Tooru Shimosegawa

Tokyo Metropolitan Komagome Hospital, Edo, Tōkyō, Japan

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Publications (652)2747.66 Total impact

  • Kaname Uno, Katsuaki Kato, Tooru Shimosegawa
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    ABSTRACT: Helicobacter pylori (H. pylori) infects the human stomach during infancy and develops into chronic active inflammation. The majority of H. pylori tend to colonize within the mucous gel layer of the stomach. The stomach lacks its own immune function, thus innate immunity as the first line of defense is vital for specific immunity against H. pylori. We review recent discoveries in the pathophysiologic roles of toll-like receptors (TLRs), mainly TLR2 and TLR4, in H. pylori-induced inflammation. In addition, the TLR pathways activated by H. pylori-induced inflammation have been shown to be closely associated not only with gastric carcinogenesis, but also with formation of the tumor microenvironment through the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Although the correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear, a recent study demonstrated that STAT3-driven up-regulation of TLR2 might promote gastric tumorigenesis independent of inflammation. Further research on the regulation of TLRs in H. pylori-associated gastric carcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.
    World Journal of Gastroenterology 05/2014; 20(18):5244-5251. · 2.55 Impact Factor
  • Katsunori Iijima, Tooru Shimosegawa
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    ABSTRACT: Over the last 3 decades, the incidence of esophageal adenocarcinoma has dramatically increased in Western countries; a similar increase may be observed in Asian countries in the near future. Esophageal adenocarcinoma arises from a sequential gastroesophageal reflux disease (GERD) spectrum from reflux erosive esophagitis, to Barrett's esophagus, and finally to esophageal adenocarcinoma. At present, gastric acid and bile are assumed to be primarily involved in the etiology of the GERD spectrum. We reported in 2002 that, at the gastroesophageal junction in humans, abundant amounts of nitric oxide (NO) are generated luminally through the entero-salivary re-circulation of dietary nitrate. Since then, we have carried out a series of experiments to demonstrate that NO diffuses into the adjacent epithelium at cytotoxic levels. This diffusion results in disruption of the epithelial barrier function, exacerbation of inflammation, acceleration of columnar transformation in the esophagus (Barrett's esophagus) via the induction of caudal-type homeobox 2, and the shifting of carcinogenic N-nitroso compound formation from the luminal to epithelial compartment. These results suggest that, in addition to conventionally recognized causative factors, luminal NO could also be involved in the pathogenesis of the GERD spectrum. In addition, we recently showed that there is a prominent gender-related difference in NO-related cytotoxicity in the esophagus and that estrogen attenuated the esophageal tissue damage via the estrogen receptor in female rats. The role of estrogen in attenuating the esophageal tissue damage in NO-related esophageal damage could explain the well-recognized male predominance in the GERD spectrum in humans.
    Journal of gastroenterology and hepatology. 05/2014; 29(5):898-905.
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    ABSTRACT: Most patients with chronic pancreatitis develop intractable abdominal pain and malnutrition. A low-fat diet is one of the options used to manage intractable abdominal pain and malnutrition. However, few reports have examined the pain-suppression effect. To investigate the effects of oral ingestion of a low-fat elemental diet composed of purified amino acids on pain and nutritional status in patients with chronic pancreatitis, a multicenter prospective study was conducted. Patients with chronic pancreatitis with symptoms of abdominal pain were enrolled. In addition to meals, patients ingested a low-fat elemental diet composed of purified amino acids for 12 weeks. Before and after treatment, patients were asked to indicate their pain grade using a 100-mm horizontal visual analog scale, and nutritional indices, including body mass index and blood levels of pancreatic enzymes, were measured. A total of 596 patients were eligible for analysis. Marked pain reduction was observed with a significant decrease of the mean visual analog scale score by 32.9 mm from 52.9 mm after 12 weeks (P < 0.001). There were also significant improvements in nutritional indices. An oral low-fat elemental diet composed of purified amino acids, which requires no special treatment procedures, may improve patients' quality of life.
