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1.  Activated Platelets from Diabetic Rats Cause Endothelial Dysfunction by Decreasing Akt/Endothelial NO Synthase Signaling Pathway 
PLoS ONE  2014;9(7):e102310.
Diabetes is associated with endothelial dysfunction and platelet activation, both of which may contribute to increased cardiovascular risk. The purpose of this study was to characterize circulating platelets in diabetes and clarify their effects on endothelial function. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Each experiment was performed by incubating carotid arterial rings with platelets (1.65×107 cells/mL; 30 min) isolated from STZ or control rats. Thereafter, the vascular function was characterized in isolated carotid arterial rings in organ bath chambers, and each expression and activation of enzymes involved in nitric oxide and oxidative stress levels were analyzed. Endothelium-dependent relaxation induced by acetylcholine was significantly attenuated in carotid arteries treated with platelets isolated from STZ rats. Similarly, treatment with platelets isolated from STZ rats significantly reduced ACh-induced Akt/endothelial NO synthase signaling/NO production and enhanced TXB2 (metabolite of TXA2), while CD61 (platelet marker) and CD62P (activated platelet marker) were increased in carotid arteries treated with platelets isolated from STZ rats. Furthermore, the platelets isolated from STZ rats decreased total eNOS protein and eNOS dimerization, and increased oxidative stress. These data provide direct evidence that circulating platelets isolated from diabetic rats cause dysfunction of the endothelium by decreasing NO production (via Akt/endothelial NO synthase signaling pathway) and increasing TXA2. Moreover, activated platelets disrupt the carotid artery by increasing oxidative stress.
PMCID: PMC4105471  PMID: 25047034
2.  Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in preeclampsia 
Emerging evidence suggests that in addition of being the “power houses” of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mitochondrial DNA (mtDNA) that acts via Toll-like receptor 9 (TLR9), a pattern recognition receptor of the immune system, which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9 in a similar fashion with bacterial DNA stems from evolutionary conserved similarities between bacteria and mitochondria. Mitochondrial DNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. Preeclampsia (PE) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The etiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulate TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and intrauterine growth restriction. The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE and anti-TLR9 treatments may be promising in the management of the disease.
PMCID: PMC4004352  PMID: 22671429
3.  Prospective postsurgical capsule endoscopy in patients with Crohn’s disease 
AIM: To clarify the usefulness of postsurgical capsule endoscopy (CE) in the diagnosis of recurrent small bowel lesions of Crohn’s disease (CD).
METHODS: This prospective study included 19 patients who underwent ileocolectomy or partial ileal resection for CD. CE was performed 2-3 wk after surgery to check for the presence/absence and severity of lesions remaining in the small bowel, and for any recurrence at the anastomosed area. CE was repeated 6-8 mo after surgery and the findings were compared with those obtained shortly after surgery. The Lewis score (LS) was used to evaluate any inflammatory changes of the small bowel.
RESULTS: One patient was excluded from analysis because of insufficient endoscopy data at the initial CE. The total LS shortly after surgery was 428.3 on average (median, 174; range, 8-4264), and was ≥ 135 (active stage) in 78% (14 of 18) of the patients. When the remaining unresected small bowel was divided into 3 equal portions according to the transition time (proximal, middle, and distal tertiles), the mean LS was 286.6, 83.0, and 146.7, respectively, without any significant difference. Ulcerous lesions in the anastomosed area were observed in 83% of all patients. In 38% of the 13 patients who could undergo CE again after 6-8 mo, the total LS was higher by ≥ 100 than that recorded shortly after surgery, thus indicating a diagnosis of endoscopic progressive recurrence.
CONCLUSION: Our pilot study suggests that CE can be used to objectively evaluate the postoperative recurrence of small bowel lesions after surgery for CD.
PMCID: PMC3952165  PMID: 24634713
Crohn’s disease; Postoperative recurrence; Capsule endoscopy; Lewis score; Small bowel
4.  Characterization of gut microbiota profiles by disease activity in patients with Crohn’s disease using data mining analysis of terminal restriction fragment length polymorphisms 
Biomedical Reports  2014;2(3):370-373.
The gut microbiota plays a significant role in the pathogenesis of Crohn’s disease (CD). In this study, we analyzed the disease activity and associated fecal microbiota profiles in 160 CD patients and 121 healthy individuals. Fecal samples from the CD patients were collected during three different clinical phases, the active (n=66), remission-achieved (n=51) and remission-maintained (n=43) phases. Terminal restriction fragment length polymorphism (T-RFLP) and data mining analysis using the Classification and Regression Tree (C&RT) approach were performed. Data mining provided a decision tree that clearly identified the various subject groups (nodes). The majority of the healthy individuals were divided into Node-5 and Node-8. Healthy subjects comprised 99% of Node-5 (91 of 92) and 84% of Node-8 (21 of 25 subjects). Node-3 was characterized by CD (136 of 160 CD subjects) and was divided into Node-6 and Node-7. Node-6 (n=103) was characterized by subjects in the active phase (n=48; 46%) and remission-achieved phase (n=39; 38%) and Node-7 was characterized by the remission-maintained phase (21 of 37 subjects; 57%). Finally, Node-6 was divided into Node-9 and Node-10. Node-9 (n=78) was characterized by subjects in the active phase (n=43; 55%) and Node-10 (n=25) was characterized by subjects in the remission-maintained phase (n=16; 64%). Differences in the gut microbiota associated with disease activity of CD patients were identified. Thus, data mining analysis appears to be an ideal tool for the characterization of the gut microbiota in inflammatory bowel disease.
