Cardiac ischemia-reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity.

BACKGROUND: Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium-glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. METHODS AND RESULTS: The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. CONCLUSIONS: Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

Risk Factors for Mortality in Pneumocystis jirovecii Pneumonia in Patients with Inflammatory Bowel Disease.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is highly fatal once infection is established. In this study, we investigated the risk of PJP mortality in patients with inflammatory bowel disease (IBD). METHODS: We conducted a retrospective observational study of case data from IBD patients who developed PJP, compiled from 17 collaborating institutions. Parameters such as age, sex, medications used, and blood test results were analyzed to identify risk factors for mortality. RESULTS: The mortality rate among the 28 IBD patients who developed PJP was 17.9%. A low serum albumin level at the start of IBD treatment was identified as a risk factor for mortality and showed the following association with probability of death (P): P = 1/[1 + exp(-5.5 + 2.4 × Alb). The probability of death exceeded 0.5 when serum albumin was 2.2 g/dL or lower. CONCLUSION: Patients with IBD who develop PJP have a high mortality rate and often cannot continue treatment with medication alone. Therefore, it is necessary to pay attention to albumin levels at the start of immunosuppressive therapy when creating a treatment plan.

Controlled isoflurane anesthesia exposure is required for reliable behavioral testing in murine surgical models.

We investigated the effects of variations in anesthesia exposure time prior to conducting anxiety response behavioral testing in sham controls from an experimental murine model. The staying time in the center area of the Open Field test in the "long exposure" group was significantly decreased compared to that of the "short exposure" group. Significant correlation was found between anesthesia time and the duration of staying time in the center area. We conclude that anesthesia time may have a significant impact on behavioral anxiety testing in this context, and advise careful control of this parameter in protocol optimization in related surgical animal models.

Tumor recognition of peanut agglutinin-immobilized fluorescent nanospheres in biopsied human tissues.

We are investigating an imaging agent for early detection of colorectal cancer. The agent, named the nanobeacon, is coumarin 6-encapsulated polystyrene nanospheres whose surfaces are covered with poly(N-vinylacetamide) and peanut agglutinin that reduces non-specific interactions with the normal mucosa and exhibits high affinity for terminal sugars of the Thomsen-Friedenreich antigen, which is expressed cancer-specifically on the mucosa, respectively. We expect that cancer can be diagnosed by detecting illumination of intracolonically administered nanobeacon on the mucosal surface. In the present study, biopsied human tissues were used to evaluate the potential use of the nanobeacon in the clinic. Prior to the clinical study, diagnostic capabilities of the nanobeacon for detection of colorectal cancer were validated using 20 production batches whose characteristics were fine-tuned chemically for the purpose. Ex vivo imaging studies on 66 normal and 69 cancer tissues removed from the colons of normal and orthotopic mouse models of human colorectal cancer, respectively, demonstrated that the nanobeacon detected colorectal cancer with excellent capabilities whose rates of true and false positives were 91% and 5%, respectively. In the clinical study, normal and tumor tissues on the large intestinal mucosa were biopsied endoscopically from 11 patients with colorectal tumors. Histological evaluation revealed that 9 patients suffered from cancer and the rest had adenoma. Mean fluorescence intensities of tumor tissues treated with the nanobeacon were significantly higher than those of the corresponding normal tissues. Correlation of magnitude relation of the intensity in individuals was observed in cancer patients with a high probability (89%); however, the probability reduced to 50% in adenoma patients. There was a reasonable likelihood for diagnosis of colorectal cancer by the nanobeacon applied to the mucosa of the large intestine.

Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation-Implications for Abdominal Aortic Aneurysm Susceptibility.

Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness. Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed. Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening. Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery.

Seven days triple therapy for eradication of Helicobacter pylori does not alter the disease activity of patients with inflammatory bowel disease.

