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Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorβ1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.

Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-β1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-β1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-β1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

Background A higher risk of cardiovascular events has been reported in patients with hypertension due to primary aldosteronism (PA) than essential hypertension. This study sought to determine the independent predictors for the risk of cardiovascular events in hypertensive patients with PA. Methods The Japan Primary Aldosteronism Study (JPAS) has retrospectively recruited 3,654 patients with PA between January 2006 and January 2019 as a nationwide registry and we evaluated the differences between patients with and without AF from these data. The patients underwent general laboratory test, electrocardiography, echocardiography, diagnostic confirmatory tests including saline-loading, captopril-challenge, and upright furosemide-loading tests and adrenal venous sampling (AVS). We evaluated the cardiovascular events including myocardial infarction, stroke, heart failure and renal failure, with a mean follow-up duration of approximately 4 years. Results The prevalence of AF was 2.4% (88/ 3,654). PA patients with AF were older (60.3 vs 52.8 years old), more male (77.3% vs 46.6%) and had longer duration of hypertension (14.3 vs 8.3 years) than those without AF. Each prevalence of cerebral infarction (12.5% vs 3.5%), chronic kidney disease (12.5% vs 4.8%), coronary artery disease (CAD) (10.2% vs 1.7%), heart failure (5.7% vs 0.7%) and left ventricular hypertrophy evaluated by echocardiography (46.4% vs 31.9%) was higher in PA patients with AF. Patients with AF had more kinds of antihypertensive drugs (1.3 vs 1.1). There was no significant difference of basal plasma aldosterone concentration (PAC), plasma renin activity, each confirmatory tests, lateralized ratio in AVS after stimulation with adrenocorticotropic hormone (ACTH) and laterality between the 2 groups. Logistic regression analysis showed that age, cardiothoracic ratio (CTR), past history of CAD and heart failure were independent determinants for AF. PA patients with AF had higher rates of cardiovascular events compared to those without AF (Figure, P Conclusions This study provides evidence that comorbid AF is associated with older age, male sex, X-ray CTR and prevalence of CAD and heart failure. Furthermore, AF is an independent predictor of cardiovascular events in patients with PA, in addition to the adrenal venous concentration of aldosterone, hypokalemia, older age and duration of hypertension. Earlier recognition and intervention of AF can prevent cardiovascular events in PA. Funding Acknowledgement Type of funding sources: None. Figure 1

Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorβ1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorβ1 is associated with insulin resistance and the rapid progression of transforming growth factorβ1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorβ1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorβ1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorβ1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorβ1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.

Introduction: A higher risk of cardiovascular events has been reported in patients with hypertension due to primary aldosteronism (PA) than essential hypertension. Hypothesis: This study sought to determine the independent predictors for the risk of cardiovascular events in hypertensive patients with PA. Methods: The nation-wide PA registration study (JPAS/JRAS) included patients aged 20 years and older. Data were collected between January 2006 and January 2019, with a mean follow-up duration of approximately 4 years. Characteristics of patients with or without atrial fibrillation (AF) on the diagnosis of PA were compared. Patients were treated by surgery or MR antagonists and incident cardiovascular events were followed up. Results: A total of 3,647 patients with PA were included at the time of analysis. Prevalence of AF was 2.4% (87/ 3,647). PA patients with AF were older, more male and had longer duration of hypertension than those without AF. Each prevalence of cerebral infarction, chronic kidney disease, coronary artery disease, heart failure and left ventricular hypertrophy evaluated by echocardiography was higher in PA patients with AF than those without AF. Patients with AF had more kinds of antihypertensive drugs. There was no significant difference of basal plasma aldosterone concentration, plasma renin activity, unilateral subtype and rate of surgery between the 2 groups. PA patients with AF had higher rates of cardiovascular events compared to those without AF (14.9% vs 6.7%, P=0.002). Multivariate cox regression analyses demonstrated AF in addition to older age, male gender, duration of hypertension and surgery performance as an independent prognostic factor for cardiovascular events (HR, 1.950 [95%CI, 1.021-3.726], P Conclusions: Among patients with PA, male gender, older age, and longer duration of hypertension are the predisposing factors of AF in PA patients. In addition, AF was an independent risk factor for cardiovascular events in PA patients. It is warranted to prevent and to treat appropriately AF in patients with PA.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Case A 64-year-old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow-up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin-associated lactic acidosis with acute renal failure caused by dehydration was detected. Outcome Her condition was improved by continuous veno-venous hemodiafiltration and hemodialysis, known to be useful to remove metformin. Conclusion We reported a case of metformin-associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy.

Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wild-type and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet β-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of β-cells and the development of diabetic nephropathy.

The early stages of acromegaly are characterized by slow and progressive acral overgrowth without major systemic complications. Failure to diagnose acromegaly at an early stage may have devastating consequences on patient care. The case in the present report was a 44-year-old Japanese man, referred to Kuwana City Medical Center due to severe hyperglycemia detected in a general checkup. The patient had no acromegaly-related complaints. Laboratory data revealed high blood levels of hemoglobin A1c and glucose. Careful physical examination revealed enlargement of extremities and soft tissues. Laboratory investigation indicated a high blood concentration of growth hormone, and magnetic resonance imaging disclosed an enhanced pituitary tumor. The diagnosis was pituitary tumor-associated acromegaly with severe diabetic complications. The pituitary tumor became large and unresectable following 10 years of misdiagnosis. The patient was treated with somatostatin receptor ligands (lanreotide and pasireotide), as well as bromocriptine in Mie University Hospital. The tumor size was reduced following treatment, though it was still unresectable at the time of this report. The case highlights the importance of hyperglycemia and abnormal manifestations of the feet in patients with acromegaly. In addition, these findings highlight the need for a thorough examination of the feet in diabetic patients, and the critical importance of the early diagnosis of acromegaly for preventing the consequences of inappropriate patient care.

A 47-year-old woman with diabetes treated with high-dose insulin was admitted to Mie University Hospital, Tsu, Japan, for screening of secondary diabetes mellitus and obesity. Laboratory tests and imaging studies were consistent with Cushing's disease (CD). The patient underwent trans-sphenoidal pituitary surgery. The patient exhibited loss of body weight (85.9 to 80.0 kg), improved glycated hemoglobin (HbA1c) (11.2 to 7.8%) and required lower doses of insulin (112 to 46 U/day) 6 months after surgery. The patient's body weight and daily insulin dose remained stable during the following 5 months (6–11 months after surgery). At that point, the patient was administered with canagliflozin, a sodium-glucose cotransporter 2 inhibitor. The patient required lower daily insulin dose without decreasing the dose of postoperative hydrocortisone concurrent to the administration of canagliflozin (100 mg/day). The patient's body weight decreased to 69.5 kg and withdrawal of insulin therapy was possible 8 months after initiation of canagliflozin. Despite withdrawal of insulin therapy, the HbA1c levels remained at

Background In this study, survival and cause of death were investigated in patients with Crohn’s disease (CD) at a tertiary referral center. Methods A database was created based on the medical records of 1108 CD patients who had a history of visiting our hospital to investigate background characteristics, cumulative survival rates from diagnosis, causes of death, and the standardized mortality ratio (SMR) for each cause of death. A follow-up questionnaire survey of patients followed up inadequately was also conducted. The cumulative survival rate from diagnosis was determined using the life table method and compared with that of a sex- and age-matched population model from the year 2000. Results The study included 1108 patients whose mean age at diagnosis was 25.6 ± 10.8 years. The mean duration of follow-up was 14.6 ± 9.4 years, and there were 52 deaths. The cumulative survival rate was significantly lower 25 years after the diagnosis of CD (91.7%) than in the standard population model (95.7%). SMRs for both all causes [3.5; 95% confidence interval (CI): 2.7–4.6] and CD-specific causes (36.7; 95% CI 26.1–51.6) were high. Among the CD-specific causes, SMRs were especially high for small intestine and colorectal cancers, gastrointestinal diseases including intestinal failure (IF), perioperative complications, and amyloidosis. Conclusion The SMRs for both all causes and CD-specific causes were high in CD patients. CD-specific causes including intestinal cancer, IF, perioperative complications, and amyloidosis showed especially high SMRs.

