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Biomedical subjects

H Nishimura

Publications and source records attributed to H Nishimura.

At least 199 records · Page 11Linked to original sources
PubMed1998

A new quadruple therapy for the eradication of Helicobacter pylori. Effect of pretreatment with omeprazole on the cure rate.

To elucidate whether pretreatment with omeprazole decreases the cure rate of Helicobacter pylori infection with a new quadruple therapy, and thus, whether this pretreatment should not be used in clinical practice, we conducted a randomized trial. Ninety patients with chronic peptic ulcer disease and nonulcer dyspepsia, with biopsy-proven H. pylori infection were randomly assigned to the two following regimens: Group 1 (n = 45) received omeprazole 20 mg once daily for 2 weeks (days 1-14), and 500 mg amoxicillin granules and 250 mg metronidazole thrice daily, and roxithromycin 150 mg twice daily for 1 week (days 8-14), Group 2 (n = 45) received the same antibiotic treatment as group 1 for 1 week (days 1-7), in addition to omeprazole treatment for 2 weeks (days 1-14). Four weeks after the treatment ended, endoscopy was repeated, with two biopsy specimens each taken from the antrum and the corpus (total of four specimens) for a urease test, histological analysis, and culture to establish cure of infection. A patient was regarded as cured only if all three methods gave negative results for H. pylori. In the intention-to-treat analysis, 42 of 45 patients (93.3%; 95% confidence intervals [CI], 81.7%-98.6%) in group 1 were cured compared with 43 of 45 patients (95.6%; 95% CI, 84.9%-99.5%) in group 2. In the per-protocol analysis, the corresponding figures were 42/44 (95.5%; 95% CI 84.5%-99.4%) and 43/44 (97.7%; 95% CI, 88.0%-99.9%). There were no significant differences in the cure rate between the two groups on either analysis. All patients, except for one who had an allergic reaction, completed the treatment regimens. Fifty to sixty percent of the patients had no side effects while the rest had mild to moderate side effects. The new quadruple therapy consisting of omeprazole, amoxicillin, metronidazole, and roxithromycin appears suitable for use in clinical practice, as the cure rate was 95% and no severe side effects were observed. Pretreatment with omeprazole did not reduce the cure rate for this new quadruple therapy.

Adult↗
PubMed1998

Interleukin 15 activity in the rectal mucosa of inflammatory bowel disease.

BACKGROUND & AIMS: Interleukin (IL)-15 has been found to share many immunoregulatory activities in lymphocytes with IL-2. The aim of this study was to investigate IL-15 activity in organ cultures, localization of IL-15 messenger RNA (mRNA), and proliferation of lamina propria mononuclear cells (LPMCs) in response to recombinant IL-15 using the mucosal tissues obtained from patients with inflammatory bowel disease (IBD). METHODS: The contents of IL-15, tumor necrosis factor alpha, and IL-2 in the culture supernatant of the rectal mucosal tissues were determined by an enzyme-linked immunosorbent assay. Expression of IL-15 mRNA was analyzed by in situ hybridization, and proliferative response of LPMCs to recombinant IL-15 was determined by [3H]thymidine incorporation into DNA. RESULTS: Significantly greater IL-15 activity was detected in active IBD, and this elevation was also observed in inactive ulcerative colitis. In contrast, greater tumor necrosis factor alpha activity was observed only in active IBD, and IL-2 was not detected in organ cultures. In situ hybridization showed IL-15 mRNA in macrophages and epithelial cells in active IBD specimens, and recombinant IL-15 induced a dose-dependent proliferative response in LPMCs. CONCLUSIONS: Mucosal IL-15 may be involved in the pathogenesis of IBD as one of the important mediators in activation of mucosal immune cells.

Adolescent↗
PubMed1998

The significance of the Trp 64 Arg mutation of the beta3-adrenergic receptor gene in impaired glucose tolerance, non-insulin-dependent diabetes mellitus, and insulin resistance in Japanese subjects.

