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Biomedical subjects

H Ohno

Publications and source records attributed to H Ohno.

At least 19 recordsLinked to original sources
PubMed1999

Cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement delivers an inhibitory signal through the membrane-proximal region in the absence of the tyrosine motif in the cytoplasmic tail.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif ((165)YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain-containing tyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinase upon phosphorylation, the mechanism of negative signaling remains unclear. Here, we report a new mechanism of negative signaling based on the analysis of murine T cell clones transfected with various mutants of CTLA-4. Upon T cell activation by cross-linking with anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibited both proliferation and interleukin 2 production in tyrosine mutants as well as in wild-type CTLA-4 transfectants. Furthermore, the mutant CTLA-4 lacking most of the cytoplasmic region strongly suppressed interleukin 2 production as well. These data suggest that negative signals by CTLA-4 could be mediated through the membrane-proximal region of CTLA-4 but not through the YVKM motif and that the association of CTLA-4 with SHP-2 is not required for CTLA-4-mediated suppression of T cell activation.

Abatacept↗
PubMed1999

Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease.

Microtubule-associated protein tau in cerebrospinal fluid (CSF) has been proposed as a diagnostic marker for Alzheimer's disease (AD), but there is overlap between AD patients and non-AD controls. To improve the diagnostic accuracy, we measured phosphorylated tau in CSF, because phosphorylated tau accumulates as pathological paired helical filaments in neurons of the AD brain. Immunoblot showed that CSF contained a 32 kDa N-terminal fragment of tau that was partially phosphorylated on Ser199, Thr231 and Ser235. A sandwich enzyme immunoassay revealed that phosphorylated CSF-tau levels were significantly higher in AD patients than those in non-AD controls. Discrimination between the two groups was clearer in phosphorylated CSF-tau than in total CSF-tau. The data indicate that elevated phosphorylated CSF-tau level is a more specific diagnostic marker for AD.

Alzheimer Disease↗
PubMed1999

Dependence of T cell antigen recognition on the dimensions of an accessory receptor-ligand complex.

The T cell antigen receptor (TCR) and its ligand peptide-major histocompatibility complex (MHC) are small (approximately 7 nm) compared with other abundant cell surface molecules such as integrins, CD43, and CD45 (23-50 nm). We have proposed that molecules at the T cell/antigen-presenting cell (APC) interface segregate according to size, with small "accessory" molecules (e.g., CD2, CD4, CD8, CD28, and CD154) contributing to the formation of a close-contact zone, within which the TCR engages peptide-MHC, and from which large molecules are excluded (Davis, S.J., and P.A. van der Merwe. 1996. Immunol. Today. 17:177-187). One prediction of this model is that increasing the size of these small accessory molecules will disrupt their function. Here, we test this prediction by varying the dimensions of the CD2 ligand, CD48, and examining how this affects T cell antigen recognition. Although the interaction of CD2 on T cells with wild-type or shortened forms of CD48 on APCs enhances T cell antigen recognition, the interaction of CD2 with elongated forms of CD48 is strongly inhibitory. Further experiments indicated that elongation of the CD2/CD48 complex inhibited TCR engagement of peptide-MHC, presumably by preventing the formation of sufficiently intimate contacts at the T cell/APC interface. These findings demonstrate the importance of small size in CD2/CD48 function, and support the hypothesis that T cell antigen recognition requires segregation of cell surface molecules according to size.

Animals↗
PubMed1999

Mu1B, a novel adaptor medium chain expressed in polarized epithelial cells.

The apical and basolateral plasma membrane domains of polarized epithelial cells contain distinct sets of integral membrane proteins. Biosynthetic targeting of proteins to the basolateral plasma membrane is mediated by cytosolic tail determinants, many of which resemble signals involved in the rapid endocytosis or lysosomal targeting. Since these signals are recognized by adaptor proteins, we hypothesized that there could be epithelial-specific adaptors involved in polarized sorting. Here, we report the identification of a novel member of the adaptor medium chain family, named mu1B, which is closely related to the previously described mu1A (79% amino acid sequence identity). Northern blotting and in situ hybridization analyses reveal the specific expression of mu1B mRNA in a subset of polarized epithelial and exocrine cells. Yeast two-hybrid analyses show that mu1B is capable of interacting with generic tyrosine-based sorting signals. These observations suggest that mu1B may be involved in protein sorting events specific to polarized cells.