It remains unknown which surrogate markers can predict diagnostic test results for primary hyperaldosteronism (PA). The Secondary Hypertension Registry Investigation in Mie Prefecture (SHRIMP) study has sequentially and prospectively recruited 128 patients with hypertension with an aldosterone-to-renin ratio (ARR) greater than 20, evaluated the differences among essential hypertension (EHT), idiopathic hyperaldosteronism (IHA), and aldosterone-producing adenoma (APA), and analyzed the predictors for the confirmatory tests. The patients underwent saline-loading, captopril-challenge, and upright furosemide-loading tests. Carotid, renovascular, and cardiac echography, brachial ankle pulse wave velocity (baPWV), endothelial function, nocturnal blood pressure decline, and the apnea hypopnea index were evaluated. Multivariate regression analyses showed that the plasma aldosterone concentration (PAC) at screening was a strong predictor of the saline and captopril test results. The plasma renin activity (PRA) at screening, urine β2-microglobulin, and left ventricular mass index (LVMI) were independent predictors for the captopril test. The estimated saline PAC and captopril 60 and 90 min ARRs predicted by the equations were highly correlated with the real values. The ROC curve analysis showed PAC at screening among each of predictors for the diagnostic tests and PAC after the saline-loading test had the highest diagnostic abilities of APA. Patients with IHA were older and had glucose intolerance and increased U-Alb/gCre and resistive indices. In patients with APA, the levels of U-Alb/gCre and urine β2-microglobulin were increased, and levels of insulin and the HOMA-IR were decreased. In conclusion, our proposed equations may be useful for estimating saline PAC and captopril ARR. Diagnostic predictors may differ for each confirmatory test.

In Japan, the incidence of type 2 diabetes mellitus (T2DM) is increasing for several reasons, including increased consumption of sugar-sweetened beverages (SSBs). However, whether SSBs cause T2DM by excess of energy production resulting in obesity remains unclear. Therefore, the present study was designed to evaluate the effects of SSB intake on the development of T2DM in subjects with impaired glucose tolerance (IGT). Ninety-three subjects (30 males and 63 females) with IGT aged 40-69 y and residing in the Mihama district (southern Mie Prefecture, Japan) were included in the study. The mean observational period was 3.6 y. All subjects underwent the 75-g oral glucose tolerance test (OGTT) and completed a lifestyle questionnaire survey related to SSB intake. OGTT results and SSB intake were evaluated before and after the observational period. In addition, the correlation between SSB intake and development of T2DM was investigated. Of the 93 subjects, 20 (21.5%) developed T2DM (T2DM group) and demonstrated a significantly high SSB intake compared with the group that did not develop the disease (non-T2DM group). The odds ratio for the incidence of T2DM based on SSB intake was 3.26 (95% confidence interval, 1.17-9.06). The body mass index (BMI; kg/m(2)) and the homeostasis model assessment for insulin resistance (HOMA-R) values was significantly higher in the T2DM group than in the non-T2DM group, while the insulinogenic indices were significantly lower in the former than in the latter group. The sum of insulin secretion levels during OGTT was not significantly different between groups. SSB intake correlated with the predisposition for developing T2DM, possibly by influencing body weight, insulin resistance, and the ability of the pancreatic beta cells to effectively compensate for the insulin resistance.

Background Chronic progression of diabetes is associated with decreased pancreatic islet mass due to apoptosis of β-cells. Patients with diabetes have increased circulating matrix metalloproteinase-2 (MMP2); however, the physiological significance has remained elusive. This study tested the hypothesis that MMP2 inhibits cell apoptosis, including islet β-cells. Methods Samples from diabetic patients and newly developed transgenic mice overexpressing human MMP2 (hMMP2) were harnessed, and diabetes was induced with streptozotocin. Results Circulating hMMP2 was significantly increased in diabetic patients compared to controls and significantly correlated with the serum C-peptide levels. The diabetic hMMP2 transgenic mice showed significant improvements in glycemia, glucose tolerance and insulin secretion compared to diabetic wild type mice. Importantly, the increased hMMP2 levels in mice correlated with significant reduction in islet β-cell apoptosis compared to wild-type counterparts, and an inhibitor of hMMP2 reversed this mitigating activity against diabetes. The increased activation of Akt and BAD induced by hMMP2 in β-cells compared to controls, links this signaling pathway to the anti-apoptotic activity of hMMP2, a property that was reversible by both an hMMP2 inhibitor and antibody against integrin-β3. Conclusion Overall, this study demonstrates that increased expression of hMMP2 may attenuate the severity of diabetes by protecting islet β-cells from apoptosis through an integrin-mediated activation of the Akt/BAD pathway.