PMCID: PMC3990205  PMID: 24748976
data mining; microbiota; terminal restriction fragment length polymorphism; inflammatory bowel disease
5.  Efficacy and safety of adalimumab in Japanese patients with moderately to severely active ulcerative colitis 
Journal of Gastroenterology  2013;49(2):283-294.
Adalimumab is a fully human, monoclonal antibody against tumor necrosis factor that is approved in Western countries for the treatment of moderately to severely active ulcerative colitis (UC).
This 52-week, phase 2/3, randomized, double-blind study evaluated adalimumab for induction and maintenance treatment in 273 anti-TNF–naive Japanese patients with UC who were refractory to corticosteroids, immunomodulators, or both. Patients received placebo, adalimumab 80/40 (80 mg at week 0, then 40 mg every other week), or adalimumab 160/80 (160/80 mg at weeks 0/2, then 40 mg every other week) in addition to background UC therapy.
At week 8, remission rates were similar among treatment arms, but more patients treated with adalimumab 160/80 achieved response (placebo, 35 %; 80/40, 43 %; 160/80, 50 %; P = 0.044 for 160/80 vs placebo) and mucosal healing (placebo, 30 %; 80/40, 39 %; 160/80, 44 %; P = 0.045 for 160/80 vs placebo) compared with placebo. At week 52, more patients receiving adalimumab 40 mg every other week achieved response (18 vs 31 %; P = 0.021), remission (7 vs 23 %; P = 0.001), and mucosal healing (16 vs 29 %; P = 0.015) compared with placebo. Week 8 response to adalimumab was associated with greater rates of response (61 %), remission (46 %), and mucosal healing (57 %) at week 52 relative to the overall population. Rates of serious adverse events were similar between treatment arms.
Induction with adalimumab 160/80 mg led to early response and mucosal healing. Maintenance adalimumab had greater rates of long-term response, remission, and mucosal healing compared with placebo. No new safety signals were identified.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-013-0922-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3925299  PMID: 24363029
Clinical remission; Japan; Ulcerative colitis; Mucosal healing; Adalimumab
6.  Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma: Recent progress in pathogenesis and management 
Recent progress in the research regarding the molecular pathogenesis and management of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is reviewed. In approximately 90% of cases, Helicobacter pylori (H. pylori) infection plays the causative role in the pathogenesis, and H. pylori eradication is nowadays the first-line treatment for this disease, which leads to complete disease remission in 50%-90% of cases. In H. pylori-dependent cases, microbe-generated immune responses, including interaction between B and T cells involving CD40 and CD40L co-stimulatory molecules, are considered to induce the development of MALT lymphoma. In H. pylori-independent cases, activation of the nuclear factor-κB pathway by oncogenic products of specific chromosomal translocations such as t(11;18)/API2-MALT1, or inactivation of tumor necrosis factor alpha-induced protein 3 (A20) are considered to contribute to the lymphomagenesis. Recently, a large-scale Japanese multicenter study confirmed that the long-term clinical outcome of gastric MALT lymphoma after H. pylori eradication is excellent. Treatment modalities for patients not responding to H. pylori eradication include a “watch and wait” strategy, radiotherapy, chemotherapy, rituximab immunotherapy, and a combination of these. Because of the indolent behavior of MALT lymphoma, second-line treatment should be tailored in consideration of the clinical stage and extent of the disease in each patient.
PMCID: PMC3857439  PMID: 24363507
Gastric lymphoma; Mucosa-associated lymphoid tissue lymphoma; Helicobacter pylori; Nuclear factor κB
7.  Haemoglobin A1c even within non-diabetic level is a predictor of cardiovascular disease in a general Japanese population: the Hisayama Study 
There is little information about predictive ability of haemoglobin A1c (HbA1c) for cardiovascular disease (CVD) in Asians. To investigate the discriminatory ability of HbA1c to identify subjects who are at greater risk of developing CVD in a prospective study of a defined community-dwelling Japanese population.
A total of 2,851 subjects aged 40–79 years were stratified into five groups (HbA1c levels with ≤ 5.0, 5.1–5.4, 5.5–6.4, and ≥ 6.5% and a group with antidiabetic medication) and followed up prospectively for 7 years (2002–2009).
During the follow-up, 119 subjects developed CVD. The multivariable-adjusted risk of CVD was significantly increased in subjects with HbA1c levels of 5.5–6.4 and ≥ 6.5% and diabetic medication compared to HbA1c level with ≤ 5.0% (hazard ratio, 2.26 [95% confidence interval, 1.29–3.95] for the 5.5–6.4%; 4.43 [2.09–9.37] for the ≥ 6.5%; and 5.15 [2.65–10.0] for the antidiabetic medication group). With regard to CVD subtype, the positive associations between HbA1c levels and the risk of coronary heart disease (CHD) and ischaemic stroke were also significant, but no such associations were seen for haemorrhagic stroke. The C statistic for developing CVD was significantly increased by adding HbA1c values to the model including other risk factors (0.789 vs. 0762, p = 0.006), and the net reclassification improvement was 0.105 (p = 0.004).