Adaptor Protein Complex 1↗
PubMed1999

Involvement of cysteinyl leukotrienes in biphasic increase of nasal airway resistance of antigen-induced rhinitis in guinea pigs.

We examined the effect of a specific cysteinyl leukotriene (LT) receptor antagonist, 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzopyran hemihydrate (pranlukast), on a novel model of allergic rhinitis induced by repeated intranasal ovalbumin challenge in actively sensitized guinea pigs. Repeated intranasal ovalbumin challenge caused a biphasic increase of nasal airway resistance, peaking 0.5 and 4 h after the final challenge. The early-phase response was accompanied by an increase in sneezing and nasal secretion, while that in the late phase was associated with edema and eosinophil infiltration of the nasal mucosa. Analysis of nasal lavage fluid showed that cysteinyl LTs increased in both phases. Pranlukast, when administered 1 h before every ovalbumin challenge, dose-dependently suppressed the increase of nasal airway resistance in the early- and late phase with evidence of histopathological improvements in the late phase. Pranlukast, however, failed to suppress sneezing and nasal secretion. We suggest that cysteinyl LTs play an important role in allergic rhinitis especially in the nasal obstruction due to edema of the nasal mucosa membrane.

Airway Resistance↗
PubMed1999

Monitoring of mercury pollution in Tanzania: relation between head hair mercury and health.

Through 1996 into 1997, a spot investigation on mercury contamination was conducted three times in Tanzania, especially around the Lake Victoria. A total of 150 goldminers, 103 fishermen and their families, and 19 residents of Mwanza City volunteered for the current study. A high total mercury level of 48.3 ppm (near to 50 ppm, a critical level of Minamata disease) and over in the head hair was observed in six goldminers (highest value, 953 ppm), four fishermen and their families (highest value, 416 ppm), and four Mwanza people (highest value, 474 ppm). With the exception of these 14 subjects, however, each mean total mercury level was well within the normal range (below 10 ppm). Out of the goldminers examined, 14 cases were diagnosed as a mild form of inorganic-mercury poisoning according to their clinical symptoms (such as polyneuropathy mercurialis, neuroasthemia, or tremor mercurialis) and the low ratio of methylmercury to total mercury, whereas neither inorganic-mercury poisoning nor methylmercury poisoning (Minamata disease) was noted in the fishermen and their families or in the Mwanza people. In addition, some subjects who showed a high total mercury level made habitual use of toilet soap containing much mercury. The findings obtained suggest that the mercury pollution in Tanzania is not very serious, however, it should be observed continuously.

Adolescent↗
PubMed1999

Human hepatitis B virus X protein augments the DNA binding of nuclear factor for IL-6 through its basic-leucine zipper domain.

The X gene product of human hepatitis B virus, HBx, transactivates the expression of viral and cellular genes through a wide variety of cis elements, including the nuclear factor for IL-6 (NF-IL6) binding sites, although HBx does not appear to bind DNA directly. We previously reported that HBx transactivated the interleukin 8 promoter through NF-kappaB binding site and C/EBP-like binding site (NF-IL6 binding site). In this study, the interactions were examined between NF-IL6 and HBx using recombinant proteins. In a DNA-protein binding assay, the formation of a specific complex between NF-IL6 and a DNA probe harboring an NF-IL6 binding site was increased by the addition of either the full or the C-terminal 104 amino acids of HBx. A direct protein-protein binding assay (far-Western blot) revealed the direct interaction between the C-terminal 104 amino acids of HBx and the basic region-leucine zipper domain of NF-IL6. These results indicate that HBx alters the DNA-binding affinity of NF-IL6 through the direct interaction between the C-terminal domain of HBx and the basic region-leucine zipper domain of NF-IL6.

Binding Sites↗
PubMed1999

Primary biliary cirrhosis associated with type A gastritis and chronic thyroiditis.