Summary Background Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. Methods In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45–69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c 1c 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Findings Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3–9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p vs 283 [22%] in the conventional therapy group, p vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Interpretation Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Funding Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Background and Aim The prevalence of ulcerative colitis (UC) is increasing steadily in Japan. In Western countries, a bimodal distribution, with UC onset peaks in youth and middle age, is observed, and smoking cessation is reported as a risk factor for UC. However, there are few reports on a bimodal distribution of onset age among Japanese patients. Therefore, the distribution of onset age and factors related to late onset (i.e. onset at 50 years old or later) were investigated in UC patients in Japan. Methods A questionnaire survey of UC patients was conducted to investigate the distribution of the age of onset and factors that may be related to UC onset in a Japanese university hospital. Results Among 465 UC patients, 343 patients responded. In the distribution of onset age, a large peak was seen in patients aged 10–20s, and small peaks were seen at age 40–44 years and then in 50–60s. In addition, the onset age was older in the UC patients diagnosed in 2001 or later than in those diagnosed in 2000 or earlier. Late onset was more common among the UC patients diagnosed in 2001 or later (vs 2000 or earlier: interaction odds ratio = 4.98, 95% CI: 2.21–11.25, P

Background and Aim The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients. Methods This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow-up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long-term follow up, correlations between mucosal healing and long-term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated. Results Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long-term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044). Conclusions Complete mucosal healing after 1–2 years was a predictive factor for long-term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long-term prognosis of Crohn's disease patients.

In order to elucidate mechanisms of tyramine accumulation during fish sauce production, two tyramine-producing bacterial strains, referred to as TyrA and TyrB, were isolated from fish sauce mash accumulating over 141 mg of tyramine per 100 g of sample. Both strains were identified as Tetragenococcus halophilus based on phenotypic characterization and a 16S rRNA gene sequence analysis. Molecular analysis of the tyramine-producing gene in the two strains confirmed the presence of a ~30-kb plasmid encoding a single copy of the pyridoxal phosphate-dependent tyrosine decarboxylase gene (tdcA) along with three other genes related to tyramine synthesis (tdc cluster). The complete nucleotide sequences of plasmids extracted from the two strains indicated that both plasmids were almost identical, except for a 1.6-kb transposon sequence in the plasmid from the strain TyrB. Both plasmids had a replication region, a plasmid maintenance region, and two putative mobile genetic elements located upstream and downstream of the tdc cluster. This structure was identical to that of tetragenococcal plasmids encoding histidine decarboxylase (hdcA), which were sequenced previously. These results suggest a common origin for plasmids encoding hdcA and tdcA. In addition, the genes for both these biogenic amines are distributed among tetragenococcal species via this plasmid.

Inland farming of marine shrimp species is a relatively recent development, in response to increasing demand for the products. This study aimed to investigate the prevalence and antimicrobial resistance of potentially pathogenic Vibrio species in shrimps cultured at inland ponds with low salinity in Thailand. Of 16 shrimp samples (white-leg shrimps and black-tiger shrimps) from ponds with water temperatures from 29 to 32 °C, and salinities from 1 to 5 parts per trillion, 15 contained Vibrio cholerae (densities: 62–252,000 MPN/g). Vibrio parahaemolyticus was present in six samples (370–6,300,000 MPN/g), and Vibrio vulnificus was present in two samples (16–1300 MPN/g). V. parahaemolyticus has higher affinity for non-native white-leg shrimp than for native black-tiger shrimp. The minimum inhibitory concentrations were then measured for 12 common antimicrobial agents. Resistance to ampicillin and oxytetracycline (8% and 2% of the isolates) was documented in V. cholerae isolates, resistance to ampicillin and oxytetracycline (72% and 3%) was found in V. parahaemolyticus isolates, and resistance to nalidixic acid (20%) was detected in V. vulnificus isolates. β-lactamase and tetracycline resistance genes were detected in the resistant Vibrio isolates. The oxytetracycline-resistance phenotype was eliminated by plasmid curing, suggesting that the resistance was related to R-plasmids. Our results show that shrimps cultured even in low salinity ponds are potentially contaminated with pathogenic Vibrio species, and that shrimp are a vehicle for transfer of species with antimicrobial resistance genes to the public.