Our findings suggest that elevated HbA1c levels are an independent risk factor for CVD, especially CHD and ischaemic stroke, and that the addition of HbA1c to the model with traditional risk factors significantly improves the predictive ability of CVD.
PMCID: PMC4176981  PMID: 24195452
Haemoglobin A1c; Cardiovascular disease; Risk factor; Prospective cohort study; Epidemiology
8.  The 2nd edition of consensus statements for the diagnosis and management of intestinal Behçet’s disease: indication of anti-TNFα monoclonal antibodies 
Journal of Gastroenterology  2013;49(1):156-162.
Clinical evidence regarding intestinal Behçet’s disease (BD) management is lacking and intestinal lesions are a poor prognostic factor. In 2007, the Japan consensus statement for diagnosis and management of intestinal BD was developed. Recently, the efficacy of anti-tumor necrosis factor (TNF)α monoclonal antibodies (mAbs), and infliximab (IFX) was reported and adalimumab (ADA) was approved for intestinal BD in Japan. This study renewed consensus-based practice guidelines for diagnosis and treatment of intestinal BD focusing on the indication of anti-TNFα mAbs.
An expert panel of Japanese gastroenterology and rheumatology specialists was involved. Clinical statements for ratings were extracted from the literature, a professional group survey, and by an expert panel discussion, which rated clinical statements on a nine-point scale. After the first round of ratings, a panelist meeting discussed areas of disagreement and clarified areas of uncertainty. The list of clinical statements was revised after the panelist meeting and a second round of ratings was conducted.
Fifteen relevant articles were selected. Based on the first edition consensus statement, improved clinical statements regarding indications for anti-TNFα mAbs use were developed. After a two-round modified Delphi approach, the second edition of consensus statements was finalized.
In addition to standard therapies in the first edition, anti-TNFα mAbs (ADA and IFX) should be considered as a standard therapy for intestinal BD. Colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapies.
PMCID: PMC3895195  PMID: 23955155
Intestinal Behçet’s disease; Anti-TNFα mAb; Consensus statements
9.  G Protein–Coupled Receptor Kinase 2, With β-Arrestin 2, Impairs Insulin-Induced Akt/Endothelial Nitric Oxide Synthase Signaling in ob/ob Mouse Aorta 
Diabetes  2012;61(8):1978-1985.
In type 2 diabetes, impaired insulin-induced Akt/endothelial nitric oxide synthase (eNOS) signaling may decrease the vascular relaxation response. Previously, we reported that this response was negatively regulated by G protein–coupled receptor kinase 2 (GRK2). In this study, we investigated whether/how in aortas from ob/ob mice (a model of type 2 diabetes) GRK2 and β-arrestin 2 might regulate insulin-induced signaling. Endothelium-dependent relaxation was measured in aortic strips. GRK2, β-arrestin 2, and Akt/eNOS signaling pathway proteins and activities were mainly assayed by Western blotting. In ob/ob (vs. control [Lean]) aortas: 1) insulin-induced relaxation was reduced, and this deficit was prevented by GRK2 inhibitor, anti-GRK2 antibody, and an siRNA specifically targeting GRK2. The Lean aorta relaxation response was reduced to the ob/ob level by pretreatment with an siRNA targeting β-arrestin 2. 2) Insulin-stimulated Akt and eNOS phosphorylations were decreased. 3) GRK2 expression in membranes was elevated, and, upon insulin stimulation, this expression was further increased, but β-arrestin 2 was decreased. In ob/ob aortic membranes under insulin stimulation, the phosphorylations of Akt and eNOS were augmented by GRK2 inhibitor. In mouse aorta, GRK2 may be, upon translocation, a key negative regulator of insulin responsiveness and an important regulator of the β-arrestin 2/Akt/eNOS signaling, which is implicated in diabetic endothelial dysfunction.
PMCID: PMC3402304  PMID: 22688330
10.  Data mining analysis of terminal restriction fragment length polymorphism shows geographical differences in the human gut microbiota 
Biomedical Reports  2013;1(4):559-562.
Environmental factors are important for shaping the gut microbiota. In this study, terminal-restriction fragment length polymorphism (T-RFLP) analysis was performed, and data mining analysis was applied to investigate the geographical differences in the gut microbiota in Japan. A total of 121 healthy individuals living in four different districts (Shiga, Hyogo, Fukuoka and Chiba prefectures) in Japan were enrolled. Their gut microbiota profiles were evaluated by T-RFLP analysis, and data mining analysis using the Classification and Regression Tree (C&RT) approach was performed. Data mining analysis provided a decision tree that clearly identified the various groups of subjects (nodes). Some nodes characterized the subjects from the four geographically distinct regions. Overall, 21 of the 35 subjects from the Hyogo Prefecture were mainly included in Node 21, 11 of the 16 subjects from the Shiga Prefecture were mainly included in Node 19, 37 of 40 subjects from the Chiba Prefecture were mainly included in Node 6 and 28 of 30 subjects from the Fukuoka Prefecture were included in Node 3. Only eight operational taxonomic units (OTUs) of the total 100 OTUs contributed to the characterization of the gut microbiota of the four geographically distinct districts in Japan. Geographical differences in the human gut microbiota were identified in Japan. Data mining analysis appears to be one of the optimal tools for characterization of the human gut microbiota.