We report a patient with primary biliary cirrhosis (PBC) associated with type A gastritis, chronic thyroiditis, and iron deficiency anemia. The patient was a 45-year-old Japanese woman who was admitted to our hospital with severe microcytic and hypochromic anemia, abnormal results for liver function tests, and a diffuse goiter. The diagnosis of PBC (Scheuer's stage II) was confirmed by the presence of specific anti-mitochondrial antibody in high titers and histological examination showing chronic non-suppurative destructive cholangitis with bridging fibrosis. Additionally, marked atrophic mucosa throughout the body and fundus of the stomach was observed endoscopically, and there was positivity for intrinsic factor antibody, an extremely low ratio of serum pepsinogen A to C, and hypergastrinemia, indicating coexisting type A gastritis. The severe anemia was thought to be caused by failure of dietary iron absorption related to achlorhydria with this gastritis. However, the serum level of vitamin B12 was normal. She also had autoimmune thyroiditis. PBC is frequently associated with extrahepatic autoimmune diseases, including ductular lesions. However, the association of PBC with type A gastritis is quite rare, although the stomach is also an exocrine glandular structure. This particular case, in addition to previous reports, leads to a discussion of whether type A gastritis should be regarded as a possible, although uncommon, component disorder of so-called dry gland syndrome.

Anemia, Iron-Deficiency↗
PubMed1999

The long-term results of commissure plication annuloplasty for congenital mitral insufficiency.

BACKGROUND: Mitral valve repair in the pediatric population remains demanding because of a diversity of apparatus anomalies and the young age of the patients. METHODS: We reviewed our clinical results for mitral valve repairs for congenital mitral insufficiency. Forty-nine consecutive patients aged 2 months to 34 years (mean, 4.4 years) had mitral valve repair between June 1984 and December 1996. Forty-one patients (83.7%) had associated cardiac anomalies. The predominant pathologies for the regurgitations were chordal anomalies in 34 patients (69%), annular dilatation in 8 (16%), and leaflet anomalies in 7 (14%). Mitral valve repair included commissure plication annuloplasty in 43 patients (88%), modified DeVega in 11, cleft closure in 5, plication of the anterior leaflet in 3, triangular resection of the anterior leaflet in 2, chordal shortening in 1, and placement of artificial chordae in 1. Several combined techniques were required in 19 patients. RESULTS: There were no early or late deaths. The follow-up period was from 6 to 166 months (mean, 88.4 months). Forty-seven patients (95.9%) were in New York Heart Association class I. The long-term echocardiographic studies showed that 2 of 30 patients without reoperation had moderate regurgitation. The actuarial freedom from reoperation was 85.6% (95% confidence limits, 72.8%, 98.4%) at 13 years. Five patients (10.2%) required valve replacement from 13 days to 75 months after the valve repair. Two patients had cerebral ischemic events as a result of cardiomegaly and atrial fibrillation. CONCLUSIONS: Valve repair for congenital mitral insufficiency gave adequate results in combination with commissure plication annuloplasty and other techniques with excellent long-term functional status.

Adolescent↗
PubMed1999

Investigation of albumin-synthesizing ability in rat cirrhotic liver-derived hepatocytes using primary hepatocyte culture.

BACKGROUND/AIMS: In cirrhosis, despite a decrease in the total number of hepatocytes, a normal serum albumin level is maintained during the compensatory stage of the disease in many cases. Therefore, to elucidate the mechanism in hepatocytes related to the regulation of the serum albumin level, the albumin-synthesizing ability of individual hepatocytes was investigated in cirrhotic rats. METHODS: Cirrhotic rats were prepared by oral administration of furfural to male Wistar rats for 20 weeks. Albumin-synthesizing abilities of liver and of isolated hepatocyte culture were evaluated by measuring the albumin concentration in blood and culture supernatant. Expressions of albumin mRNA were compared using Northern blotting. Furthermore, transcriptional activity of the albumin gene was measured using the promoter domain of the gene. RESULTS: The total number of hepatocytes in rat cirrhotic liver was significantly decreased compared to that in normal rat liver. However, there were no significant differences in levels of serum albumin or albumin mRNA expression between cirrhotic and normal liver. In primary hepatocyte culture, albumin mRNA expression, the amount of albumin secretion and the albumin promoter activity were clearly enhanced in cirrhotic hepatocytes compared to normal hepatocytes. CONCLUSION: Although the total number of hepatocytes was decreased in the rat cirrhosis models used in this study, the serum albumin level was maintained and albumin-synthesizing ability was enhanced at the transcriptional level in the individual hepatocytes. These results suggest that the maintenance of serum albumin levels in compensated cirrhosis may be due to enhanced albumin synthesis by the hepatocytes.