Background and Aim Endoscopic balloon dilation (EBD) is an alternative to surgery for small bowel strictures of patients with Crohn's disease (CD). However, little is known about the long-term efficacy of EBD. The aim of the present study was to clarify the long-term outcome of EBD for small bowel strictures in patients with CD. Methods Subjects comprised 65 patients with CD who underwent EBD for small intestinal strictures and were followed up for at least 6 months. All subjects had obstructive symptoms as a result of small bowel strictures. Short-term success was defined as technical success and the disappearance of obstructive symptoms. The short-term success rate of EBD, its safety profile, the cumulative surgery-free rate and the cumulative redilation-free rate were investigated. Results Short-term success rate was 80.0% (52/65). Complications were encountered in six of the 65 patients (9.2%). Seventeen patients (26.2%) underwent surgery during the observation period of this study. Cumulative surgery-free rate after initial EBD was 79% at 2 years and 73% at 3 years, respectively. EBD successful cases showed significantly higher surgery-free rates than unsuccessful cases (P

Gram-stain-negative, aerobic, halophilic bacteria, designated SCM-1T, LCM10-1 and CTBL-B-147, were isolated from modified half-strength SWM-III medium, PES medium and thalli after laboratory cultivation of a red alga, Porphyra yezoensis. Phylogenetic analysis of 16S rRNA gene sequences indicated that the new isolates were affiliated to the genus Sulfitobacter of the class Alphaproteobacteria , and the 16S rRNA gene sequence similarity of the new isolates with the closest related species, Sulfitobacter mediterraneus CH-B427T, was 98.8 %. The DNA G+C contents of the new isolates were in the range of 61.4–62.3 mol%. DNA–DNA relatedness values of strain SCM-1T with other type strains of the genus Sulfitobacter were less than 15.9 %. The new isolates contained Q-10 as the predominant ubiquinone, phosphatidylcholine, phosphatidylglycerol, an unidentified amino lipid and an unidentified lipid as the main polar lipids, and C18 : 1ω7c, C19 : 1ω7c and C16 : 0 as the major fatty acids (>10 % of the total). Strain SCM-1T could be differentiated from Sulfitobacter mediterraneus JCM 21792T by 35 morphological and phenotypic characteristics. On the basis of the phylogenetic, genetic and phenotypic properties of the new isolates, the name Sulfitobacter porphyrae sp. nov. is proposed, with strain SCM-1T ( = LMG 27110T = NBRC 109054T) as the type strain.

We demonstrate wavelength- and mode-division multiplexed transmission over a fiber re-circulating loop comprising 50-km of low-DMGD few-mode fiber, and an optimized few-mode EDFA with reduced wavelength-dependent gain and mode-dependent gain. We characterize the channel matrix in terms of its singular value spread, and investigate its long-term stability.

Background and Aim The pharmacokinetics of tacrolimus (Tac) differ among individuals, and genetic polymorphisms of cytochrome P-450 (CYP) 3A4, CYP3A5, and ABCB1 are thought to be involved. The aim of this study was to clarify whether these genetic polymorphisms affect the pharmacokinetics of Tac in patients with ulcerative colitis. Methods The subjects in this study were 45 patients with moderate-to-severe ulcerative colitis who were resistant to other therapies and were treated with Tac. The subjects were tested for genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, and the relationship between Tac pharmacokinetics and the remission rate was investigated. Results Of the 45 subjects, 24 (53.3%) were CYP3A5 expressers (Exp), and 21 (46.7%) were non-expressers (Non-Exp). The trough level and the dose-adjusted trough level on days 2–5 were significantly higher in the Non-Exp group than in the Exp group (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P

Summary Background Apart from its role in the coagulation system, thrombin plays an important role in the inflammatory response through its protease-activated receptors (PARs). However, the role of thrombin in the immune response is not clear. Objective To evaluate whether thrombin has a modulatory role in allergic bronchial asthma. Methods Bronchial asthma was induced in mice by intraperitoneal sensitization and inhalation challenge with ovalbumin. Thrombin or its inhibitors were administered by inhalation before each allergen challenge. Results Mice with low but sustained coagulation activation had reduced allergic inflammation, and allergic asthma was inhibited by low doses of thrombin but worsened by high doses. Allergic asthma was worsened by antithrombin, argatroban, hirudin, and anti-thrombomodulin antibody. Mice with a higher level of an inhibitor of both thrombin and activated protein C had worse disease. Heterozygous PAR-1 mice had less allergic inflammation, but PAR-1 agonist worsened it. Allergic bronchial inflammation was worsened in mice that received adoptive transfer of PAR-1 agonist-treated Th2 cells as compared with controls. Low levels of thrombin suppressed the maturation and secretion of cytokines in dendritic cells, but high levels enhanced this. Conclusions The effects of thrombin on allergic asthma are dose-dependent, with detrimental effects at high doses and protective effects at low doses. These data demonstrate that thrombin modulates the outcome in allergic bronchial asthma.