PMCID: PMC3916989  PMID: 24648986
data mining; microbiota; terminal-restriction fragment length polymorphism
11.  Impaired β-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced KCa channel activity 
Pharmacological Research  2012;65(5):537-545.
β-Adrenoceptor (β-AR)-mediated relaxation plays an important role in the regulation of vascular tone. β-AR-mediated vascular relaxation is reduced in various disease states and aging. We hypothesized that β-AR-mediated vasodilatation is impaired in DOCA-salt hypertension due to alterations in the cAMP pathway. β-AR-mediated relaxation was determined in small mesenteric arteries from DOCA-salt hypertensive and control uninephrectomized (Uni) rats. To exclude nitric oxide (NO) and cyclooxygenase (COX) pathways, relaxation responses were determined in the presence of L-NNA and indomethacin, NO synthase inhibitor and COX inhibitors, respectively. Isoprenaline (ISO)-induced relaxation was reduced in arteries from DOCA-salt compared to Uni rats. Protein kinase A (PKA) inhibitors (H89 or Rp-cAMPS) or adenylyl cyclase inhibitor (SQ22536) did not abolish the difference in ISO-induced relaxation between the groups. Forskolin (adenylyl cyclase activator)-induced relaxation was similar between the groups. The inhibition of IKCa/SKCa channels (TRAM-34 plus UCL1684) or BKCa channels (iberiotoxin) reduced ISO-induced relaxation only in Uni rats and abolished the relaxation differences between the groups. The expression of SKCa channel was decreased in DOCA-salt arteries. The expression of BKCa channel α subunit was increased whereas the expression of BKCa channel β subunit was decreased in DOCA-salt arteries. The expression of receptor for activated C kinase 1 (RACK1), which is a binding protein for BKCa channel and negatively modulates its activity, was increased in DOCA-salt arteries. These results suggest that the impairment of β-AR-mediated relaxation in DOCA-salt mesenteric arteries may be attributable to altered IKCa/SKCa and/or BKCa channels activities rather than cAMP/PKA pathway. Impaired β-AR-stimulated BKCa channel activity may be due to the imbalance between its subunit expressions and RACK1 upregulation.
PMCID: PMC3327799  PMID: 22388053
β-adrenoceptor; calcium-activated potassium channel; DOCA-salt; relaxation; mesenteric artery; RACK1
12.  Prognosis following emergency surgery for ulcerative colitis in elderly patients 
Surgery Today  2013;44(1):39-43.
Since 2000, the incidence of ulcerative colitis (UC) in patients over 60 years old has been rapidly increasing. We reviewed our surgical experience of elderly patients with UC treated at our hospital.
Patients aged 60 years or older at the time of surgery were defined as “elderly”. The medical records of all elderly patients who underwent surgery for UC during a 26-year period were retrospectively analyzed.
The prognosis of elderly patients who underwent emergency surgery was extremely poor: 8 (26.7 %) of 30 such patients died within 30 postoperative days (PODs), whereas only 1 (0.88 %) of 114 who underwent elective surgery died within 30 PODs. Respiratory tract infection and sepsis resulting from methicillin-resistant Staphylococcus aureus or mycotic infection were the most common causes of death after emergency surgery.
The prognosis of elderly UC patients undergoing emergency surgery is very poor; thus, physicians and surgeons should collaborate to treat severe and fulminant disease, to optimize the timing of surgery. Early decisions about emergency surgery for UC will reduce postoperative mortality, especially in elderly patients.
PMCID: PMC3898127  PMID: 23553422
Ulcerative colitis; Elderly patients; Emergency operation; Prognosis
13.  Looking for predictive factors of clinical response to adsorptive granulocyte and monocyte apheresis in patients with ulcerative colitis: markers of response to GMA 
BMC Gastroenterology  2013;13:27.
Adsorptive granulocyte and monocyte apheresis (GMA) with an Adacolumn in patients with ulcerative colitis (UC) has been applied as a non-pharmacological treatment strategy, but the efficacy has been encouraging as well as discouraging, depending on patients’ demography at entry. In this study, we looked for predictive factors for clinical response to GMA in patients with UC.
In a retrospective setting, 43 outpatients who had been treated with GMA for active UC were evaluated. Patients were divided into remission group and non-remission group based on Lichtiger’s clinical activity index (CAI) before and after 10, once a week GMA sessions. The efficacy was analysed in relation to patients’ demographic variables. To determine predictive factors that closely related to the response to GMA, receiver operating characteristic (ROC) curve, and multiple logistic regression analyses were applied.