Animals↗
PubMed1999

The effect of exercise training on oxidative damage of lipids, proteins, and DNA in rat skeletal muscle: evidence for beneficial outcomes.

Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-related disorders. Molecular mechanisms that bring about these effects are not clear. In contrast, it has been claimed that some types of prolonged physical exertion are detrimental to health because active oxygen species are generated excessively by enhanced oxygen consumption. Using two age groups of rats, young (4 week) and middle aged (14 months), we investigated the effects of long-term swimming training on the oxidative status of phospholipids, proteins, and DNA. The concentration of thiobarbituric acid reactive substances and 4-hydroxynonenal protein adducts did not differ in the gastrocnemius muscle between exercised and nonexercised animals in the two age groups. The extent of carbonylation in a protein of molecular weight around 29 KDa and the amount of 8-hydroxydeoxyguanosine in nuclear DNA were smaller (p<.05) in the exercised rats than in the sedentary animals. Activities of DT-diaphorase (C1: 29.3+/-1.9; C2: 36.1+/-2.6; E1: 27.2+/-1.3; C2: 33.4+/-2.9 nmol/mg protein) and proteasome, a major proteolytic enzyme for oxidatively modified proteins were significantly higher in the exercised animals of both age groups (p<.05). The adaptive response against oxidative stress induced by moderate endurance exercise constitutes a beneficial effect of exercise.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

K-ras codon 12 and p53 mutations in biopsy specimens and bile from biliary tract cancers.

To evaluate whether it is useful for diagnosis to detect K-ras and p53 mutations in biopsy specimens and bile of biliary tract lesions, 12 cholangiocarcinomas (CC), eight cases of cholangitis, seven gallbladder carcinomas (GBC), seven gallbladder cholesterol polyps, four cases of adenomyomatosis of the gallbladder and five cases of cholecystitis were examined. K-ras and p53 mutations in bile were detected by a two-step polymerase chain reaction (PCR) and nested PCR-single-strand conformation polymorphism (SSCP) analysis. In addition, p53 protein expression in biopsy specimens from CC were examined by immunostaining. K-ras mutations at codon 12 were detected in 50% of CC and 57.1% of GBC in both biopsy specimens and bile. The incidence of p53 mutations was 33.3% in CC and 42.9% in GBC. p53 protein overexpression was observed in 60% CC biopsy specimens. In contrast, K-ras and p53 abnormalities were not detected in any non-neoplastic biliary tract lesion. K-ras and p53 mutations in biliary tract cancers showed the same mutation patterns in spite of differences in the collection methods used between bile and biopsy specimens or surgically resected tissue. Genetic analysis of K-ras and p53 mutations in biopsy specimens and bile may be useful for the diagnosis of biliary tract cancers, although it may be effectively limited to patients with advanced disease.

Base Sequence↗
PubMed1999

Upregulation of type I interferon receptor by IFN-gamma.

Type I interferon (IFN) receptor has a multichain structure composed of at least two distinct subunits, IFNAR-1 and IFNAR-2. In the present study, we demonstrated that IFN-gamma induced the expression of mRNA for IFNAR-1 and IFNAR-2 in a human hepatoma cell line, HepG2 cells. The induction was dose and time dependent. Because of this result, we examined the effect of combined treatment with type I IFN and IFN-gamma. The intracellular 2-5A-synthetase activity induced by combined treatment was significantly higher than that by type I IFN alone. This study suggests that combined treatment with type I IFN and IFN-gamma may be more effective than that of type I IFN alone and that the upregulation of type I IFN receptor may be one of the reasons. Our findings may have some relevance to the clinical use of IFN.

2',5'-Oligoadenylate Synthetase↗
PubMed1999

Fenestrated oculomotor nerve caused by meningioma around the cavernous sinus: a surgical pitfall in tumor removal: case report.