BACKGROUND/AIMS: The influences of Helicobacter pylori eradication therapy on the disease course of inflammatory bowel disease (IBD) are still unclear. We therefore conducted a multicenter, retrospective cohort study to evaluate the safety of H. pylori eradication therapy for IBD patients. METHODS: IBD patients with H. pylori eradication from 2005 to 2015 (eradication group) and control patients (non-eradication group; 2 paired IBD patients without H. pylori eradication matched with each eradicated patient) were included. IBD exacerbation (increased/additional IBD drug or IBD-associated hospitalization/surgery) and disease improvement based on the physicians' global assessment were investigated at baseline, and at 2 and 6 months after eradication or observation. RESULTS: A total of 429 IBD (378 ulcerative colitis, 51 Crohn's disease) patients, comprising 144 patients in the eradication group and 285 patients in the non-eradication group, were enrolled at 25 institutions. IBD exacerbation was comparable between groups (eradication group: 8.3% at 2 months [odds ratio, 1.76; 95% confidence interval, 0.78-3.92; P=0.170], 11.8% at 6 months [odds ratio, 1.60; 95% confidence interval, 0.81-3.11; P=0.172]). Based on the physicians' global assessment at 2 months, none of the patients in the eradication group improved, whereas 3.2% of the patients in the non-eradication group improved (P=0.019). Multivariate analysis revealed that active disease at baseline, but not H. pylori eradication, was an independent factor for IBD exacerbation during 2 months' observation period. The overall eradication rate was 84.0%-comparable to previous reports in non-IBD patients. CONCLUSIONS: H. pylori eradication therapy does not alter the short-term disease activity of IBD.

MicroRNA-Mediated Therapy Modulating Blood-Brain Barrier Disruption Improves Vascular Cognitive Impairment.

OBJECTIVE: There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood-brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood-brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment. APPROACH AND RESULTS: Using a mouse model of vascular cognitive impairment, chronic cerebral hypoperfusion within the white matter was induced with bilateral common carotid artery stenosis (BCAS) surgery. TNFα gene expression was increased in white matter post-BCAS surgery, and TNFα stimulation decreased claudin-5, ZO-1 (tight-junction protein 1), and occludin gene expression in murine brain endothelial cells. In silico analysis predicted 8 candidate microRNAs as regulators of claudin-5, ZO-1, and occludin gene expression. Of these, only miR-501-3p was upregulated by TNFα in vitro and was upregulated in the white matter after BCAS surgery. Further, miR-501-3p directly bound to the 3'-untranslated region of human ZO-1 and downregulated transendothelial electric resistance. In vivo administration of a locked nucleic acid -modified antisense oligonucleotide versus miR-501-3p suppressed BCAS-induced reduction of ZO-1 gene expression and blood-brain barrier disruption within the white matter and significantly ameliorated working memory deficits after BCAS surgery. CONCLUSIONS: We here provide the first evidence that the TNFα-miR-501-3p-ZO-1 axis plays an important role in the pathogenesis of cerebral hypoperfusion-induced working memory deficits and white matter lesions, as a result of blood-brain barrier breakdown via tight junction disruption. Therapeutic manipulation of miR-501-3p holds promise for limiting vascular cognitive impairment progression.

Long-term retention of adalimumab treatment and associated prognostic factors for 1189 patients with Crohn's disease.

BACKGROUND AND AIM: There are few studies on the long-term efficacy of adalimumab treatment for patients with Crohn's disease. We have conducted a large, multicenter, retrospective cohort study to evaluate the long-term retention rate and prognostic factors associated with the discontinuation of adalimumab treatment in patients with Crohn's disease. METHODS: Data were collected from all patients with Crohn's disease who had received at least one induction dose of 160 mg of adalimumab between October 2010 and December 2013 at 41 institutions. The cumulative retention rates of adalimumab treatment following the first administration were estimated using the Kaplan-Meier method. Prognostic factors related to the cumulative retention rates were evaluated by log-rank tests and multivariate Cox regression analysis. RESULTS: A total of 1189 patients were included in the study. The 1-, 2-, 3-, and 4-year cumulative retention rates of adalimumab were 81%, 72%, 65%, and 62%, respectively. The multivariate Cox regression analysis confirmed female sex, previous infliximab use, perianal disease, concomitant treatment with prednisolone at baseline, higher C-reactive protein levels, and lower albumin levels as significant independent predictors of poor retention rate of adalimumab treatment. Significantly, more female patients than male patients discontinued adalimumab because of adverse events, especially skin reactions, infections, and arthralgia. CONCLUSIONS: Our data demonstrated a good retention rate of adalimumab in patients with Crohn's disease over a 4-year period. Female sex, perianal disease, concomitant treatment with prednisolone at baseline, previous infliximab use, higher C-reactive protein levels, and lower albumin levels were associated with poor retention of adalimumab treatment.