    Pancreas 04/2014; 43(3):451-7. · 2.95 Impact Factor
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    ABSTRACT: It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.Mucosal Immunology advance online publication, 26 March 2014; doi:10.1038/mi.2014.19.
    Mucosal Immunology 03/2014; · 7.00 Impact Factor
  • Journal of Gastroenterology 03/2014; · 3.79 Impact Factor
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    ABSTRACT: In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese consensus guidelines for managing AIP required revision. Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Fifteen specialists for AIP extracted the specific clinical statements from 1,843 articles published between 1963 and 2012 (obtained from Pub Med and a secondary database, and developed the CQs and statements. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. The professional committee created 13 CQs and statements for the current concept and diagnosis of AIP, 6 for extra-pancreatic lesions, 6 for differential diagnosis, and 11 for treatment. After evaluation by the moderators, amendments to the Japanese consensus guidelines for AIP have been proposed for 2013.
    Journal of Gastroenterology 03/2014; · 3.79 Impact Factor
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    ABSTRACT: The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2-4 weeks. The dose is then tapered by 5 mg every 1-2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5-5 mg/day) over a period of 2-3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.
    Journal of Gastroenterology 03/2014; · 3.79 Impact Factor
  • Nihon Naika Gakkai Zasshi 03/2014; 103(3):557-60.
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    ABSTRACT: To explore the relationship between UPR and autophagy in intestinal epithelial cells, we investigated whether autophagy was induced by endoplasmic reticulum (ER) stress in colon cancer cell lines. We demonstrated that autophagy was induced by ER stress in HT29, SW480, and Caco-2 cells. In these cells, inositol-requiring enzyme1α (IRE1α) and C/EBP homologous protein (CHOP) were involved in the ER stress-autophagy pathway, and CHOP was a regulator of IRE1α protein expression. Our findings suggest that CHOP promotes IRE1α and autophagy especially in ER stress conditions. This study will provide important insights into the disclosure of the ER stress-autophagy pathway.
    Biochemical and Biophysical Research Communications 02/2014; · 2.41 Impact Factor
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    ABSTRACT: We have reported that the total number of peptic ulcers (PUs) had increased 1.5-fold after the Great East Japan Earthquake compared with those of the previous year, and that hemorrhagic ulcers were more prominently increased by 2.2-fold. The aim of this study is to determine the risk factors for bleeding ulcers after the Great East Japan Earthquake. Clinical data of all peptic ulcer subjects endoscopically detected at the 7 major hospitals in the middle of the stricken area during the 3 months after the earthquake were retrospectively collected. Based on endoscopic and laboratory findings, peptic ulcer cases were divided into 227 bleeding ulcer cases and 102 non-bleeding controls. Other than ordinary risk factors for bleeding ulcers, the refugee shelter was included in the analysis as a unique confounder after the earthquake. Multiple logistic regression analyses were used to adjust for potential confounders. Eighty-seven (27 %) of 329 PUs emerged from refuge shelters, and the majority (76 of 87) of PUs occurring in such shelters was the bleeding type. Multivariate regression showed that residence in a shelter was a strong risk factor for ulcer bleeding with OR (95 % CI): 4.4 (2.1-9.6, p < 0.0001), independent of the progressiveness of ulcer diseases. Accommodation in a refugee shelter can be a strong risk factor for ulcer bleeding after a large-scale disaster. Since acid-suppressive drugs are supposed to decrease the risk for stress-induced ulcer bleeding, our results will encourage effective use of a limited medical resource in such catastrophic events.