It has been reported that the Trp 64 Arg mutation of the human beta3-adrenergic receptor (beta3-AR) gene is related to an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and features of insulin resistance and weight gain in morbidly obese patients. However, such findings have not been consistent in varying ethnic populations. In the present study, we investigated the frequency of the Trp 64 Arg mutation of the human beta3-AR gene in Japanese control subjects (n = 253) and in NIDDM (n = 314) and impaired glucose tolerance (IGT) patients (n = 100). We compared the frequency of the mutation with the body-mass index (BMI) in these groups and with the metabolic clearance rate (MCR) of glucose in the NIDDM patients. A Trp 64 Arg mutation was observed in 36.7%, 31.6%, and 37.0% of the control, NIDDM, and IGT subjects, respectively. The frequency of the homozygotes for the mutation was 4.3%, 4.8%, and 3.0%, respectively. Neither the genotype frequency (Trp/Arg, Arg/Arg) nor the frequency of the mutated allele was significantly different among the three groups. The BMI of the subjects with the mutation was not significantly higher than that of the subjects without the mutation in each group. Furthermore, the allele frequency (A) was not different among the subjects with different BMIs (BMI < 22.0, 22.0 < or = BMI < or = 26.4, BMI > 26.4) in each group. In a separate group of NIDDM patients, the MCR of the subjects with intermediate BMIs (22.0 < or = BMI < or = 26.4) with the mutation tended to be lower than that of those without the mutation. In addition, the MCR of the subjects with the mutation in this group was significantly lower compared with that of those with a BMI less than 22. These results indicate that the Trp 64 Arg mutation of the beta3-AR gene may not contribute to the development of NIDDM or be a determinant of obesity in the Japanese population. However, the mutation may contribute to insulin resistance in NIDDM patients with an intermediate BMI.

Adult↗
PubMed1998

Kinetics of apoptosis in the lung of mice with allergic airway inflammation.

BACKGROUND: Apoptosis has been suggested as a means to facilitate the resolution of eosinophilic inflammation in bronchial asthma. However, the natural course of apoptosis has not been elucidated in vivo, and there is no direct evidence for eosinophilic apoptosis within lung tissue. OBJECTIVE: The purpose of this study is to clarify whether the apoptosis occurs within the lung tissue, and to define the time-course of change in apoptosis ratio during the resolution of pulmonary eosinophilic inflammation. METHODS: Ovalbumin (OVA)-sensitized Balb/c mice were challenged with aerosolized OVA. We studied apoptotic cells in the lung of OVA-sensitized mice at 1, 3, 7 and 14 days after OVA challenge by in situ detection of DNA fragmentation with deoxynucleotidyl transferase deoxyuridyl triphosphatase nick endlabelling (TUNEL) technique. Apoptotic cells also were identified by electron microscopic analysis in the lung 7 days after OVA challenge. RESULTS: The TUNEL-method revealed that eosinophils localized in the subepithelium of bronchi undergo apoptosis following OVA challenge. Electron microscopy confirmed the presence of apoptotic cells, apoptotic bodies, and macrophages ingesting apoptotic bodies within the lung tissue. The number of apoptotic cells increased concomitantly with the increase in eosinophilic infiltration for 3 days post-challenge. However, both the apoptotic cell counts and the apoptotic ratio continued to increase even after the eosinophil count peaked, indicating rather late induction of apoptosis in the lung. In addition, TUNEL-positive cells were localized in the lung for 14 days post-challenge, indicating prolonged induction of apoptosis after the OVA challenge. CONCLUSION: Our findings constitute direct evidence of eosinophilic apoptosis in situ, and display the kinetics of apoptosis in the lung of the allergic inflammation.

Animals↗
PubMed1998

Post-translational modification and intracellular localization of a splice product of CD46 cloned from human testis: role of the intracellular domains in O-glycosylation.