The thermogenic actions of natriuretic peptide in brown adipocytes: The direct measurement of the intracellular temperature using a fluorescent thermoprobe.

In addition to the various effects of natriuretic peptides (NPs) on cardiovascular systems, increasing attention is being paid to the possibility that NPs induce adipose tissue browning and activate thermogenic program. We herein established a direct intracellular temperature measurement system using a fluorescent thermoprobe and investigated the thermogenic effects of A-type NP (ANP) on brown adipocytes. The thermoprobe was successfully introduced into rat brown adipocytes, and the temperature dependent change in fluorescence intensity ratio was measured using a fluorescence microscope. After one-hour incubation with ANP, the degree of the change in fluorescence intensity ratio was significantly higher in ANP-treated (P < 0.01) adipocytes compared to untreated controls. The ANP treatment increased uncoupling protein-1 (UCP1) mRNA levels, which is one of the markers of thermogenesis in adipocytes, while the intracellular ATP content was not changed, indicating mitochondrial uncoupled respiration. Intriguingly, these thermogenic actions of ANP were more prominent when brown adipocytes were incubated at 35 °C than at 37 °C. Moreover, the increase in the intracellular temperature and the expression of UCP1 induced by ANP were cancelled by p38MAPK inhibition. Taken together, this study directly demonstrated the thermogenic actions of ANP in brown adipocytes through the use of a novel method of intracellular temperature measurement.

Real-world Experience of Anti-tumor Necrosis Factor Therapy for Internal Fistulas in Crohn's Disease: A Retrospective Multicenter Cohort Study.

BACKGROUND: Internal fistula in Crohn's disease is a condition likely to require surgery, although few reports showed successful medical treatments such as anti-tumor necrosis factor (TNF) therapy. We performed a multicenter retrospective cohort study to investigate the outcome of anti-TNF therapy for internal fistula in Crohn's disease. METHODS: Data were retrospectively collected from patients with Crohn's disease diagnosed with internal fistula treated with anti-TNF agents (infliximab or adalimumab) between January 2002 and November 2015. Need for surgery and fistula closure were assessed as primary and secondary endpoints. Cumulative rate of surgery was evaluated by the Kaplan-Meier analysis. Prognostic factors for the outcomes were also assessed by univariate and multivariate analyses. RESULTS: A total of 93 Crohn's disease cases were included in the study with a mean follow-up period of 1452.8 days. Fistula locations were entero-entero/colonic (n = 72, 77.4%), enterovesical (n = 16, 17.2%), or enterovaginal (n = 5, 5.4%). Cumulative surgery rate was 47.2%, and fistula closure rate was 27.0% at 5 years from the induction of anti-TNF agents. Lower Crohn's Disease Activity Index and shorter duration from the diagnosis of fistula were independently associated with the lower risk of surgery (P = 0.017 and 0.048, respectively). Single fistula was associated with the successful fistula closure. Second-line surgical treatments were mostly successful for anti-TNF failures. CONCLUSIONS: In the present retrospective cohort study, approximately half of patients with internal fistulas avoided surgery for long periods. It may be reasonable to treat quiescent single internal fistulas with anti-TNF agents soon after the diagnosis of internal fistulas.

Evaluation of a novel fluorescent nanobeacon for targeted imaging of Thomsen-Friedenreich associated colorectal cancer.

The Thomsen-Friedenreich (TF) antigen represents a prognostic biomarker of colorectal carcinoma. Here, using a nanobeacon, the surface of which was fabricated with peanut agglutinin as TF-binding molecules, we demonstrate that the nanobeacon is able to detect TF antigen in frozen and freshly biopsied polyps using fluorescence microscopy. Our results provide important clues about how to detect aberrant colonic tissues in the most timely fashion. Given the versatile application method for this topical nanobeacon, the protocol used in this work is amenable to clinical colonoscopy. Moreover, the prospects of clinical translation of this technology are evident.

Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy.