    Journal of Gastroenterology 02/2014; · 3.79 Impact Factor
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    ABSTRACT: The efficacy of colorectal endoscopic submucosal dissection (ESD) has been reported mainly from Japanese referral centers. However, ESD is technically difficult and associated with a higher risk of adverse events than endoscopic mucosal resection, especially for novices performing colorectal ESD with little experience in gastric ESD. The current study evaluated the results of colorectal ESD during the clinical learning curve by retrospectively examining the results of colorectal ESD performed by four endoscopists who had experience with fewer than five cases of gastric ESD. The study retrospectively investigated the first 20 cases managed by each endoscopist, for a total of 80 cases. The main outcome measurements were procedural time, en bloc resection rate with tumor-free margins (R0 resection rate), and adverse events rate. From among clinicopathologic characteristics, factors that affected main outcome measurements were identified. Of the 80 cases (56 colonic and 24 rectal lesions; 44 granular laterally spreading tumors (LSTs) and 23 nongranular LSTs, 5 depressed, and 8 protruding), 54 cases (67.5 %) had resection using a standard tip-type knife, and 26 cases (32.5 %) had resection using a small scissors-type knife. The mean tumor diameter was 34.9 ± 14.1 mm, and the mean procedural time was 108.8 ± 53.4 min. The resection in 75 cases (93.8 %) was performed en bloc, and the R0 resection rate was 75 % (60/80). Perforation occurred in six cases (7.5 %) and postoperative hemorrhage in three cases (3.8 %). Multivariate analyses showed that colonic lesions and larger lesions (≥40 mm) were significantly associated with prolonged procedural time (≥90 min). Use of the scissors-type knife was significantly associated with a higher R0 resection rate. Perforation occurred only in colonic lesions. For novices in colorectal ESD, beginning with rectal and smaller lesions may be advisable. Also, using scissors-type knives may increase the R0 resection rate.
    Surgical Endoscopy 02/2014; · 3.43 Impact Factor
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    ABSTRACT: Since the discovery of Helicobacter pylori (H. pylori) infection in the stomach, the bacteria infection and non-steroidal anti-inflammatory drugs (NSAIDs) use had been considered to be the 2 main causes of peptic ulcers. However, there have been recent reports of an increase in the proportion of peptic ulcers without these known risk factors; these are termed idiopathic peptic ulcers. Such trend was firstly indicated in 1990s from some reports in North America. In Asia, numerous studies reported that idiopathic ulcers accounted for a small percentage of all ulcers in the 1990s, but in the 2000s, multiple studies reported that the proportion of idiopathic ulcers had reached 10%-30%, indicating that the incidence of idiopathic ulcers in Asia has also been rising in recent years. While a decline in H. pylori infection rates of general population in Asia is seen as the main reason for the increased incidence of idiopathic ulcers, it is also possible that the absolute number of idiopathic ulcer cases has increased. Advanced age, serious systemic complication, and psychological stress are considered to be the potential risk factors for idiopathic ulcers. Management of idiopathic ulcers is challenging, at present, because there is no effective preventative measure against recurrence in contrast with cases of H. pylori-positive ulcers and NSAIDs-induced ulcers. As it is expected that H. pylori infection rates in Asia will decline further in the future, measures to treat idiopathic ulcers will also likely become more important.
    World Journal of Gastroenterology 01/2014; 20(3):706-713. · 2.55 Impact Factor
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    ABSTRACT: Abstract Objective. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. Materials and methods. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. Results. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. Conclusions. Our results suggest a novel role of miRNAs in the activation of PSCs.