OBJECTIVE AND IMPORTANCE: The preservation of oculomotor nerves is one of the most significant issues regarding the resection of meningiomas around the cavernous sinus. CLINICAL PRESENTATION: We report the case of a patient whose oculomotor nerve was fenestrated, caused by a large meningioma around the cavernous sinus. The nerve function remained intact until surgery. INTERVENTION: During surgery, one trunk of the fenestrated nerve behind the tumor was sacrificed. The fenestrated shape of the nerve led us to the misjudgment that the preserved other trunk located along the upper margin of the tumor was the whole nerve. CONCLUSION: Although fenestrated oculomotor nerves may be rare, their possibility should be kept in mind during surgery around the cavernous sinus.

Aged↗
PubMed1999

Superoxide dismutase gene expression in skeletal muscle: fiber-specific adaptation to endurance training.

The effects of endurance training on the enzyme activity, protein content, and mRNA abundance of Mn and CuZn superoxide dismutase (SOD) were studied in various phenotypes of rat skeletal muscle. Female Sprague-Dawley rats were randomly divided into trained (T, n = 8) and untrained (U, n = 8) groups. Training, consisting of treadmill running at 27 m/min and 12% grade for 2 h/day, 5 days/wk for 10 wk, significantly increased citrate synthase activity (P < 0. 01) in the type I (soleus), type IIa (deep vastus lateralis, DVL), and mixed type II (plantaris) muscles but not in type IIb (superficial vastus lateralis, SVL) muscle. Mitochondrial (Mn) SOD activity was elevated by 80% (P < 0.05) with training in DVL. SVL and plantaris muscle in T rats showed 54 and 42% higher pooled immunoreactive Mn SOD protein content, respectively, than those in U rats. However, no change in Mn SOD mRNA level was found in any of the muscles. CuZn SOD activity, protein content, and mRNA level in general were not affected by training, except for a 160% increase in pooled CuZn SOD protein in SVL. Training also significantly increased glutathione peroxidase and catalase activities (P < 0.05), but only in DVL muscle. These data indicate that training adaptations of Mn SOD and other antioxidant enzymes occur primarily in type IIa fibers, probably as a result of enhanced free radical generation and modest antioxidant capacity. Differential training responses of mRNA, enzyme protein, and activity suggest that separate cellular signals may control pre- and posttranslational regulation of SOD.

Adaptation, Biological↗
PubMed1999

t(9;14)(p13;q32) involving the PAX-5 gene: a unique subtype of 14q32 translocation in B cell non-Hodgkin's lymphoma.

Newly identified t(9;14)(p13;q32) is a subtype of the well-defined 14q32 translocation and is closely associated with lymphoplasmacytic lymphoma (Revised European-American Classification of Lymphoid Neoplasms). The analysis of the breakpoint of t(9;14) unraveled its molecular structure as being the recombination of the PAX-5 gene on 9p13 with IgH locus located on 14q32. The molecular event does not seem to cause structural alteration of the protein product of PAX-5 and, instead, its deregulation is most likely the essential outcome of this translocation. In vitro experiments have shown that the overexpression of PAX-5 resulted in enhanced proliferation of B cells, implicating its potential capacity for lymphomagenesis. PAX-5 is crucial during most developmental stages of B cells mainly through regulating the expression of a variety of genes. Therefore, elucidating the nature of the altered expression of these downstream genes as well as the PAX-5 gene itself would be indispensable in clarifying the precise mechanism of lymphomagenesis caused by t(9;14).

Animals↗
PubMed1999

[Itraconazole-induced hypokalemia in a patient with pulmonary aspergilloma].

An 80-year-old man was admitted to the hospital with a diagnosis of pulmonary aspergilloma. A new azole antifungal agent, D 0870, was administered to the patient for 7 days orally, and itraconazole (400 mg/day) was started on March 5, 1997. After 1 month of chemotherapy, facial and pretibial edema were observed and the patient's serum potassium concentration decreased to 2.5 mEq/l. A chest radiograph disclosed cardiomegaly with cardiac effusion and right pleural effusion on admission. The serum potassium concentration rose after the cessation of itraconazole therapy. The serum ITCZ concentration remained high for 2 weeks after admission. Although reports of hypopotassemia induced by ITCZ are rare, we concluded that blood concentrations should be monitored more carefully when treating pulmonary aspergilloma patients with high-dose regimens of ITCZ.

Aged↗