BACKGROUND: Thrombin is a serine protease known to be the final product of the coagulation cascade. However, thrombin plays other physiological roles in processes such as gastric contractions and vessel wound healing, and a state of coagulability is increased in patients with dilated cardiomyopathy (DCM). In this study, we investigate the role of thrombin in the pathogenesis of DCM. The purpose of this study is to clarify the role of thrombin in the pathogenesis of DCM and investigate the possibility of treatment against DCM by thrombin inhibition. METHODS: We investigated the expression of thrombin in the left ventricles of five patients with DCM who underwent the Batista operation and four patients without heart disease. Furthermore, we investigated the involvement of thrombin in the development of DCM using knock-in mice with a deletion mutation of cardiac troponin T that causes human DCM (∆K210 knock-in mouse) (B6;129-Tnnt2tm2Mmto) and assessed the effects of a direct thrombin inhibitor, dabigatran on ∆K210 knock-in mice using echocardiographic examinations, the Kaplan-Meier method and Western blotting. RESULTS: The immunohistochemical analysis showed a strong thrombin expression in the DCM patients compared to the patients without heart disease. In immunohistochemical analysis, a strong thrombin expression was observed in the heart tissues analysis in the ∆K210 knock-in mice. Dabigatran administration significantly improved fractional shortening according to the echocardiographic examination and the survival outcomes in ∆K210 knock-in mice. CONCLUSION: Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.

Risk factors for developing colorectal cancer in Japanese patients with ulcerative colitis: a retrospective observational study-CAPITAL (Cohort and Practice for IBD total management in Kyoto-Shiga Links) study I.

BACKGROUND AND AIMS: Patients with ulcerative colitis (UC) are at risk for developing colorectal cancer (CRC), despite the development of new therapeutic agents. Stratification of the individual UC-patient's risk would be helpful to validate the risk factors for CRC. The aim of this study was to evaluate the risk factors for the development of CRC in a large cohort of patients with UC. METHODS: Data were obtained from 12 hospitals in the Kyoto-Shiga region during 2003-2013. We performed a retrospective cohort study of 2137 patients with UC. RESULTS: In total, 60 lesions of CRC were detected in 43 (2.0%) of 2137 patients. 30 of the 43 patients were male. The median age was 53 years. The median duration of disease was 13 years, and 67.4% of these patients had a disease duration >10 years. Of the 43 patients, 34 (79.1%) had extensive colitis. Primary sclerosing cholangitis was detected in 2 patients (4.7%). The median corticosteroids (CS) dose was 6.4 g, and 4 patients were treated with a total of more than 10 g of CS. 18 of these patients underwent more than 1 year CS treatment. Of all 60 CRC lesions, 43 (71.7%) were located in the distal colon and 35 (58.3%) were of the superficial type. Moreover, the stage of CRC was stage 0 or I in 55.8% of the 43 patients with CRC. Multivariate analysis suggested that extensive colitis could be a risk factor for the development of advanced CRC in patients with UC. CONCLUSIONS: Our findings indicated that male, extensive colitis, long-term duration of UC and family history of CRC, but not concomitant primary sclerosing cholangitis, are important factors for predicting CRC in Japanese patients with UC. Moreover, long-standing extensive colitis might contribute to the progression of CRC. Further studies are required to establish CRC surveillance in Japanese patients with UC.

Effectiveness of cyclosporine as a treatment for steroid-resistant Cronkhite-Canada syndrome; two case reports.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare non-inherited disorder, characterized by gastrointestinal polyposis and ectodermal changes. The pathophysiology remains unclear. Treatment with corticosteroids is considered the mainstay treatment because of its high efficacy. However, some patients have steroid-resistant CCS. The therapeutic strategy for steroid-resistant CCS is not yet established. We report two cases with steroid-resistant CCS that were effectively treated with cyclosporine (CyA). We evaluated the therapeutic strategy for steroid-resistant CCS based on reviews of previous reports. CASE PRESENTATION: Our patients with CCS were first treated with prednisolone. No clinical response was noted, and treatment with CyA was initiated. After beginning CyA treatment, both clinical symptoms and polyposis markedly improved. Up to the present, 55 cases of CCS treated with corticosteroids and their response were reported. Out of the 57 patients, including our 2 cases, 9 (16 %) did not respond clinically to corticosteroids. In 7 of the 9 steroid-resistant cases, the prognosis after corticosteroids treatment was described. In 5 of the 7 steroid-resistant cases, immunosuppressive treatments induced remission. In 4 of these 5 cases, moreover, the key drug of treatments was calcineurin inhibitor. CONCLUSIONS: Treatment with calcineurin inhibitor, such as CyA, could be a potential option for steroid-resistant CCS.

Usefulness of sulfasalazine for patients with refractory-ulcerative colits.

