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Biomedical subjects

Kenji Ina

Publications and source records attributed to Kenji Ina.

At least 19 recordsLinked to original sources
PubMed2006

Alterations of mesenchymal and endothelial cells in inflammatory bowel diseases.

The pathogenesis of complex chronic diseases like inflammatory bowel disease (IBD) can no longer be viewed as a one-way street in which classical immune cells have exclusive control over the initiation, duration and outcome of the disease. There is enough experimental evidence to demonstrate that nonimmune cells, among which are mucosal mesenchymal and endothelial cells, also play a decisive role by interacting with immune cells and establishing a two-way reciprocal exchange of signals and responses that dictate the ultimate outcome of inflammation. Smooth muscle cells and fibroblasts/myofibroblasts display a variety of immune functions and modulate the activity and survival of T-cells. Mucosal microvascular cells, through the expression of adhesion molecules and secretion of chemokines, regulate the quantity and quality of leukocytes transmigrating into the interstitial space. A number of receptor-ligand pairs are expressed by immune and nonimmune cells that control their functional interplay, but the CD40/CD40 ligand system may be the most effective because CD40 is expressed by activated muscle and endothelial cells, while the CD40 ligand is expressed by activated T-cells and platelets. The activation of this system in IBD can lead to the establishment of a continuous cycle of nonimmune cell-dependent, antigen-independent interactions that perpetuates gut inflammation.

Animals↗
PubMed2006

[Three advanced gastric cancer cases with liver metastases successfully treated by TS-1/CDDP combination therapy].

Three cases with unresectable advanced gastric cancer with liver metastases were successfully treated by the combination therapy of TS-1 and cisplatin( CDDP). TS-1 (1.25 m2>: 80 mg/day, 1.25 m2-1.50 m2: 100 mg/day, > or =1.50 m2: 120 mg/day) was administered orally for 14 consecutive days followed by 14 days rest,and a 24-h infusion of CDDP (70 mg/m2) was administered on day 8 of each course. Treatment was repeated every 4 weeks unless disease progression was observed. Partial response was obtained in all of the following three advanced gastric cancer cases with liver metastases. Case 1: 67-year-old male with Borrmann type I gastric cancer with multiple liver metastases. Case 2: 55-year-old female with multiple liver and lymph node metastases whose primary gastric lesion was surgically resected. Case 3: 53-year-old-male with Borrmann type III gastric cancer with liver and lymph node metastases. TS-1/CDDP therapy can be highly recommended for the treatment of advanced gastric cancer with liver metastases.

Aged↗
PubMed2006

[Two metastatic colonic cancer patients successfully treated by combination therapy of tegafur/uracil (UFT) and oral Leucovorin].

Two metastatic colonic cancer patients were successfully treated by the combination therapy of UFT plus oral Leucovorin (UFT/LV). UFT was administered orally every eight hours at a dose of 300 mg/day in case of less than 1.20 m(2), 400 mg/day in case of between 1.20 and 1.70 m(2), 500 mg/day in case of over 1.70 m(2), and Leucovorin (75 mg/day) was simultaneously given for 28 consecutive days and stopped for seven days. This cycle was repeated until the patients requested the therapy be discontinued or a severe adverse reaction was observed. Case 1: A 79-year-old male had undergone sigmoidectomy for colonic cancer in 2001 and was diagnosed with pulmonary metastases in August, 2005. His performance status (PS) was grade 3. Case 2: A 61-year-old male with liver metastasis whose primary colonic lesion was surgically resected. After 2 cycles of UFT/LV therapy, a good partial response was achieved in both cases. Adverse effects were very mild, indicating that this therapy was very safe and recommendable for the treatment of metastatic colonic cancer patients with poor PS.

Adenocarcinoma↗
PubMed2005

Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization.

