotion of tumorigenesis by PPARγ antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor. Keywords:: peroxisome proliferator-activated receptor γ (PPARγ), T0070907, aberrant crypt foci (ACF), β-catenin, intestinal tumor

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Iron is regarded as a putative element that interacts with oxygen radicals, and high rates of hyperferritinemia and increased hepatic iron stores have been demonstrated in NASH. We investigated serum ferritin concentrations, HFE gene mutations, and insulin resistance in Japanese NASH patients and the diagnostic utility of serum ferritin concentrations as a means of distinguishing NASH. Serum ferritin concentrations were measured in 86 patients with histopathologically verified NAFLD (24 with steatosis and 62 with NASH) and 20 control subjects, they were tested for HFE gene mutations and their insulin resistance was measured. The serum ferritin concentration was significantly higher in the NASH patients than in the patients with simple steatosis (P = 0.006). There was no significant difference between the groups in HFE gene mutation (C282Y, H63D, and S65C), and the serum ferritin level was related with insulin resistance. The area under the ROC curve was 0.732 for distinguishing NASH from simple steatosis (P = 0.005; 95% CI, 0.596-0.856). In conclusion high serum ferritin concentrations are a distinguishing feature of Japanese NASH patients independent of HFE gene mutations.

The association between obesity and the risk of colorectal cancer (CRC) cannot be easily evaluated because CRC itself is associated with a gradual loss of bodyweight. Aberrant crypt foci (ACF) can be classified as dysplastic ACF or non-dysplastic ACF by magnifying colonoscopy, and dysplastic ACF are thought to be a biomarker of CRC. Ninety-four participants who underwent colonoscopy at Yokohama City University Hospital, Japan, were enrolled in the current study. We detected 557 ACF, including 67 dysplastic ACF (12.0%). Univariate regression analysis was conducted to determine correlations between the number of dysplastic ACF and various potential risk factors, including patient age, waist circumference, body mass index, visceral fat area (VFA), and plasma adiponectin level. The results of multiple regression analysis revealed that the number of dysplastic ACF correlated with age (correlation coefficient r=0.212, P=0.0383) and plasma adiponectin level (r=-0.201, P=0.0371), even after adjustments for sex, waist circumference, body mass index, and VFA. Our univariate correlation analysis data showed a significant correlation with the number of dysplastic ACF with VFA (r=0.238, P=0.0209), no correlation with subcutaneous fat area, and an inverse correlation with the plasma level of adiponectin (r=-0.258, P=0.0118). Thus, our results suggest that aging and visceral fat accumulation could correlate moderately with colorectal carcinogenesis. The novelty of our study lies in the finding that visceral fat accumulation and a low plasma adiponectin level may promote colorectal carcinogenesis; therefore, these obesity-related parameters may serve as novel targets for CRC prevention.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in the carcinogenesis and progression of various solid tumors, including pancreatic carcinomas. We aimed to clarify the role of this receptor in pancreatic cell motility in vitro and in metastasis in vivo. Cell motility was examined by assaying transwell migration and wound filling in Capan-1 and Panc-1 pancreatic cancer cells, with or without the PPARgamma-specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPARgamma inhibition on pancreatic cancer metastasis. In both transwell-migration and wound-filling assays, inhibition of PPARgamma activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPARgamma also suppressed liver metastasis in vivo in metastatic mice. In PPARgamma-inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras-homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPARgamma in pancreatic cancer cells decreased cell motility by altering p120ctn localization and by suppressing the activity of the Ras-homologous GTPases Rac1 and Cdc42. Based on these findings, PPARgamma could function as a novel target for the therapeutic control of cancer cell invasion or metastasis.