Background and Aim There have been very few reported investigations on the standardized incidence ratio (SIR) of intestinal cancer and all cancers other than intestinal cancer with Crohn's disease (CD) by organ in Japan. This study examined the risk of developing cancer (i.e. SIR) that occurs in association with CD. Methods The subjects were 770 CD patients managed at our hospital department, which specializes in inflammatory bowel disease, during the approximately 25 years from July 1985 to August 2010. The number of expected cancer patients in a healthy population matched for sex and age with the CD patients in our hospital was then calculated. The relative risk, or SIR, was also calculated. Results The total observation period was 10 552 person-years, during which 19 cases (2.5%) of cancer were discovered in 770 subjects. The cancer cases included nine cases of colorectal cancer (CRC), one case of small bowel cancer, one case of stomach cancer, three cases of acute myeloid leukemia, two cases of endometrial cancer, one case of lung cancer, one case of skin cancer, and one case of thyroid cancer. The SIR for cancers in Japan in 2003 was 0.87 (95% confidence interval [CI] 0.52–1.35) for all cancers, 2.79 (95% CI 1.28–5.29) for CRC, and 6.94 (95% CI 1.43–20.3) for leukemia. Conclusions Among the cancers in CD patients in our hospital, no significant difference was seen in the risk for all cancers in comparison with the standard population. However, the risks for CRC and leukemia were significantly higher than in the standard population.

Crystal-storing histiocytosis (CSH) localized to the stomach is very rare, with only two cases reported to date. The present patient was a 55-year-old woman with no noteworthy symptoms. An area of discoloration was seen in the greater curvature of the gastric body on upper endoscopy by a local physician, and CSH was strongly suspected on biopsy examination. On upper endoscopy performed at our hospital, a flat, whitish, finely granular membrane with a diameter of 10 mm was seen in the greater curvature of the gastric body on white light observation. On magnifying endoscopy of the focal site, white granular material could be seen in the subepithelium, and the surface layer microvascular architecture image seen below the mucosal subepithelium was similar to the background, suggesting localization of the white material in a deep mucosal layer. On endoscopic ultrasound, this was depicted as multiple hyperechoic spots within the second layer corresponding to the involved area. Endoscopic submucosal dissection (ESD) was performed for a definitive diagnosis. Histopathological assessment of resected specimens revealed infiltration of abundant histiocytes including acidophilic crystalline structured material and positive plasma cells on anti-κ chain immunostaining, and CSH was diagnosed. Since this patient could have had a concomitant background autoimmune or hematologic disease, a systemic search was done. During this search, comorbid Sjögren's syndrome was discovered. This case of asymptomatic Sjögren's syndrome discovered during investigation of very rare gastric CHS is reported.

Three Gram-negative, stalked, motile bacteria, designated 0C-2-2T, 0C-17 and LNM-3, were isolated from the red alga Porphyra yezoensis. 16S rRNA gene sequence analysis revealed that the three novel strains belonged to the family Hyphomonadaceae , and were closely related to Litorimonas taeanensis G5T (96.5 % 16S rRNA gene sequence similarity) and Hellea balneolensis 26III/A02/215T (94.3 %). The DNA G+C contents of the novel isolates (58.5–60.2 mol%) were clearly distinguished from those of L. taeanensis G5T (47.1 mol%) and H. balneolensis DSM 19091T (47.9 mol%). The G+C content of L. taeanensis G5T obtained in this study was quite different from a previous report (63.6 mol%). DNA–DNA hybridization experiments showed that the novel strains constituted a single species. Eleven phenotypic features of the three isolates differed from those of both related genera. The predominant respiratory quinone was ubiquinone-10 and the major fatty acid was C18 : 1ω7c. On the basis of this polyphasic taxonomic analysis, the novel strains represent a novel genus and species, for which the name Algimonas porphyrae gen. nov., sp. nov. is proposed. The type strain of Algimonas porphyrae is 0C-2-2T ( = LMG 26424T = NBRC 108216T).