    Scandinavian journal of gastroenterology 01/2014; · 2.08 Impact Factor
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    ABSTRACT: OBJECTIVES:Few studies have simultaneously evaluated the long-term outcomes of endoscopic resection (ER) for squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus in Japan. The objective of this study was to evaluate the long-term outcomes of ER for superficial esophageal cancer in consecutive patients.METHODS:This was a retrospective study from a single institution. From April 2001 to June 2012, 204 patients with SCC and 26 patients with AC were included from a total of 355 consecutive patients who were treated by esophageal ER at the Tohoku University Hospital. Patients with submucosal invasion deeper than 200 μm and lymphovascular involvement were excluded. The intervention followed was endoscopic therapy.RESULTS:Overall survival, disease-free survival, and recurrence rates were evaluated as long-term outcomes. In the SCC group, during the median observation time of 36.5 months (range, 6-120 months), 22 (10.8%) patients experienced metachronous recurrence, 4 (2.0%) patients experienced local recurrence, and 27 (13.2%) patients died from causes unrelated to SCC. In the AC group, during the median observation time of 45.5 months (range, 6-131 months), one patient (3.8%) experienced metachronous recurrence and two (7.7%) died from causes unrelated to AC. The cumulative 5-year overall survival rates were not significantly different between SCC (75.9%) and AC (88.9%) (P=0.120). The cumulative 5-year disease-free survival rates of SCC (57.1%) were significantly lower than those of AC (85.2%; P=0.017). The cumulative 5-year recurrence rates of SCC (32.0%) were significantly higher than those of AC (4.2%; P=0.023).CONCLUSIONS:The rate of recurrence after ER was higher in patients with SCC than that in patients with AC. These findings suggest that, by detecting AC of the esophagus earlier, a satisfactory prognosis without recurrence can be expected after ER in Japan, and more rigorous endoscopic follow-up is necessary after ER in patients with SCC than in those with AC.Am J Gastroenterol advance online publication, 7 January 2014; doi:10.1038/ajg.2013.450.
    The American Journal of Gastroenterology 01/2014; · 7.55 Impact Factor
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    ABSTRACT: Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.
    Postgraduate medical journal 01/2014; 90(1059):18-25. · 1.38 Impact Factor
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    ABSTRACT: Measurement of the gastric acid secretion is useful for estimating the risk for various diseases in the upper gastro-intestinal tract; however, the procedure causes significant distress to the subjects. Pepsinogens I and II are secreted from the gastric fundic glands, and thus, the serum pepsinogen levels reflect the gastric functional statuses. The aim of this study is to establish appropriate serum pepsinogen cutoff points for predicting the gastric acid secretion status. In a total of 627 Japanese subjects, gastric acid secretion was measured with an endoscopic gastrin test, and the serum pepsinogen values and serum Helicobacter (H.) pylori-IgG antibody were also measured. After checking the correlation between gastric acid secretion and serum pepsinogen, the receiver operating characteristics analyses were employed for determining the most suitable cutoff points of serum pepsinogen for the gastric acid secretion status (i.e., hypochlorhydria, profound hypochlorhydria, and hyperchlorhydria). The pepsinogen I/II ratio and pepsinogen I showed the best correlation with gastric acid secretion in H. pylori-positive and H. pylori-negative subjects, respectively. The serum pepsinogen I/II ratio (or pepsinogen I in cases of H. pylori-negative subjects) was useful to determine the gastric acid secretion status with acceptable to outstanding diagnostic accuracy (the range of the area under the curve: 0.79-0.93). The diagnostic accuracy was further improved after stratifying the subjects by H. pylori-infection status. Estimating gastric acid secretion levels by simple measurement of serum pepsinogens will have significant clinical implications in estimating the risks for various diseases of the upper gastrointestinal tract.
    The Tohoku Journal of Experimental Medicine 01/2014; 232(4):293-300. · 1.37 Impact Factor
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    ABSTRACT: A 66-year-old male was referred to our hospital because of a high CRP level. CT and MRI revealed cord-like contrast effects along the periphery of the liver, and peripheral portal vein occlusion was suspected. Histopathological analysis revealed fibrotic occlusion and eosinophil and histiocytic infiltration of the portal vein. Taking into account various clinical imaging tests, blood tests, and histopathological tests and of his current clinical history, he was diagnosed with previous infection of schistosomiasis japonica. We believe that this case illustrates the importance of a comprehensive diagnosis; in addition, we implemented real-time virtual sonography and EOB-MRI that provided useful visual information.
    Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2014; 111(5):948-955.