BACKGROUND: Patients with refractory-ulcerative colitis (UC) require therapy escalation. Sulfasalazine (SASP) could deliver a high concentration of 5-aminosalicylic acid to the colon. The usefulness of SASP for refractory-UC patients, however, is unclear. AIM: The aim was to evaluate the usefulness of SASP for refractory-UC patients. METHOD: We retrospectively analysed 36 (11.4%) of 316 patients with refractory-UC who had been treated with SASP. Clinical and endoscopic activities were evaluated with Lichtiger index and Mayo score, respectively. We analysed the induction-remission rate, predictive factors for the efficacy of SASP, and adverse events. RESULTS: Of 36 refractory-UC patients, 14 (38.9%) were treated with concomitant mesalazine enemas, 10 (27.8%) with azathiopurine, 4 (11.1%) with tacrolimus and 6 (16.7%) with an antitumour necrosis factor-α agent. After initiating SASP treatment, 25 patients (69.4%) achieved clinical remission. In 9 (64.3%) of 14 patients with UC treated with mesalazine enemas, mesalazine enemas could be discontinued with SASP. In all patients treated with tacrolimus, tacrolimus could be discontinued with SASP. Clinical activity score upon the initiation of SASP was significantly lower (p=0.024) and the number of patients treated with thiopurine was significantly higher (p=0.016) in the clinical remission group than in the non-clinical remission group. These factors might be predictive for the efficacy of SASP, although multivariate analysis demonstrated no statistically significant effect. Adverse events occurred in 7 patients (19.4%), and reduction or discontinuation of SASP led to improvement. CONCLUSIONS: SASP appears to be more effective for refractory-UC patients with low clinical-activity and/or thiopurine-use. TRIAL REGISTRATION NUMBER: UMIN000021615; Results.

The predictive variable regarding relapse in patients with ulcerative colitis after achieving endoscopic mucosal healing.

BACKGROUND/AIMS: Mucosal healing (MH) is a proposed therapeutic goal for patients with ulcerative colitis (UC). Whether MH is the final goal for UC, however, remains under debate. Therefore, to elucidate clinical variables predicting relapse after MH in UC could be useful for establishing further therapeutic strategy. The aim of this study is to evaluate the predictive variables for relapse in UC-patients after achieving MH. METHODS: From April 2010 to February 2015, 298 UC-patients treated at Kitano Hospital were retrospectively analyzed. MH was defined as Mayo endoscopic subscore of 0 or 1. The cumulative relapse free rate after achieving MH was evaluated. Predictive variables for relapse in UC-patients were assessed by Cox regression analysis. RESULTS: Of 298 UC-patients, 88 (29.5%) achieved MH. Of the 88 UC patients who achieved MH, 21 (23.9%) experienced UC-relapse. Based on Kaplan-Meier analysis, the cumulative relapse free rate at 1, 3, and 5 years after achieving MH was 87.9%, 70.2%, and 63.8%, respectively. The cumulative relapse free rate tended to be higher in the Mayo-0 group (76.9%) than in the Mayo-1 group (54.1%) at 5 years, although the difference was not statistically significant (P=0.313). Cox regression analysis indicated that the use of an immunomodulator was a predictive variable for relapse in UC-patients after achieving MH (P=0.035). CONCLUSIONS: Our data demonstrated that the prognosis of UC patients after achieving endoscopic MH could be based on UC refractoriness requiring an immunomodulator.

Ischemic enteritis with intestinal stenosis.

A 75-year-old man was admitted to our hospital with sudden onset of vomiting and abdominal distension. The patient was taking medication for arrhythmia. Computed tomography showed stenosis of the ileum and a small bowel dilatation on the oral side from the region of stenosis. A transnasal ileus tube was placed. Enteroclysis using contrast medium revealed an approximately 6-cm afferent tubular stenosis 10 cm from the terminal ileum and thumbprinting in the proximal bowel. Transanal double-balloon enteroscopy showed a circumferential shallow ulcer with a smooth margin and edema of the surrounding mucosa. The stenosis was so extensive that we could not perform endoscopic balloon dilation therapy. During hospitalization, the patient's nutritional status deteriorated. In response, we surgically resected the region of stenosis. Histologic examination revealed disappearance of the mucosal layer and transmural ulceration with marked fibrosis, especially in the submucosal layer. Hemosiderin staining revealed sideroferous cells in the submucosal layers. Based on the pathologic findings, the patient was diagnosed with ischemic enteritis. The patient's postoperative course was uneventful.