AIM: To determine the role of interleukin (IL)-17 in gastric ulcerogenesis. METHODS: Thirty-six gastric ulcer (GU) patients and 29 non-ulcer (NU) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used in in situ stimulation for 48 h in the presence of 10 microg/mL phytohemagglutinin-P (PHA), histological examination, and Helicobacter pylori (H pylori) culture. IL-17 and IL-8 protein levels in culture supernatants were assayed by ELISA. IL-17 mRNA expression was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). H pylori cagA and vacA status was assessed by reverse hybridization using a line probe assay (LiPA). IL-8 levels in culture supernatants were assayed after AGS cells were co-cultured with H pylori strain 26,695 or recombinant human (rh) IL-17. RESULTS: All 36 GU patients and 15 of 29 NU patients were found to be H pylori-positive, while 14 NU patients were H pylori-negative. All 51 H pylori strains from both GU and NU patients were cagA- and vacAs1/m1-positive. Antral mucosal tissues from H pylori-positive patients contained significantly (H pylori-positive NU patients: median 467 pg/mg/protein, range 53-2,499; H pylori-negative NU patients: median 104 pg/mg/protein, range 16-312, P< 0.0005) higher levels of IL-17 than those from uninfected patients. IL-17 levels at the ulcer site were significantly (ulcer site: median 1,356 pg/mg/protein, range 121-1,3730; antrum: median 761 pg/mg/protein, range 24-7,620, P< 0.005) higher than those at distant sites in the antrum. Biopsies from H pylori-positive GU and NU patients showed IL-17 mRNA expression in all samples whereas those from the antrum of the H pylori-negative controls showed no detectable expression. A significant correlation was seen between IL-17 and IL-8 levels at each biopsy site (ulcer: r = 0.62, P< 0.0001; antrum: r = 0.61, P< 0.0001) in GU patients. RhIL-17 and H pylori strain 26,695 each stimulated IL-8 production from AGS cells. CONCLUSION: IL-17 may play an important role in the inflammatory response to H pylori colonization, and may ultimately influence the outcome of H pylori-associated diseases that arise within the context of gastritis.

Animals↗
PubMed2005

Intestinal fibroblast-derived IL-10 increases survival of mucosal T cells by inhibiting growth factor deprivation- and Fas-mediated apoptosis.

Mucosal T cells are essential to immune tolerance in the intestine, an organ constantly exposed to large amounts of dietary and bacterial Ags. We investigated whether local fibroblasts affect mucosal T cell survival, which is critical for maintenance of immune tolerance. Coculture with autologous fibroblasts significantly increased viability of mucosal T cells by inhibiting IL-2 deprivation- and Fas-mediated apoptosis, an effect that was both contact- and secreted product-dependent. Investigation of anti-apoptotic factors in the fibroblast-conditioned medium (FCM) revealed the presence of IL-10 and PGE2, but not IFN-beta, IL-2, or IL-15. Although recombinant IFN-beta, but not PGE2, effectively prevented T cell apoptosis, neutralizing Ab studies showed that only IL-10 blockade significantly increased T cells apoptosis, whereas neutralizing IFN-beta or IFN-alpha failed to inhibit the anti-apoptotic effect of FCM. To confirm that fibroblast-derived IL-10 was responsible for preserving mucosal T cell viability, IL-10 mRNA was demonstrated in fibroblasts by Southern blotting and RT-PCR. When FCM was submitted to HPLC fractionation, only the peak matching rIL-10 contained the anti-apoptotic activity, and this was eliminated by treatment with an IL-10-neutralizing Ab. Finally, when fibroblasts were transiently transfected with IL-10 antisense oligonucleotides, the conditioned medium lost its T cell anti-apoptotic effect, whereas medium from fibroblasts transfected with IFN-beta antisense oligonucleotides displayed the same anti-apoptotic activity of medium from untransfected fibroblasts. These results indicate that local fibroblast-derived IL-10 is critically involved in the survival of mucosal T cells, underscoring the crucial importance of studying organ-specific cells and products to define the mechanisms of immune homeostasis in specialized tissue microenvironments like the intestinal mucosa.

Apoptosis↗
PubMed2005

Possible involvement of the interleukin-15 and interleukin-15 receptor system in a heightened state of lamina propria B cell activation and differentiation in patients with inflammatory bowel disease.