We obtained a unique CD46 cDNA, STc/CY4, from the human testis, the predicted amino acid sequence of which suggested the presence of a novel isoform of CD46. This message was present predominantly in the testis, and the predicted isoform possessed a short (11 amino acids) transmembrane section (TM) and an unidentified cytoplasmic tail (CY). When expressed in Chinese hamster ovary (CHO) cells, this CD46 isoform underwent no O-glycosylation and was mostly retained in the endoplasmic reticulum. This unusual behaviour of the new isoform was due in part to the short TM and the unusual sequences of the CY. The molecular mass of this isoform was 42,000, approximately 20,000 smaller than conventional CD46. These properties of the STc/CY4 isoform were similar to those of sperm CD46. The only difference between sperm CD46 and the STc/CY4 isoform expressed on CHO cells was that only the latter possessed N-linked sugars of high mannose types. Since the STc/CY4 isoform may behave like sperm CD46 in cellular localization and post-translational modification, studies of sperm-egg interassociation were performed using hamster eggs and CHO cell clones expressing various isoforms including the STc/CY4. Rosette formation was seen most effectively between hamster eggs and STc/CY4-expressing CHO cells. These results infer that O-glycosylation perturbs CD46-mediated sperm-binding to eggs and thus sperm CD46 lacking O-linked sugars can serve as an adhesion molecule. The possible role of CD46 in fertilization and the structural differences between sperm and conventional CD46 are discussed.

Alternative Splicing↗
PubMed1998

Diazepam potentiates the positive inotropic effects of histamine and forskolin in guinea-pig papillary muscles.

There have been diverse reports on the effects of diazepam on cardiac contractility. The purpose of this study was to examine whether diazepam modifies the inotropic response elicited by histamine on an isolated guinea-pig papillary muscle. The responses of electrically driven papillary muscle to histamine and cyclic AMP-related inotropic agents were recorded in the absence and in the presence of diazepam. Histamine and forskolin, which directly stimulate adenylate cyclase, significantly increased the contractile force in the papillary muscle in a concentration-dependent manner. A histaminergic H2-receptor antagonist, cimetidine, but not a H1-receptor antagonist, diphenhydramine, at 10 microM produced a rightward shift in the concentration-response curve for histamine. Diazepam (10 microM) shifted the concentration-response curve for histamine and forskolin to the left by 1.8 and 1.6 times, respectively. Neither a central type (fulmazenil) nor a peripheral type (PK11195) of benzodiazepine receptor antagonist modified the effect of diazepam on the histaminergic-evoked contraction. Phosphodiesterase blockade by 3-isobutyl-1-methylxanthine shifted the concentration-dependent curve for histamine to the left. A combination of 3-isobutyl-1-methylxanthine also produced a leftward shift of the curve. However, there was no significant difference between the 3-isobutyl-1-methylxanthine only group and the combination group. These results indicate that diazepam potentiates the positive inotropic effect produced by histamine, probably mediated via an increase in cyclic AMP levels induced by histamine.

Anesthetics, Intravenous↗
PubMed1998

Role of angiotensin in the congenital anomalies of the kidney and urinary tract in the mouse and the human.

The role of angiotensin in fluid and electrolyte and blood pressure homeostasis is well known. Recent developments indicate that angiotensin has a profound role not only in the developing urinary tract but also in the response of the urinary tract to specific noxious stimuli. Furthermore, the role of angiotensin II and its receptor has been understood quite poorly with respect to the developing renal unit. Knockout mice for the ATR2 gene show a significant incidence of congenital urinary tract anomalies. The congenital anomalies of the kidney and urinary tract (CAKUT) seen in these mice are very similar to the anomalies observed in humans. This has been supported further by the finding of an abnormality in the genetic sequence in patients with CAKUT. This article reviews experimental laboratory data as well as the potential implications for humans.

Angiotensin II↗
PubMed1998

The angiogenic effect of tissue factor on tumors and wounds.

We report a novel function of tissue factor (TF) as an angiogenic factor in malignant and non-malignant cells and tissue. When methylcholanthrene A-induced murine fibrosarcoma (Meth-A sarcoma) was stably transfected with mouse TF (mTF) cDNA (pXT1 expression vector), its vascularization in vivo was significantly enhanced, whereas TF-antisense suppressed the vascularization and tumor growth. In vitro expression of vascular endothelial growth factor (VEGF) was enhanced with stable transfection of mTF (pcDNA3 expression vector) into a mouse fibroblast cell line (NIH3T3). Moreover, in vivo topical transfection of mTF (pcDNA3) showed an enhanced vascularization and healing in a diabetic mouse wound-healing model. This effect of TF as an angiogenic factor might be useful as an antitumor therapy against hypervascular tumors or as a novel agent against delayed wound healing.

3T3 Cells↗
PubMed1998

Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses.