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    ABSTRACT: Sorafenib, an oral multi-kinase inhibitor, has been approved for treatment of advanced renal-cell and hepatocellular carcinoma (HCC). However, 20% of HCC patients taking sorafenib are forced to withdraw due to adverse effects within one month after administration. Orally administered sorafenib is oxidatively metabolized, predominantly by cytochrome P450 3A4 (CYP3A4), in small-intestinal mucosa or liver. We aimed to characterize the CYP3A4-mediated metabolism of sorafenib in HCC patients and explore the contribution of the major metabolite sorafenib N-oxide to adverse effects and therapeutic efficacy. We have therefore developed a method for quantitative determination of sorafenib and its N-oxide in the present study. To optimize the preanalytical procedure, we initially ascertained the solubility of the analytes. Because they are lipophilic, solvents containing more than 40% acetonitrile were required for efficient recovery. The pretreatment procedure that we ultimately developed consists of acetonitrile precipitation, followed by extraction using octadecyl silyl-silica gel to eliminate water-soluble and hydrophilic components of serum. Application of this procedure before HPLC enabled accurate and reproducible quantitation of analytes in a linear range from 0.03 to 30 μg/mL. After characterizing the peaks in the HPLC-ultraviolet chromatogram obtained from a medicated patient by LC-tandem mass spectrometry, we applied this method to HCC patients taking sorafenib, showing large inter-individual differences in the pharmacokinetic profile. In conclusion, our assay system should be useful for follow-up of patients taking sorafenib and for exploring the association between the pharmacokinetics of sorafenib and its N-oxide and the adverse effects or therapeutic efficacy.
    The Tohoku Journal of Experimental Medicine 01/2014; 233(2):103-12. · 1.37 Impact Factor
  • Medicina Intensiva 01/2014; 38(4):211-7. · 1.32 Impact Factor
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    ABSTRACT: Various kinds of autoimmune diseases have been reported to have a significant relationship with persistent hepatitis c virus (HCV) infection and Th17 cells. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development of CD4+ helper T cells and their proliferation, in addition to the induction of immunoglobulin hyper-mutation.
    PLoS ONE 01/2014; 9(6):e98521. · 3.73 Impact Factor

Publication Stats

8k Citations
2,747.66 Total Impact Points

Institutions

  • 2012–2014
    • Tokyo Metropolitan Komagome Hospital
      Edo, Tōkyō, Japan
    • Miyagi Cancer Center
      Сендай, Miyagi, Japan
  • 2013
    • Israelitisches Krankenhaus Hamburg
      Hamburg, Hamburg, Germany
    • Cardarelli Hospital
      Napoli, Campania, Italy
  • 2009–2013
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
    • National Hospital Organization Sendai Medical Center
      Сендай, Miyagi, Japan
    • Nagoya University
      • Division of Emergency and Critical Care Medicine
      Nagoya-shi, Aichi-ken, Japan
  • 1985–2013
    • Tohoku University
      • • Department of Gastroenterology
      • • Division of Internal Medicine
      • • Graduate School of Medicine
      Sendai, Kagoshima-ken, Japan
  • 2010–2012
    • Kyushu University
      • • Department of Surgery and Oncology
      • • Graduate School of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2011
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2008
    • Tokyo Women's Medical University
      Edo, Tōkyō, Japan
    • Jichi Medical University
      • Division of Virology
      Totigi, Tochigi, Japan
  • 2007–2008
    • Numazu City Hospital
      Sizuoka, Shizuoka, Japan
    • University of California, Davis
      • Division of Rheumatology/Allergy/Clinical Immunology
      Davis, CA, United States
  • 2006
    • Kansai Medical University
      • Third Department of Internal Medicine
      Moriguchi, Ōsaka, Japan
  • 2004–2006
    • VA Greater Los Angeles Healthcare System
      Los Angeles, California, United States
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 2002
    • Sendai City Hospital
      Sendai, Kagoshima, Japan
  • 2001
    • Social Insurance Chukyo Hospital
      Nagoya, Aichi, Japan
  • 2000
    • Akita University
      • First Department of Internal Medicine
      Akita-shi, Akita-ken, Japan
    • Iwaki Kyoritsu General Hospital
      Ивакуни, Yamaguchi, Japan