After 10 GMA sessions, the overall clinical remission rate (CAI < 4) was 53.5%. Multiple logistic regression and ROC analyses showed that the interval between relapse and the first GMA session was a significant and independent predictive factor for clinical response to GMA (P = 0.016); the clinical response was better in patients who received GMA immediately after a relapse and vice versa. Likewise, univariate analyses showed that, the duration of UC (P = 0.036) and the cumulative prednisolone (PSL) dose (P = 0.006) before the first GMA session were significantly greater in the GMA non-responder group as compared with the responder group. Additionally, a lower white blood cell (WBC) count at first GMA session was related to clinical response to GMA (P = 0.032).
In this study, patients with a short duration of UC and low cumulative PSL dose seemed to respond well to GMA. However, we found that the best responders were patients who received GMA immediately after a clinical relapse. Additionally, GMA was effective in patients with low WBC count at the first GMA session. The findings of this study should spare medical cost and reduce morbidity time for many patients, relevant for decision making in clinical settings.
PMCID: PMC3583683  PMID: 23399416
Ulcerative colitis; Predictive factors of clinical response; Duration of ulcerative colitis; Multiple logistic regression analysis; Granulocyte and monocyte adsorptive apheresis; Receiver operating characteristic; Univariate analyses
14.  Evidence-based clinical practice guidelines for Crohn’s disease, integrated with formal consensus of experts in Japan 
Journal of Gastroenterology  2012;48(1):31-72.
Crohn’s disease is a disorder of unknown etiology and complicated pathogenesis. A substantial amount of evidence has accumulated recently and has been applied to clinical practice. The present guidelines were developed based on recent evidence and the formal consensus of experts relevant to this disease. Here we provide an overview of these guidelines, as follows.Target disease: Crohn’s diseaseUsers: Clinical practitioners in internal medicine, surgery, gastroenterology, and general practicePurpose: To provide appropriate clinical indicators to practitionersScope of clinical indicators: Concept of Crohn’s disease, epidemiology, classifications, diagnosis, treatment, follow up, and special situationsIntervention: Diagnosis (interview, physical examination, clinical laboratory tests, imaging, and pathology) and treatment (lifestyle guidance, drug therapy, nutritional therapy, surgery, etc.)Outcome assessment: Attenuation of symptoms, induction and maintenance of remission, imaging findings, quality of life (QOL), prevention of complications and harm of therapyMethods for developing these guidelines: Described in the textBasis of recommendations: Integration of evidence level and consensus of expertsCost-benefit analysis: Not implementedEvaluation of effectiveness: Yet to be confirmedStatus of guidelines: Updated version of the first Guidelines published in 2010Publication sources: Printed publication available and electronic information in preparationPatient information: Not availableDate of publication: October 2011
These guidelines were intended primarily to be used by practitioners in Japan, and the goal of these guidelines is to improve the outcomes of patients with Crohn’s disease.
PMCID: PMC3541931  PMID: 23090001
Crohn’s disease; Guidelines; Practice guidelines; Evidence; Consensus
15.  Consensus of the Present and Prospects on Endoscopic Diagnosis and Treatment in East Asian Countries 
Background and Aim. New diagnostic or therapeutic methods in endoscopy have been used. Current clinical application of these procedures is not well known. The aim of this study is to investigate the present situation on endoscopic diagnosis and treatment of gastrointestinal disorders in East Asian countries. Method. A representative member from the International Gastrointestinal Consensus Symposium Committee provided a questionnaire to physicians in China, Indonesia, Japan, Korea, the Philippines, and Thailand. Results. In total, 514 physicians including gastroenterologists, surgeons, and general practitioners enrolled. The most frequently occurring disorder as the origin of upper gastrointestinal bleeding is gastric ulcer. Capsule endoscopy is selected as the first choice for the diagnosis of small intestine bleeding. The second choice was double-balloon endoscopy or angiography. For patients with gastric adenoma, the number of physicians who choose endoscopic mucosal resection is larger than those selecting endoscopic submucosal dissection (ESD) in China, Indonesia, the Philippines, and Thailand. ESD is chosen first in Japan and Korea. Conclusion. New instruments or techniques on endoscopy have not come into wide use yet, and there is diversity in the situation on it in Asian countries. We should unify the endoscopic diagnostic criteria or treated strategy in patients with GI disease.
PMCID: PMC3474969  PMID: 23093833
16.  Adsorptive Granulocyte/Monocyte Apheresis for the Maintenance of Remission in Patients with Ulcerative Colitis: A Prospective Randomized, Double Blind, Sham-Controlled Clinical Trial 
Gut and Liver  2012;6(4):427-433.
Weekly granulocyte/monocyte adsorption (GMA) to deplete elevated and activated leucocytes should serve as a non-pharmacological intervention to induce remission in patients with ulcerative colitis (UC). This trial assessed the efficacy of monthly GMA as a maintenance therapy to suppress UC relapse.
Thirty-three corticosteroid refractory patients with active UC received 10 weekly GMA sessions as a remission induction therapy. They were then randomized to receive one GMA session every 4 weeks (True, n=11), extracorporeal circulation without the GMA column every 4 weeks (Sham, n=11), or no additional intervention (Control, n=11). The primary endpoint was the rate of avoiding relapse (AR) over 48 weeks.