BACKGROUND: We investigated the possible roles of the interleukin (IL)-15 and IL-15 receptor (IL-15R) system in a heightened state of B-cell activation and differentiation in intestinal mucosa with inflammatory bowel disease (IBD). METHODS: The expression of IL-15 and IL-15Ralpha mRNA and protein in inflamed colonic mucosal tissues with IBD, and in control tissues was examined by reverse transcriptase-polymerase chain reaction and immunohistological methods. The effects of recombinant (r)IL-15 on the expression of IL-15Ralpha on lamina propria B cells and the production of immunoglobulin G (IgG) were analyzed in vitro, using lamina propria mononuclear cells (LPMCs) isolated from control tissues. RESULTS: The intensity of IL-15 and IL-15Ralpha mRNA was greater in the mucosal tissues of patients with IBD, especially in those of patients with ulcerative colitis (UC), than in control tissues. Compared to control tissues, mononuclear cells positive for IL-15Ralpha protein were observed in greater proportions in tissue sections from patients with IBD, especially in those from patients with UC, where IL-15Ralpha protein was localized to CD20-positive B cells to a significant degree. There were increases in the proportions of IL-15Ralpha-positive B cells and IgG-producing cells in rIL-15- or rCD40L-stimulated cultures of LPMCs, with stimulatory effects being greater in the presence of their combination. CONCLUSIONS: These data suggest that the IL-15 and IL-15R system may play important roles in the activation and differentiation of lamina propria B cells in patients with IBD, especially in those with UC.

Adolescent↗
PubMed2005

Long-term follow-up after eradication of Helicobacter pylori with omeprazole, clarithromycin, and tinidazole (OCT regimen) in a Japanese population.

BACKGROUND: The long-term benefit of Helicobacter pylori eradication treatment that includes metronidazole on peptic ulcer disease in Japan is unclear. We investigated the rate of H. pylori re-infection and ulcer relapse after H. pylori eradication. MATERIALS AND METHODS: A total of 266 patients with endoscopically confirmed peptic ulcer disease and H. pylori infection were treated with triple therapy of omeprazole 40 mg (20 mg b.i.d.), clarithromycin 800 mg (400 mg b.i.d.), and tinidazole 1000 mg (500 mg b.i.d.) for 7 days. Endoscopy with gastric biopsy was performed before and 1 month, 6 months, 1.5 years, and 3.5 years after therapy. H. pylori status was determined by H. pylori culture, rapid urease test, and histopathology. 13C-urea breath test was done at 6 months after eradication therapy. Treatment was deemed successful when all tests were negative at 6 months after therapy by endoscopic biopsy. RESULTS: Successful H. pylori eradication was achieved in 262/266 (98.5%) patients with peptic ulcer. Total relapse of peptic ulcer occurred in 8/262 (3%) patients after eradication, with 3/262 (1.1%) occurring within 1.5 years after treatment and 5/262 (1.9%) within 3.5 years. All relapsed patients were found to be H. pylori-positive at the time of relapse. Of the 262 patients who experienced eradication, 20 (7.6%) were subsequently re-infected, six (2.3%) within 1.5 years and 14 (5.3%) within 3.5 years. CONCLUSION: Triple therapy with omeprazole, clarithromycin, and tinidazole (OCT) is useful for H. pylori eradication in Japan, but there is an appreciable re-infection rate in this population.

Adult↗
PubMed2005

Intestinal gene expression in TNBS treated mice using genechip and subtractive cDNA analysis: implications for Crohn's disease.

So far it has proven difficult to identify a causative gene(s) or gene product initiating the events that lead to inflammation of the intestinal mucosa and, ultimately, progression to Crohn's disease (CD), an inflammatory bowel disease. However, gene transcripts identified in the intestine of trinitrobenzene sulfonic acid (TNBS)-treated mice might suggest a clue, and even represent candidate genes leading to inflammation and mucosal damage, and to subsequent fibrosis. In the present study, DNA microarray (13000 transcripts) methodology was applied to mucosal RNA extracted from TNBS-treated mice, some transcripts of which were validated via cDNA subtraction and RT-PCR analyses. Intestinal biopsy samples from CD patients were then analyzed using cDNA mini-array (1300 cDNAs), focusing on gene transcripts associated with cancer and immunity. Mini-array results revealed transcript changes similar and also dissimilar to those found from the DNA microarray analysis. These changes, previously known or newly identified, possibly occurring during the initial and progressive stages of inflammatory conditions may provide a clue to identify marker transcripts and/or targets for the development of future gene therapy.