PD-1, an Ig superfamily member, contains an immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic tail. It is expressed in a minor fraction of CD4-CD8- normal thymocytes and induced in peripheral lymphocytes following activation. To assess the possible roles of PD-1 in the immune responses, PD-1-deficient (PD-1-/-) mice were generated by a gene-targeting strategy. PD-1-4- mice developed and grew normally. Although the thymus was apparently normal, PD-1-/- mice showed moderate but consistent splenomegaly, which reflected the increased cellularity of both lymphoid and myeloid cells. The proliferative response of B cells by anti-IgM antibodies, but not of T cells by an anti-CD3 (145-2C11) mAb in vitro, was augmented in PD-1-/- mice as compared with control littermates. PD-1-/- mice showed increased serum levels of IgG2b, IgA and most strikingly IgG3, while those of IgM and IgG1 were comparable with control mice. Furthermore, PD-1-/- mice exhibited significantly augmented IgG3 anti-DNP antibody response to a type 2 T-independent antigen, DNP-Ficoll, with comparable IgM and IgG1 antibody responses with littermate controls. In the peritoneal cavity, the B-1 cell population in PD-1-/- mice exhibited significantly reduced expression of CD5, a negative regulator of B-1 cell activation, despite a marginal increase in the number of B-1 cells. Thus, PD-1 was suggested to be involved in the negative regulation for particular aspects of B cell proliferation and differentiation including class switching.

Animals↗
PubMed1998

The regulatory role of heat shock protein 70-reactive CD4+ T cells during rat listeriosis.

Protection against infection with Listeria monocytogenes depends primarily on Listeria-specific T cells. We show here that CD4+ TCR alphabeta+ T cells are capable of recognizing the mycobacterial heat shock protein (HSP) 70, that appears in the peritoneal cavity of F344 rats infected i.p. with L. monocytogenes. The HSP70-reactive CD4+ T cells recognized a peptide comprising 234-252 residues as present in the 70 kDa HSP of Mycobacterium tuberculosis in the context of RT1.B MHC class II molecules. Analysis of TCR Vbeta gene expression with RT-PCR revealed that the HSP70-reactive CD4+ T cells predominantly used the Vbeta16 gene segment, whereas the heat-killed Listeria (HKL)-specific T cells expressed a diverse set of Vbeta gene segments. In contrast to the HKL-specific T cells producing IFN-gamma, the HSP70-reactive CD4+ T cells produced TGF-beta1 and IL-10 but neither Th1- or Th2-type cytokines. Adoptive transfer with HSP70-reactive T cells rendered rats susceptible to listerial infection. Collectively, these results proposed that the HSP70-reactive CD4+ T cells appearing during rat listeriosis may be involved in termination of Th1 cell-mediated excessive inflammation after the battle against L. monocytogenes has been won.

Adoptive Transfer↗
PubMed1998

Plasminogen activator inhibitor-1 promoter 4G/5G genotype is not a risk factor for myocardial infarction in a Japanese population.

There is little question that the blood clotting process is triggered and causes the vascular occlusion associated with myocardial infarction. Although it is less clear what part blood coagulation events might play in the etiology of coronary artery disease, impaired regulation of anticoagulation or fibrinolysis might be involved. Among anticoagulant and fibrinolytic factors, an elevated plasma plasminogen activator inhibitor-1 (PAI-1) concentration has been identified as a risk factor for the development of myocardial infarction. An association between one polymorphism of the PAI-1 promoter (4G/5G single nucleotide deletion/ insertion at position -675) and plasma PAI-1 levels was described in 1995. However, most recent studies seem to point to the lack of such an association. This is the first report on the frequency of this polymorphism in the Japanese population with respect to the risk of myocardial infarction. Sixty-six patients with myocardial infarction and sixty-two healthy control patients were chosen for the analysis of the PAI-1 promoter 4G/5G genotype with polymerase chain reaction-single strand conformation polymorphism. Five myocardial infarction patients and six in the control group were homozygous for the 4G/4G genotype. Twenty-eight and 27 4G/5G and 33 and 29 5G/5G genotypes were found in myocardial infarction and control groups, respectively. The total frequencies of the 4G and 5G alleles were approximately 30% and 70% in both control and myocardial infarction groups. In conclusion, the PAI-1 promoter genotype is not a risk factor for myocardial infarction in the Japanese population. This is in contrast to the first report in Caucasians, suggesting an interaction with other genetic or environmental factors which influences the risk of myocardial infarction.