A rare case of ulcerative colitis exacerbated by VZV infection.

A 16-years old man with severe ulcerative colitis (UC) was admitted to our hospital. After initiating treatment with corticosteroid for UC, chicken pox appeared. At the same time of appearance of chicken pox, the disease activity of UC was exacerbated. After initiating the treatment with acyclovir, both chicken pox and UC improved. Because colonoscopic findings revealed the remaining of moderately active UC, initiating the treatment with infliximab could induce clinical remission of UC without relapse of varicella-zoster virus (VZV) infection. This is a very rare case of UC with concomitant VZV infection. According to our report, the vaccination for VZV prior to immunosuppressive treatments would be necessary for VZV naïve patients with UC.

Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study.

OBJECTIVE: Treatment of severe ulcerative colitis (UC) is challenging. Although the efficacy of tacrolimus (TAC) and infliximab (IFX) have been evaluated in patients with severe UC, the safety and efficacy levels of sequential therapies (TAC→IFX/IFX→TAC) in these patients remain unclear. The aim of this study was to assess short-term and long-term outcomes in patients with severe UC treated with TAC and IFX. METHODS: From October 2001 to February 2014, 29 patients with consecutive severe UC treated with TAC or IFX were retrospectively evaluated. Median follow-up duration was 27 months (range 0.5-118 months). The primary end point was short-term outcomes at 8 weeks after induction of TAC (TAC group, n=22) or IFX (IFX group, n=7). The secondary end point included long-term outcomes and colectomy-free survival. The clinical response was evaluated based on a partial Mayo score. RESULTS: The clinical remission (CR) rate at 8 weeks in the TAC and IFX groups was 63.6% and 71.4%, respectively. In 13 of the 29 patients (10 in the TAC group, 3 in the IFX group), sequential therapies were used in their clinical courses. In 9 of these 13 patients (6 in the TAC group, 3 in the IFX group), CR was achieved and maintained by sequential therapies. Overall cumulative colectomy-free survival was 79.3% at 118 months. CONCLUSIONS: TAC and IFX had similar effects on remission induction in patients with severely active UC. Sequential therapies could rescue patients with UC who failed initial treatment with TAC or IFX. In clinical practice, sequential therapies might be deliberately performed.

Osteopontin Deficiency Accelerates Spontaneous Colitis in Mice with Disrupted Gut Microbiota and Macrophage Phagocytic Activity.

BACKGROUND: Osteopontin (OPN) is a multifunctional protein expressed in a variety of tissues and cells. Recent studies revealed increased OPN expression in the inflamed intestinal tissues of patients with inflammatory bowel disease (IBD). The role of OPN in the pathophysiology of IBD, however, remains unclear. AIMS: To investigate the role of OPN in the development of intestinal inflammation using a murine model of IBD, interleukin-10 knock out (IL-10 KO) mice. METHODS: We compared the development of colitis between IL-10 KO and OPN/IL-10 double KO (DKO) mice. OPN expression in the colonic tissues of IL-10 KO mice was examined by fluorescence in situ hybridization (FISH) analysis. Enteric microbiota were compared between IL-10 KO and OPN/IL-10 DKO mice by terminal restriction fragment length polymorphism analysis. The effect of OPN on macrophage phagocytic function was evaluated by phagocytosis assay. RESULTS: OPN/IL-10 DKO mice had an accelerated onset of colitis compared to IL-10 KO mice. FISH analysis revealed enhanced OPN synthesis in the colonic epithelial cells of IL-10 KO mice. OPN/IL-10 DKO mice had a distinctly different enteric bacterial profile with a significantly lower abundance of Clostridium subcluster XIVa and a greater abundance of Clostridium cluster XVIII compared to IL-10 KO mice. Intracellular OPN deletion in macrophages impaired phagocytosis of fluorescence particle-conjugated Escherichia coli in vitro. Exogenous OPN enhanced phagocytosis by OPN-deleted macrophages when administered at doses of 1 to 100 ng/ml, but not 1000 ng/ml. CONCLUSIONS: OPN deficiency accelerated the spontaneous development of colitis in mice with disrupted gut microbiota and macrophage phagocytic activity.