Animals↗
PubMed2004

Immunomodulatory therapy for inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) have intestinal and extraintestinal symptoms that can greatly impair their quality of life. They must rely on multiple medications with aminosalicylates, corticosteroids, and purine analogues to control these symptoms. Although decades of clinical experience in IBD management has led to optimized approaches for achieving the induction and maintenance of remission, the disease in some patients is still refractory to conventional medical treatment, or the effectiveness of these drugs can be limited by treatment-related side effects. Significant progress in our understanding of the pathogenesis of IBD has yielded several immunomodulatory approaches with novel biological agents or apparatus, such as cyclosporine, cytoprotective agents, infliximab, and leukocytapheresis. Further immunomodulatoy therapy, aiming at the inhibition of molecular and cellular mediators, is anticipated, in parallel with the clarification of im-munoinflammatory pathways in IBD. An additional goal will be to identify factors predictive of response to treatment with each novel immunomodulatory agent or apparatus. This will help provide each patient with optimized and individualized therapy, thereby increasing therapeutic efficacy and reducing possible side effects.

Antibodies, Monoclonal↗
PubMed2004

Characteristics of Helicobacter pylori-induced gastritis and the effect of H. pylori eradication in patients with chronic idiopathic thrombocytopenic purpura.

BACKGROUND: The association between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) has been reported widely. We investigated the prevalence of H. pylori infection, its virulence profile and the effectiveness of its eradication in patients with ITP. MATERIALS AND METHODS: Twenty patients with ITP, 20 with peptic ulcer (10 gastric ulcer (GU), 10 duodenal ulcer (DU)) and 20 with NUD were studied. The virulence profile of the strains was assessed by genotyping for cagA, vacA, iceA, and hpyIIIR/hrgA and by assaying for IL-8 and DNA fragmentation after incubation with AGS cells. Infected patients and two uninfected ITP patients received triple therapy and platelets were counted before and 1 month, 6 months, 1 year, and 2 years after eradication therapy. RESULTS: H. pylori infection was found in 17 ITP (85%), 20 ulcer (100%) and 13 NUD (65%) patients. Biopsies and strains were collected from five ITP, 20 ulcer and 13 NUD patients. The ITP patients had a pangastritis or corpus-predominant gastritis pattern. All H. pylori isolates, from ITP, ulcer and NUD patients, were cagA(+) and vacA s1/m1, and did not differ in levels of IL-8 induction or DNA fragmentation. Fifteen ITP (88%) and 17 ulcer (85%) patients had successful eradication of H. pylori. Ten of these 15 (67%) H. pylori-eradicated ITP patients had platelet recovery. There was no significant change in platelet count in the two ITP patients in whom eradication failed or in the two originally H. pylori-uninfected ITP patients, or in the treated ulcer patients. Age at onset of ITP was the main determinant of platelet recovery: 100% of patients diagnosed after the age of 60 recovered compared with only 22% of those diagnosed before 50. CONCLUSIONS: H. pylori-infected ITP patients have a corpus-predominant pattern of gastritis but the virulence profile of their strains does not differ from that of ulcer or NUD patients. Eradication of H. pylori infection is a good therapeutic option for some patients with chronic ITP, especially for those who develop ITP in older age.

Adult↗
PubMed2004

Effect of glycine on Helicobacter pylori in vitro.

Glycine is the simplest amino acid and is used as a metabolic product in some bacteria. However, an excess of glycine inhibits the growth of many bacteria, and it is used as a nonspecific antiseptic agent due to its low level of toxicity in animals. The effect of glycine on Helicobacter pylori is not precisely known. The present study was conducted to investigate (i) the effect of glycine on clarithromycin (CLR)-resistant and -susceptible strains of H. pylori, (ii) the effect of glycine in combination with amoxicillin (AMX), and (iii) the postantibiotic effect (PAE). The MIC at which 90% of strains are inhibited for glycine was almost 2.5 mg/ml for 31 strains of H. pylori, including CLR-resistant strains. We constructed isogenic CLR-resistant mutant strains by natural transformation and investigated the difference between clinical wild-type strains and isogenic mutants. There were no differences in the MICs between CLR-resistant and -susceptible strains or between clinical wild-type and mutant strains. The combination of AMX and glycine showed synergistic activity, with the minimum bactericidal concentration of AMX with glycine decreasing to 1/10 that of AMX alone. Glycine showed no PAE against H. pylori. These results suggest that glycine may be a useful antimicrobial agent against H. pylori not only alone but also in combination with antibacterial drugs for the treatment of H. pylori-associated diseases. Glycine may represent a component of a new type of eradication therapy for CLR-resistant H. pylori.

Amoxicillin↗
PubMed2003

Bacterial hemorrhagic enterocolitis.