At week 48, the AR rates in the True, Sham, and Control groups were 40.0%, 9.1%, and 18.2%, respectively. All patients were steroid-free, but no statistically significant difference was seen among the three arms. However, in patients who could taper their prednisolone dose to <20 mg/day during the remission induction therapy, the AR in the True group was better than in the Sham (p<0.03) or Control (p<0.05) groups.
Monthly GMA may potentially prevent UC relapse in patients who have achieved remission through weekly GMA, especially in patients on <20 mg/day PSL at the start of the maintenance therapy.
PMCID: PMC3493721  PMID: 23170145
Granulocyte monocyte apheresis; Inflammatory bowel diseases; Maintenance treatment; Randomized controlled trial; Ulcerative colitis
17.  Effectiveness of Concomitant Enteral Nutrition Therapy and Infliximab for Maintenance Treatment of Crohn’s Disease in Adults 
Digestive Diseases and Sciences  2012;58(5):1329-1334.
One of the problems associated with infliximab (IFX) treatment for Crohn’s disease (CD) is loss of response during maintenance therapy.
The aim of this multicenter, retrospective, cohort study was to determine whether enteral nutrition (EN) added to the IFX therapy regimen is effective for maintaining remission in adult CD patients.
Patients with CD who had started IFX therapy between April 2003 and March 2008 at any one of the seven participating medical centers and who met the following inclusion criteria were enrolled in the study: remission after triple infusions of IFX followed by IFX maintenance therapy every 8 weeks, and follow-up data available for ≥1 year. Remission was defined as a C-reactive protein (CRP) level of <0.3 mg/dL, and recurrence was defined as an increase in CRP to ≥1.5 mg/dL or shortening of the IFX interval. Patients were classified by EN dosage into two groups (EN group and non-EN group). The cumulative remission period and related factors were analyzed.
Of the 102 adult CD patients who met the inclusion criteria, 45 were in the EN group and 57 were in the non-EN group. The cumulative remission rate was significantly higher in the EN group than in the non-EN group (P = 0.009). Multivariate analysis revealed that EN was the only suppressive factor for disease recurrence (P = 0.01).
The results demonstrate that among this CD patient cohort, EN combined with IFX maintenance treatment was clinically useful for maintaining remission.
PMCID: PMC3661072  PMID: 22926500
Crohn’s disease; Infliximab; Loss of response; Enteral nutrition
18.  Alterations in vasoconstrictor responses to the endothelium-derived contracting factor uridine adenosine tetraphosphate are region specific in DOCA-salt hypertensive rats 
Pharmacological Research  2011;65(1):81-90.
Uridine adenosine tetraphosphate (Up4A) has been recently identified as a novel and potent endothelium-derived contracting factor and contains both purine and pyrimidine moieties, which activate purinergic P2X and P2Y receptors. The present study was designed to compare contractile responses to Up4A and other nucleotides such as ATP (P2X/P2Y agonist), UTP (P2Y2/P2Y4 agonist), UDP (P2Y6 agonist), and α,β-methylene ATP (P2X1 agonist) in different vascular regions [thoracic aorta, basilar, small mesenteric, and femoral arteries] from deoxycorticosterone acetate-salt (DOCA-salt) and control rats. In DOCA-salt rats [vs. control uninephrectomized (Uni) rats]: (1) in thoracic aorta, Up4A-, ATP-, and UTP-induced contractions were unchanged; (2) in basilar artery, Up4A-, ATP-, UTP- and UDP-induced contractions were increased, and expression for P2X1, but not P2Y2 or P2Y6 was decreased; (3) in small mesenteric artery, Up4A-induced contraction was decreased and UDP-induced contraction was increased; expression of P2Y2 and P2X1 was decreased whereas P2Y6 expression was increased; (4) in femoral artery, Up4A-, UTP-, and UDP-induced contractions were increased, but expression of P2Y2, P2Y6 and P2X1 was unchanged. The α,β-methylene ATP-induced contraction was bell-shaped and the maximal contraction was reached at a lower concentration in basilar and mesenteric arteries from Uni rats, compared to arteries from DOCA-salt rats. These results suggest that Up4A-induced contraction is heterogenously affected among various vascular beds in arterial hypertension. P2Y receptor activation may contribute to enhancement of Up4A-induced contraction in basilar and femoral arteries. These changes in vascular reactivity to Up4A may be adaptive to the vascular alterations produced by hypertension.
PMCID: PMC3264768  PMID: 21933714
contraction; dinucleotide; DOCA-salt; EDCF; extracellular nucleotides; P2 receptor
19.  The Role of Uridine Adenosine Tetraphosphate in the Vascular System 
The endothelium plays a pivotal role in vascular homeostasis, and endothelial dysfunction is a major feature of cardiovascular diseases, such as arterial hypertension, atherosclerosis, and diabetes. Recently, uridine adenosine tetraphosphate (Up4A) has been identified as a novel and potent endothelium-derived contracting factor (EDCF). Up4A structurally contains both purine and pyrimidine moieties, which activate purinergic receptors. There is an accumulating body of evidence to show that Up4A modulates vascular function by actions on endothelial and smooth muscle cells. In this paper, we discuss the effects of Up4A on vascular function and a potential role for Up4A in cardiovascular diseases.