Background/Aims: In Japan, aphthous-type Crohn's disease (type A CD) is thought to represent an early phase of Crohn's disease (CD), and diagnosis of type A CD is possible in the diagnostic criteria for CD in Japan. However, the details of type A CD are not well understood. Methods: Subjects comprised 649 CD patients diagnosed between 1985 and 2011. The incidence of type A CD over time was clarified in two periods (1985-2004 and 2005-2011). The course of type A CD was also investigated, and cases that did and did not progress to typical CD were compared. Results: No significant difference was seen in the incidence of type A CD between the two periods (5.2 vs. 8.5%, p = 0.125). Type A CD patients followed at our hospital progressed to typical CD at a rate of 59.3%. In comparing progressive and nonprogressive cases, the frequency of large, densely distributed aphthous lesions in the small intestine was higher among progressive cases (p = 0.018). Conclusion: Type A CD is an early phase of CD, and CD diagnostic criteria including early cases are valid in Japan.

This study used a multicenter questionnaire survey to evaluate the morphology and progression of the initial lesion in cases of colitis-associated colorectal neoplasia (CRN).Endoscopic images of lesions that had been definitively diagnosed as CRN by pathological examination were retrospectively reviewed.This resulted in the identification of 54 initial lesions in 49 patients. The 54 initial lesions fell into the following categories: 22 endoscopically visible localized lesions consisting of 18 elevated lesions and 4 depressed lesions, as well as 32 lesions that were not endoscopically visible as localized and consisted of 20 active-phase mucosal lesions and 12 remission-phase mucosal lesions. Nineteen of the lesions eventually became advanced cancers, while 35 lesions eventually became early-stage cancers. The final lesions were 40 elevated lesions, 5 flat or depressed lesions and 9 stenotic lesions. The form of growth of the advanced cancers was progressive stenosis or increased elevation. For approximately 69% of the early-stage cancers, the growth form was increasing elevation or development of elevation. For 73.6% of the advanced cancers, the initial lesion underwent rapid growth and became advanced cancer within 3 years; they accounted for 25.9% of the total cancers. Approximately 40% of the initial lesions of CRN were endoscopically visible as localized lesions, while approximately 60% were judged to be inflammatory mucosal lesions.It will be necessary to proactively take biopsy inflammatory mucosal lesions in order to discover tumors early and periodic surveillance should be performed with the knowledge that tumors may grow very quickly.

The aim of this study was to make use of underutilized red-flesh fishes and produce safe and high-quality condiment, which have a low histamine level and a rich taste. Three kinds of fish sauces were produced on a small industrial scale from the deep-sea smelt, using not only koji mold but also sucrose (S) [S sample] or halophilic lactic acid bacterium Tetragenococcus halophilus (T) [T sample] or both S and T [S plus T sample] at room temperature for 224 days. A control fish sauce (Control) was prepared using neither S nor T. In comparison with 5 log/g or more of MPN count level, the short term of histamine-producing bacterial proliferation (approximately 30 days) and low level of histamine accumulation ( 1,000 ppm) during fermentation were found in the S and T samples and the Control. Moreover, free amino acid levels in the fish sauce mash at the end of fermentation were higher in S plus T sample than in the other samples. Practical Applications Recently, the demand for fish sauces has been increasing in Japan year after year for the purpose of efficient utilization of underutilized or non-utilized fishes and discharge of wastes from fish processing factories. Consumers also have requested safe and secure high-grade condiments from marine mammalian sources since the outbreak of bovine spongiform encephalopathy. It is clear that pH value in the fish sauce mash using both sucrose and halophilic lactic acid bacterium T. halophilus quickly declined to 4.8 at initial stage of fermentation. As a result, histamine-producing bacterial proliferation and histamine accumulation were restrained and high levels of taste-active components and essential amino acid of the fish sauce mash at the end of fermentation were obtained.