Bacterial diarrhea can be classified into two clinical entities, noninflammatory diarrhea and inflammatory diarrhea syndromes. The latter type of diarrhea is characterized by bloody and puruloid mucus stool, and is often accompanied by fever, tenesmus, and severe abdominal pain. Pathogenic bacteria causing the inflammatory diarrhea syndrome include Salmonella, Vibrio, Shigella, enteroinvasive and enterohemorrhagic Escherichia coli, Campylobacter, Yersinia, Chlamydia, and Clostridium difficile. The pathologic changes in the inflammatory diarrhea syndrome range from a superficial exudative enterocolitis to a transmural enterocolitis with overt ulceration. This syndrome is also designated as bacterial hemorrhagic enterocolitis because of its usual manifestation by bloody diarrhea. The diagnostic approach needs information on the patient's age, travel history, epidemiological associations, sexual practice, and medical history, including usage of antibiotics. Bacterial information can be obtained by microscopic study, culture, and the identification of specific bacterial toxins. Flexible colonoscopy with biopsy is useful for the differentiation of bacterial hemorrhagic enterocolitis from idiopathic ulcerative colitis and ischemic colitis. Physicians should be familiar with the diagnostic modalities used to detect the specific pathogens causing hemorrhagic bacterial enterocolitis; namely, bacterial culture, serology, histology, and nucleic acid technologies.

Bacterial Infections↗
PubMed2003

Cytotoxic molecules expressed by intraepithelial lymphocytes may be involved in the pathogenesis of acute gastric mucosal lesions.

BACKGROUND: Little information is available on the precise mechanisms leading to the development of acute gastric mucosal lesions (AGMLs). We investigated whether the pathologic mechanism of AGMLs resulting in damage to epithelial cells is associated with cytotoxic molecules expressed by activated intraepithelial lymphocytes (IELs). METHODS: The expression of the lymphocyte markers, CD3, CD4, CD8, CD20, T-cell-restricted intracellular antigen (TIA)-1, and granzyme B (GrB)-7 in IELs and that of single-stranded DNA (ssDNA) in apoptotic epithelial cells were evaluated by immunohistochemistry, using endoscopic biopsy specimens from 20 patients with AGMLs and 20 controls. RESULTS: The number of CD3- and CD8-positive IELs increased in AGML specimens when compared with controls, and this increase was accompanied by a concomitant increase in TIA-1-positive cells. The epithelial cell layers of AGML specimens contained more GrB-7-positive phenotypically activated cytotoxic T cells than those in controls. Apoptotic ssDNA-positive epithelial cells were detected more frequently in AGML specimens than in controls, a feature which was paralleled by an increase in GrB-7-positive IELs in the former group of specimens. CONCLUSIONS: The present study showed that activated cytotoxic IELs and apoptotic epithelial cells are increased in number in gastric mucosa affected with AGMLs. These results provide evidence that this condition could be categorized as apoptotic gastritis with activation of the innate immune response.

Acute Disease↗
PubMed2002

Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitis.

BACKGROUND: Little information is available on the relative contribution of peptide growth factors and leukocyte-derived proteinases to the repair processes in inflammatory bowel disease (IBD). We investigated their possible roles in epithelial cell restitution and proliferation in patients with IBD. METHODS: The expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-beta (TGF-beta), and neutrophil elastase (NE) was examined in colonic mucosal tissues. The effects of organ culture supernatants of mucosal tissues on epithelial cell restitution and proliferation were analyzed in vitro using an intestinal cell line, IEC-6 cells. RESULTS: Most organ cultures detected the presence of measurable levels of HGF, with a relative paucity of KGF and TGF-beta activity. Greater levels of HGF were obtained in the mucosa involved with IBD, especially in patients with ulcerative colitis (UC). The mucosa involved with UC also showed higher amounts of NE. The supernatants from the mucosa involved with UC possessed a prominent stimulatory effect on the restitution of IEC-6 cells. By contrast, significant suppression beyond baseline levels was observed for the proliferation of IEC-6 cells when they were incubated with recombinant HGF plus the supernatants from the mucosa involved with UC. This suppression was diminished considerably by preincubation of the supernatants with the anti-NE antibody. CONCLUSIONS: HGF produced in the intestinal mucosa may be an important stimulator acting on epithelial cell restitution in patients with IBD. However, NE released in situ may impair mucosal repair through inhibiting epithelial cell proliferation in patients with UC.

Adult↗