PMCID: PMC3206368  PMID: 22110488
20.  Tissue expression of Toll-like receptors 2 and 4 in sporadic human colorectal cancer 
Toll-like receptors (TLRs) play an important role in innate immunity by sensing a variety of pathogens and inducing acquired immunity. To test our hypothesis that dysregulation of innate immune responses acts to trigger carcinogenesis, we studied the expression of TLR2 and 4 in sporadic human colorectal cancer tissue.
In specimens of cancerous and noncancerous colorectal tissue obtained at surgery, mRNA expression levels of TLR2 and 4 were quantified by TaqMan real-time polymerase chain reaction and compared between the two types of tissue. To confirm TLR2 and TLR4 protein expression levels, immunohistochemical analysis was performed using the same samples.
TLR2 mRNA expression was significantly higher in cancerous tissue than in noncancerous tissue, while TLR4 mRNA expression did not differ significantly. Immunohistochemical analysis revealed stronger staining for TLR2 in cancerous mucosal epithelial cells than in noncancerous tissue. Staining for TLR4 in the lamina propria of the mucosa was equally weakly positive in noncancerous tissue and cancerous tissue. This TLR-specific difference in expression suggested that such expression does not only reflect a local inflammatory response to cancer infiltration, i.e., if this was the case, both TLR2 and 4 expression would probably be up-regulated. Our results suggest that TLR2 expression might be involved in sporadic colorectal carcinogenesis, whereas TLR4 is not.
PMCID: PMC3249192  PMID: 21845432
Toll-like receptors (TLRs); Colorectal cancer; Real-time polymerase chain reaction (real-time PCR); Innate immunity
21.  Serotonin transporter gene polymorphism may be associated with functional dyspepsia in a Japanese population 
BMC Medical Genetics  2011;12:88.
Although familial clustering of functional dyspepsia (FD) has been reported, the role of genetics in the susceptibility to FD is still not well understood. In the present study, the association between serotonin transporter (SERT) gene (SLC6A4) polymorphism and FD was explored.
Subjects were divided into either a postprandial distress syndrome (PDS) group or an epigastric pain syndrome (EPS) group according to the Rome III criteria. The healthy controls were those who had visited a hospital for an annual health check-up. The presence of the SLC6A4 promoter polymorphism, 5-hydroxytryptamin transporter gene linked polymorphic region (5-HTTLPR), was then evaluated, and logistic regression analysis was used to test all variables.
The 5-HTTLPR genotype distribution was 448 SS, 174 SL, and 24 LL in controls and 30 SS, 20 SL, and 3 LL in FD subjects. No significant correlation was found between the 5-HTTLPR genotype and FD. When the genotypes and subtypes of FD were exploratory evaluated, the SL genotype was significantly associated with PDS [odds ratio (OR) = 2.24, 95% confidence interval (CI); 1.16-4.32, P = 0.034 after Bonferroni correction] compared to the SS genotype adjusted for sex and age. Comparison of the SS genotype with the SL/LL genotype also showed a significant association of genotype with PDS (OR = 2.32, 95% CI; 1.23-4.37, P = 0.009).
The present results suggest that 5-HTTLPR L allele may influence the susceptibility to PDS.
PMCID: PMC3142494  PMID: 21714874
22.  Long-term efficacy of infliximab maintenance therapy for perianal Crohn’s disease 
AIM: To assess the long-term efficacy of seton drainage with infliximab maintenance therapy in treatment of stricture for perianal Crohn’s disease (CD).
METHODS: Sixty-two patients with perianal CD who required surgical treatment with or without infliximab between September 2000 and April 2010 were identified from our clinic’s database. The activities of the perianal lesions were evaluated using the modified perianal CD activity index (mPDAI) score. The primary endpoint was a clinical response at 12-15 wk after surgery as a short-term efficacy. Secondary endpoints were recurrence as reflected in the mPDAI score, defined as increased points in every major element. The clinical responses were classified as completely healed (mPDAI = 0), partially improved (mPDAI score decreased more than 4 points), and failure or recurrence (mPDAI score increased or decreased less than 3 points).
RESULTS: There were 43 males and 19 females, of whom 26 were consecutively treated with infliximab after surgery as maintenance therapy. Complete healing was not seen. Failure was seen in 10/36 (27.8%) patients without infliximab and 4/26 (15.4%) patients with infliximab (P = 0.25). Partial improvement was seen in 26/36 (72.2%) patients without infliximab and 22/26 (88.5%) patients with infliximab (P = 0.25). Short-term improvement was achieved in 48/62 (77.4%) patients. Although the mPDAI score improved significantly with surgery regardless of infliximab, it decreased more from baseline in patients with infliximab (50.0%) than in those without infliximab (28.6%), (P = 0.003). In the long-term, recurrence rates were low regardless of infliximab in patients without anorectal stricture. In patients with anorectal stricture, cumulative recurrence incidences increased gradually and exceeded 40% at 5 years regardless of infliximab. No efficacy of infliximab treatment was found (P = 0.97). Although the cumulative rate of ostomy creation was also low in patients without stricture and high in patients with stricture, no protective efficacy was found with infliximab treatment (P = 0.6 without stricture, P = 0.22 with stricture).