Diabet. Med. 29, e41–e46 (2012) Abstract Aims Dehydroepiandrosterone exerts a protective effect against cardiovascular diseases. However, the relationship of dehydroepiandrosterone with the anticoagulant factor activated protein C, generated by the thrombin–thrombomodulin complex on vascular endothelial cells, remains unknown. This study aimed at studying the relationship between dehydroepiandrosterone and activated protein C generation in patients with Type 2 diabetes. Methods Sixty-two male patients with Type 2 diabetes were enrolled in this study. Data obtained from 40 healthy male subjects were used as controls. The plasma levels of dehydroepiandrosterone, the activated protein C–protein C inhibitor complex, high-sensitivity C-reactive protein and monocyte chemoattractant protein-1 were measured by enzyme immunoassays. Carotid intima-media thickness was measured by ultrasonography. Results The plasma levels of dehydroepiandrosterone (5.15 ± 2.81 vs. 3.76 ± 2.16 ng/ml; P

In order to analyze the genes related to histamine production in halophilic lactic acid bacteria, 16 strains of histamine-producing bacteria were isolated from three fermented seafoods produced in the Hokuriku region of Japan. Phenotypic and 16S rRNA gene sequence analyses identified all of the strains as those of Tetragenococcus muriaticus. Pyruvoyl-dependent histidine decarboxylase gene (hdcA) was determined from all strains using the PCR method with an hdcA-specific detection primer set. Genetic analyses (Southern blot and restriction fragment length polymorphism analysis) of hdcA and genes related to histamine production (the hdc cluster) confirmed that all of the strains harbored 21–23 kbp plasmids encoding a single copy of hdcA. The four representative strains were selected based on isolation source and genetic analysis, and subsequently full sequences of plasmids harbored in these strains were determined. hdc cluster sequences from the plasmids showed very high similarity (>99 %) to known hdc clusters of T. halophilus, Lactobacillus hilgardii 0006, and other lactic acid bacteria. The structures of the plasmids, the replication region, the hdc cluster, and the plasmid maintenance system were conserved between the plasmids present in new isolates and the T. halophilus strains. These results indicate that plasmids encoding hdcA are widely distributed among T. halophilus and T. muriaticus and function in both species.

Aim: We assessed the long-term outcome of infliximab (IFX) therapy in patients with Crohn's disease (CD) and investigated the efficacy of concomitant endoscopic balloon dilation (EBD) for intestinal stricture during treatment. Methods: The effectiveness of maintenance therapy with IFX was retrospectively evaluated in 185 patients with CD in a single center (median observation period 24 months). IFX effectiveness with and without immunomodulators (IMM) and enteral nutrition (EN), as well as cumulative surgery-free rates, were compared. The efficacy of concomitant EBD in patients with obstructive symptoms and high-level stricture was evaluated. Results: In 185 patients receiving the maintenance therapy, the long-term efficacy rate was 84.9% at 24 months and 79.0% at 48 months. The cumulative surgery-free rate was significantly higher in the maintenance group (P

Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-β1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-β1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-β1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-β1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-β1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-β1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans.

Three Gram-negative, motile, aerobic bacteria were isolated from cultures of the marine red alga Porphyra yezoensis. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the novel strains were closely related to Maritalea myrionectae CL-SK30T (97.9 % 16S rRNA gene sequence similarity) and Zhangella mobilis E6T (96.2 %). 16S rRNA gene sequence similarity between Z. mobilis E6T and M. myrionectae CL-SK30T was 97.9 %. The DNA G+C contents of the isolates (49.4–50.0 mol%) were similar to those of M. myrionectae DSM 19524T (52.3 mol%) and Z. mobilis JCM 15144T (50.3 mol%). From these results, it was difficult to differentiate the genus Zhangella from the genus Maritalea. DNA–DNA hybridization demonstrated that the isolates belonged to a single species. The isolates could also be distinguished from M. myrionectae and Z. mobilis on the basis of chemotaxonomic and phenotypic features, including fatty acid composition (particularly C16 : 1ω7c), growth with 6–9 % (w/v) NaCl, carbon utilization, oxidation patterns and so on. A novel species of the genus Maritalea is proposed to accommodate the three isolates, with the name Maritalea porphyrae sp. nov. The type strain is LCM-3T ( = LMG 25872T = NBRC 107169T). Furthermore, it is proposed that Zhangella mobilis should be transferred from the genus Zhangella to the genus Maritalea, with the name Maritalea mobilis comb. nov. (type strain E6T = CGMCC 1.7002T = JCM 15144T).