Aged↗
PubMed1998

Renal angiotensin converting enzyme promotes renal damage during ureteral obstruction.

PURPOSE: We and others have shown that angiotensin II has a pivotal role in renal damage in various renal injuries. Although most angiotensin II actions are associated with the angiotensin type 1 receptor, there is increasing evidence that the angiotensin type 2 receptor also transduces some important effects of angiotensin II. In this regard we recently observed that mice with genetically engineered disruption of the angiotensin type 2 receptor, termed Agtr2 mutants, are more susceptible to structural renal damage after ureteral obstruction. Recent evidence suggests that a genetically determined increase in angiotensin converting enzyme activity in humans promotes end organ damage. Therefore, we determined whether renal damage in Agtr2 mutants is associated with heightened angiotensin converting enzyme activity. MATERIALS AND METHODS: We studied 28 wild type and 19 Agtr2 mutant mice with unilateral ureteral obstruction. Seven days after obstruction was created serum samples were obtained to evaluate angiotensin converting enzyme activity. The obstructed and contralateral kidneys were harvested for histological analysis and determination of renal angiotensin converting enzyme activity by high pressure liquid chromatography. RESULTS: Renal angiotensin converting enzyme was uniformly higher than serum angiotensin converting enzyme in normal wild type and Agtr2 mutant mice. However, even at baseline Agtr2 mutant mice had strikingly higher renal angiotensin converting enzyme activity than normal wild type mice (mean plus or minus standard error 1,492+/-83 versus 450+/-60 milliunits per gm. tissue weight, p <0.0005). Histological analysis revealed more extensive parenchymal damage in the obstructed kidneys of mutant mice than in identically treated controls. Notably while unilateral ureteral obstruction decreased renal angiotensin converting enzyme activity in each group, activity remained persistently higher in the Agtr2 mutants than in normal mice (mean 742+/-146 versus 310+/-43 milliunits per gm. tissue weight, p <0.005). CONCLUSIONS: We propose that elevated renal angiotensin converting enzyme activity contributes to more severe renal parenchymal damage in ureteral obstruction by promoting the availability of growth factors, such as angiotensin II, or depleting antiproliferation factors, such as bradykinin or nitric oxide. These findings complement previous observations that angiotensin converting enzyme inhibition preserves the renal parenchyma after injury, including obstruction.

Animals↗
PubMed1998

Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction.

We examined the role of angiotensin in renal remodeling that is specifically channeled through the angiotensin type 2 receptor (AT2 receptor). Previously, we observed that in mouse embryonic kidneys the AT2 mRNA is predominantly expressed in the mesenchyme. We therefore chose a model of unilateral ureteral obstruction, characterized by activation of the renin-angiotensin system, while fibrosis develops prominently within the renal interstitium. Male wild-type mice (Agtr2 -/Y) and mice null mutant for the AT2 gene (Agtr2 -/Y) were subjected to a complete unilateral ureteral ligation for 5 or 14 days. Obstructed kidneys of Agtr2 -/Y mice showed more severe interstitial fibrosis than those of Agtr2 +/Y mice, confirmed by increased collagen by point-counting on Masson trichrome stained sections, and increased alpha 1(I) collagen mRNA expression by Northern blot. Immunohistochemistry staining for PCNA (a marker of cell proliferation), F4/80 (a marker of macrophages), vimentin (a marker of fibroblasts), and alpha SMA (a marker of myofibroblasts) revealed that, while the two groups were comparable in the degree of cell proliferation and macrophage infiltration, fibroblasts/ myofibroblasts were present in a greater abundance in obstructed kidneys of Agtr2 -/Y mice than in Agtr2 +/Y at both 5 and 14 days after obstruction. Moreover, cells undergoing apoptosis were significantly less in Agtr2 -/Y than in Agtr2 +/Y. Thus, the AT2 receptor significantly impacts the remodeling process within renal interstitium, potentially by regulating the population of collagen-producing cells.