BackgroundThe changes in the liver in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However it has remained difficult to differentiate between NASH and non-progressive NAFLD on the basis of the clinical findings alone.AimsIn this study we investigated the clinical usefulness of plasma Pentraxin3 (PTX3) levels to predict NASH. Plasma PTX3 was measured in 70 patients with histologically verified NAFLD (28 with non-NASH and 42 with NASH) and 10 healthy control subjects.ResultsThe plasma PTX3 level was significantly higher in the NASH cases than in the non-NASH cases (p = 0.0021) and control subjects (p = 0.045). And the plasma PTX3 level was significantly higher in the stages 3–4 NAFLD cases than in the stages 0–2 NAFLD cases (p < 0.0001). The PTX3 values were closely correlated with the stages of liver fibrosis (p < 0.0001, Kruskal-Wallis test). To detect NASH compared with non-NASH, the area under the curve for plasma PTX3 were 0.755, and to detect stages 3–4 NAFLD compared with stages 0–2 NAFLD, the area under the curve for plasma PTX3 were 0.850.ConclusionThis is the first study to demonstrate consistent and profound elevation of plasma PTX3 levels in NASH in comparison with non-NASH. The results suggest that plasma PTX3 levels may not only be laboratory values that differentiate NASH from non-NASH, but marker of the severity of hepatic fibrosis in NASH.

Aim: Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. In this study we analyzed the expression profile of genes and biological pathways involved in NASH in comparison with non-NASH by gene set enrichment analysis (GSEA) employing a DNA microarray technique. Methods: mRNA from liver biopsy specimens was collected from a group of NASH patients and a group of non-NASH patients. We analyzed the relative abundance of mRNA using high-density oligonucleotide microarrays containing probes for 54 675 known genes, and investigated the pathogenetic mechanisms of NASH by means of a powerful technique for analyzing molecular profiling data, GSEA. Results: The results showed that the level of expression of 27 gene sets was significantly higher and the level of expression of 25 gene sets was significantly lower in the NASH samples than in the non-NASH samples. Based on these results we created an online, publicly available, searchable database containing the data for the gene expression profiles of the NASH patients (http://www2.genome.rcast.u-tokyo.ac.jp/___/NASH/NASH_GSEA2/). Conclusion: Our data revealed differences in expression of many gene sets that are involved in the pathogenesis of NASH.

Background Evidence regarding the association between alcohol consumption and the gastro-esophageal reflux disease (GERD) spectrum has been conflicting. We examined the association between alcohol consumption and erosive esophagitis and Barrett's epithelium in Japanese men. Methods The study population comprised 463 men subjects who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The presence of erosive esophagitis and Barrett's epithelium was diagnosed based on the Los Angeles Classification and the Prague C and M Criteria, respectively. We divided the study population into four groups: never drinkers, light drinkers (less than 25.0 g of ethanol per day), moderate drinkers (25.0 to 50.0 g of ethanol per day), and heavy drinkers (more than 50.0 g of ethanol per day). A linear regression of the logistic regression analysis was used to analyze the dose-response trends. Results Compared with never drinkers, light drinkers (less than 25.0 g ethanol per day), moderate drinkers (25.0 to 50.0 g per day), and heavy drinkers (more than 50.0 g per day) had ORs for erosive esophagitis of 1.110 (95% CI: 0.553 – 2.228, p = 0.7688), 1.880 (95% CI: 1.015 – 3.484, p = 0.0445) and 1.988 (95% CI: 1.120 – 3.534, p = 0.0190), respectively. These groups had ORs for Barrett's epithelium of 1.278 (95% CI: 0.752 – 2.170, p = 0.3643), 1.458 (95% CI: 0.873 – 2.433, p = 0.1500), and 1.912 (95% CI: 1.185 – 3.086, p = 0.0079), respectively. The odds ratios/grams (alcohol)/day of dose response trends for erosive esophagitis and Barrett's epithelium were 1.015 (95% CI: 1.004–1.026, p = 0.0066) and 1.012 (95% CI: 1.003–1.021, p = 0.0079), respectively. Conclusion These findings suggest that alcohol consumption in Japanese men tends to be associated with an increased risk of erosive esophagitis and Barrett's epithelium.

The aim of the study was to evaluate bowel dysmotility in patients with a history of abdominal surgery by measuring both gastric transit time and small bowel transit time during capsule endoscopy and assessing the completeness of the examination. The study included 26 patients who had undergone abdominal surgery (postoperative group) and 52 patients who had not (control group). The capsule reached the cecum in 50.0% of the postoperative group and 80.8% of the control group (P = 0.005). While there was no significant difference in gastric transit time between the two groups (P = 0.882), small bowel transit time was significantly longer in the postoperative group (338.3 ± 119.2 min) than in the control group (266.4 ± 110.8 min, P = 0.010). This is the first study to report that the small bowel transit time during capsule endoscopy is prolonged in patients who had a history of abdominal surgery, resulting in a lower frequency of complete examination.