CONCLUSION: Infliximab treatment was demonstrated to have short-term efficacy for perianal lesions. Long-term benefit with infliximab was not proven, at least in patients with anorectal stricture.
PMCID: PMC3063910  PMID: 21448422
Crohn’s disease; Perianal fistula; Infliximab; Anorectal stricture; Long-term efficacy
23.  Infliximab Therapy Impacts the Peripheral Immune System of Immunomodulator and Corticosteroid Naïve Patients with Crohn's Disease 
Gut and Liver  2011;5(1):37-45.
Infliximab (IFX), an antibody to tumor necrosis factor, (TNF)-α has efficacy in treating Crohn's disease (CD). However, knowledge of the potential effects of IFX on patients' immune profiles is lacking. The purpose of this study was to reveal the immunological effects of IFX.
Twenty-two patients with a CD activity index (CDAI) of 194.2±92.9 and an average duration of disease of 3.26 months and 21 healthy controls were included. Patients were to have their first IFX remission induction therapy with 3 infusions (5 mg/kg) at weeks 0, 2, and 6. Oral 5-aminosalicylic acid was the only ongoing medication in the patient population. Blood samples at baseline, 12 hours after the first infusion and at week 14 were labeled with anti-CD4/CD25 antibodies for immunohistochemical measurement of regulatory T-cells (Treg). Serum cytokines and chemokines were measured by suspension array and ELISA.
CDAI significantly decreased prior to the second IFX infusion (p<0.001). Clinical remission rates were 77.3% and 91% by the second and third infusions, respectively. At baseline, interleukin (IL)-6 (p<0.03), IL-8 (p<0.03), IL-10 (p=0.050), IL-13 (p<0.01), transforming growth factor-β1 (p<0.01), and 'regulated on activation, normal T cell expressed and secreted' (RANTES) (p<0.01) were elevated in patients. After the initial IFX infusion, TNF-α (p<0.04), IL-6 (p<0.03), interferon (IFN)-γ (p<0.04), IFN-γ-inducible protein-10 (p<0.01), monocyte chemoattractant protein-1 (p<0.01), macrophage inflammatory protein-1β (p<0.01), and RANTES (p<0.01) were decreased. IFX infusion was associated with an increase in Treg (p<0.01) and a decrease in the Th1 (IFN-γ)/Th2 (IL-4) ratio (p<0.03).
IFX use was associated with restoration of the Th1/Th2 balance after a single infusion and seemed to promote induction of naïve Th0 lymphocytes to Treg. This knowledge should have clinical relevance.
PMCID: PMC3065091  PMID: 21461070
Crohn's disease; Infliximab; Transforming growth factor-β1; RANTES; Regulatory T-cell
24.  Clinical impact of genetic aberrations in gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence in situ hybridisation 
Gut  2007;56(10):1358-1363.
Background and aims
There is a need for genetic biomarkers to guide prognosis and management of gastric mucosa‐associated lymphoid tissue (MALT) lymphomas. We assessed the incidence and clinical significance of the MALT lymphoma‐associated genetic abnormalities t(11;18)/API2‐MALT1, t(1;14)/BCL10‐IGH, t(14;18)/IGH‐MALT1, t(3;14)/FOXP1‐IGH, and extra copies of MALT1 and FOXP1 in gastric MALT lymphomas from Japan.
The presence of translocations and copy number changes involving MALT1, IGH and FOXP1 were assessed in 90 cases of gastric MALT lymphoma using interphase fluorescence in situ hybridisation (FISH). In cases carrying a MALT1 translocation, FISH for API2‐MALT1 was performed, whereas in those carrying an IGH translocation, FISH was performed for BCL10, BCL6, BCL2, c‐MYC and/or CCND1.
t(11;18)/API2‐MALT1 was detected in 18 of 87 (21%) cases and was significantly associated with Helicobacter pylori‐negativity, resistance to H pylori eradication and Bcl10 nuclear expression. Four of 68 (6%) cases carried a translocation involving IGH and FOXP1 (n = 1), BCL2 (n = 1) or an unknown partner (n = 2). Neither t(1;14)/BCL10‐IGH nor t(14;18)/IGH‐MALT1 was detected. Extra copies of MALT1 and FOXP1 were detected in 18 of 71 (25%) cases and 10 of 59 (17%) cases, respectively. The presence of extra copies of MALT1 was significantly associated with progression or relapse of lymphoma, and was an independent adverse prognostic factor for event‐free survival as determined by multivariate analysis.
t(11;18)/API2‐MALT1 is frequent, whereas IGH‐involved translocations are rare in gastric MALT lymphoma in Japan. The presence of extra copies of MALT1, often suggestive of partial or complete trisomy 18, is a frequent genetic aberration in gastric MALT lymphoma, which appears to predict adverse clinical behaviour.
PMCID: PMC2000261  PMID: 17525089
25.  Gastric MALT lymphoma with t(14;18)(q32;q21) involving IGH and BCL2 genes that responded to Helicobacter pylori eradication 
Journal of Clinical Pathology  2007;60(10):1171-1173.
PMCID: PMC2014860  PMID: 17906071
gastric lymphoma; MALT lymphoma;  Helicobacter pylori ; t(14; 18)(q32; q21);  BCL2

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