Animals↗
PubMed1998

Interleukin-15 may be responsible for early activation of intestinal intraepithelial lymphocytes after oral infection with Listeria monocytogenes in rats.

Exogenous interleukin-15 (IL-15) stimulates intestinal intraepithelial lymphocytes (i-IEL) from mice to proliferate and produce gamma interferon (IFN-gamma) in vitro. To determine whether endogenous IL-15 is involved in activation of i-IEL during intestinal infection, we examined IL-15 synthesis by intestinal epithelial cells (i-EC) after infection with Listeria monocytogenes in rats. In in vitro experiments, invasion of L. monocytogenes into IEC-6 cells, a rat small intestine epithelial cell line, evidently induced IL-15 mRNA expression coincident with nuclear factor kappaB (NF-kappaB) activation, which is essential for IL-15 gene expression. IL-15 synthesis was detected in rat i-EC on day 1 after an oral inoculation of L. monocytogenes in vivo. The numbers of T-cell receptor (TCR) gamma delta+ T cells, NKR.P1(+) cells, and CD3(+) CD8(+) alpha alpha cells in i-IEL were significantly increased on day 1 after oral infection. The i-IEL from infected rats produced larger amounts of IFN-gamma upon stimulation with immobilized anti-TCR gamma delta or anti-NKR.P1 monoclonal antibodies. These results suggest that IL-15 produced by i-EC may stimulate significant fractions of i-IEL to produce IFN-gamma at an early phase of oral infection with L. monocytogenes.

Animals↗
PubMed1998

Protective roles of gamma delta T cells and interleukin-15 in Escherichia coli infection in mice.

The number of gamma delta T cells in the peritoneal cavity was increased after an intraperitoneal (i.p.) infection with Escherichia coli in lipopolysaccharide (LPS)-responsive C3H/HeN mice but not in LPS-hyporesponsive C3H/HeJ mice. The gamma delta T cells preferentially expressed invariant Vgamma6 and Vdelta1 chains and proliferated to produce a large amount of gamma interferon in the presence of LPS. Mice depleted of gamma delta T cells by T-cell receptor delta gene mutation showed impaired resistance against E. coli as assessed by bacterial growth. Macrophages from C3H/HeN mice infected with E. coli expressed higher levels of interleukin-15 (IL-15) mRNA than those from the infected C3H/HeJ mice. Administration of anti-IL-15 monoclonal antibody inhibited, albeit partially, the appearance of gamma delta T cells in C3H/HeN mice after E. coli infection and diminished the host defense against the infection. These results suggest that LPS-stimulated gamma delta T cells play an important role in the host defense against E. coli infection and that IL-15 may be partly involved in the protection via an increase in the gamma delta T cells.

Animals↗
PubMed1998

Functional evidence for alternative ANG II-forming pathways in hamster cardiovascular system.

Like human chymase, hamster chymase is an ANG II-forming enzyme, but pathophysiological roles of chymase are still unknown. We determined the functional conversion of ANG I and [Pro11, D-Ala12]ANG I, a chymase-selective substrate, to ANG II in the hamster cardiovascular system. ANG I and [Pro11, D-Ala12]ANG I produced similar dose-dependent pressor responses in conscious hamsters. Captopril and CV-11974, an ANG II type 1 (AT1)-receptor antagonist, inhibited the responses to ANG I; in contrast, the pressor responses to [Pro11, D-Ala12]ANG I were suppressed only by CV-11974. In the isolated aorta, captopril suppressed ANG I-induced contraction by 84%; administration of captopril with either chymostatin or aprotinin eliminated the contraction. [Pro11, D-Ala12]ANG I-induced contraction was not affected by captopril but was attenuated by chymostatin (71%) and aprotinin (57%). CV-11974 abolished the responses to both substrates, whereas PD-123319, an AT2-receptor antagonist, had no effect. In homogenates of the aorta and heart, soybean trypsin inhibitor-inhibitable ANG II formation predominated over captopril- or aprotinin-inhibitable ANG II formation. These data suggest that [Pro11,D-Ala12]ANG I and part of ANG I were functionally converted to ANG II by chymase and other serine protease(s) in hamster vessels, inducing AT1-receptor-mediated vasoconstriction. Biochemical data supported a role for chymase in the alternative pathway.

Angiotensin I↗