The aim of this study was to determine whether there is a correlation between aperitif and gastric emptying. Ten healthy male volunteers participated in this randomized, two-way crossover study. Under two conditions (after drinking an aperitif versus not), the (13)C breath test was performed for 4 h with a liquid meal (200 kcal/200 ml) containing 100 mg (13)C acetate. We used 50 ml of umeshu as the aperitif. This is a traditional Japanese plum liqueur, and contains 7 ml alcohol (14%). In the aperitif group, T(1/2), T(lag), and T(peak) were significantly delayed [T(1/2) (132: 113-174) versus (112: 92-134) (P = 0.0069); T(lag) (80: 63-94) versus (55: 47-85) (P = 0.0069); and T(peak) (81: 62-96) versus (54: 34-84) (P = 0.0069), (median: range, aperitif versus control, min)]. Gastric emptying was significantly delayed in the aperitif group as compared with the control group. This study revealed that even a small amount of alcohol such as an aperitif may contribute to delayed gastric emptying.

ANCA) and the perinuclear (P-ANCA). CANCA appears as a granular, diffuse cytoplasmic fluorescence, often with accentuated fluorescence around the nuclear lobes, and typical P-ANCA reactivity is Dear Sir, A 33-year-old woman was admitted to our hospital with cough and fever (over 39.0 ° C). About 1 month prior to the current admission, she had presented with fever (over 39.0 ° C), diarrhea and bloody bowel discharge. On admission, her hemoglobin was 8.9 g/dl and the serum C-reactive protein level was 6.8 mg/dl. Colonoscopy revealed flare and erosions in the entire large intestine and the patient was diagnosed as having ulcerative colitis ( fig. 1 ). Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was negative, whereas the proteinase 3-antineutrophil cytoplasmic antibody (PR3ANCA) titer was increased to 135 EU. As the patient was PR3-ANCA-positive, we focused our examination on the lungs, kidneys and nasopharynx, which are the most frequent sites of involvement in Wegner’s granulomatosis. However, these examinations revealed no specific findings. With mesalazine therapy and bowel rest for 10 days, the patient became afebrile, her cough remitted and the gastrointestinal symptoms, namely, diarrhea and bloody bowel discharge, resolved. ANCA is an autoantibody directed against the constituents of neutrophil granulocytes [1] . There are two basic ANCA patterns: the cytoplasmic (CPublished online: June 24, 2008

Experimentally emaciated male rats were produced by a bilateral electrical destruction of a part of hypothalamus. In a typical case, when the animals were fixed by perfusion, dissected, and organs weighted, the body weight became 1/2 of the control in 10 weeks. The weight of the viscera (including the subserous fat) was more decreased in comparison with the controls than the weight of the body wall (including extremities and the subcutaneous fat). The weight of the liver became 1/3, the adrenal 1/4, the testis 1/6 and the seminal vesicle 1/19 of the control. Light and electron microscopic examinations showed atrophy and fatty degeneration in the liver, atrophy of the zona reticularis in the adrenal, failure of spermatogenesis, especially at its spermiogenetic stage, in the testis, and an apoptosis in glandular epithelial cells of the seminal vesicle. Two weeks after partial hypothalamus destruction, the weight of the body wall was more decreased in comparison with the controls than the weight of the viscera. Possible pathophysiological mechanisms are discussed. An experimental model of electron microscopical research of apoptosis are presented.

Adiponectin is secreted by adipocytes and is a key hormone responsible for insulin sensitization. Recent studies have shown that plasma adiponectin is decreased in patients with breast, endometrial and gastric cancer. However, the effect of adiponectin on colorectal carcinogenesis is controversial. It is now well known that the adiponectin receptor exists in two isoforms, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). We examined the expression of the adiponectin receptors on normal colon mucosa and colon cancer tissues in a human study using real-time RT-PCR, Western blotting and immunohistochemical staining. Adiponectin receptors, AdipoR1/ AdipoR2, were expressed in normal colon epithelial and colon cancer cells. Furthermore, laser microdissection was performed to confirm our results. These results suggest that adiponectin may exert some effects on normal colon epithelium or colon cancer cells directly through adiponectin receptors. Further studies are required to elucidate the function of the AdipoRs activated by adiponectin and the downstream mechanisms of AdipoRs in colon cancer cells.