[Anesthesia for organ transplantations--special reference to pharmacokinetics of anesthetics and other agents used during perioperative period].
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Anesthesia↗
Biomedical subjects
Y Ohashi
Publications and source records attributed to Y Ohashi.
Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial.
BACKGROUND: Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence. METHODS: Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat. FINDINGS: 76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x10(10) [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45 [59%] vs 57 [77%]) [corrected] patients. Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09). INTERPRETATION: Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC.
Adult↗
Possible involvement of protein phosphorylation in the wound-responsive expression of Arabidopsis plastid omega-3 fatty acid desaturase gene.
The plastid omega-3 fatty acid desaturase (FAD7) catalyzes the conversion of linoleic acid to linolenic acid. Wounding enhances the expression of the FAD7 gene in leaves and induces its expression in stems and roots. The wound-induced expression of the FAD7 promoter was investigated in transgenic tobacco plants carrying the -825 Arabidopsis FAD7 promoter::beta-glucuronidase (GUS) fusion gene. The protein kinase inhibitor, staurosporine, and the protein phosphatase inhibitor, calyculin A, suppressed the wound induction of the FAD7 gene in stems. A tobacco mitogen-activated protein kinase (WIPK) was rapidly activated upon wounding not only in leaves but also in stems and roots, indicating that WIPK probably mediates the wound signals in most vegetative organs. The FAD7 promoter::GUS fusion gene was introduced into the transgenic tobacco plants in which the wipk gene was expressed constitutively at a high level or into the transgenic plants in which the wipk gene was suppressed possibly due to the transgene-induced gene silencing. The wound-induced expression of the FAD7 gene in stems was enhanced in the former transgenic tobacco plants and suppressed in the latter plants. These results suggest that the wound activation of the FAD7 promoter depends on both protein phosphorylation and dephosphorylation events especially in stems, and also that WIPK is involved in such signaling cascades.
Journal Article↗
A model for ZnII-containing-beta-lactamase: synthesis, X-ray crystal structure of a zinc(II) complex bearing thiol group and hydrolysis of phosphate diester.
A novel N3S1 typed tripodal ligand bearing an SH group, N-(mercaptoethyl)-di(2-pyridylmethyl)amine, DPASH, was prepared and its zinc(II) complex, [ZnII(DPAS)Cl], was structurally characterized by X-ray crystallography. [ZnII(DPAS)Cl] promoted hydrolysis of sodium bis(p-nitrophenyl)hydrogenphosphate), BNP-.
Crystallography, X-Ray↗
Xylem-specific expression of wound-inducible rice peroxidase genes in transgenic plants.
A peroxidase gene, poxA, was isolated from a rice (Oryza sativa L.) genomic library. The gene consists of four exons whose combined sequences were identical to that of the prxRPA mRNA whose levels were dramatically stimulated by wounding as well as by treatment of rice shoots with ethephon or UV irradiation [H. Ito, F. Kimizuka, A. Ohbayashi, H. Matsui, M. Honma, A. Shinmyo, Y. Ohashi, A.B. Caplan, R.L. Rodriguez, Molecular cloning and characterization of two complementary DNAs encoding putative peroxidases from rice (Oryza sativa L.) shoots, Plant Cell Rep. 13 (1994) 361-366]. The temporal and spatial expression properties of the poxA gene promoter as well as that from a second related peroxidase gene, poxN, were analyzed in transgenic tobacco and rice plants using the uidA gene as a reporter. In transgenic tobacco, UV- and wound-responsive cis-elements were located within 144 bp from the translational start codon of the poxA gene. The poxN promoter, however, was inactive in the heterologous host as no significant GUS activity was evident. On the other hand, chimeric uidA genes containing 2.2 kb of the poxA promoter or 1.4 kb of poxN promoter were active in transgenic rice plants. Both peroxidase promoters directed GUS activities in a spatial and tissue specific manner coincident with the expression patterns exhibited by their mRNAs. Histochemical analysis of transgenic rice plants showed that both peroxidase genes are expressed in the vascular bundles of the shoot apex and lamina joint, and in xylem-parenchyma cells of the leaf blade and sheath.
Journal Article↗
Diverse expression profiles of 21 rice peroxidase genes.
Secretory class III plant peroxidases (POXs) catalyze the oxidation of various reductants, and are encoded by a large multigene family. In rice, 42 independent expressed sequence tags for POXs have been identified. By RNA gel blot analysis using specific probes, we show here that 21 rice POX genes are unique in their developmental, organ specific and external stimuli-responsive expression. This would suggest that encoded POX isoenzymes are involved in a broad range of physiological processes in rice plants, individually.
Expressed Sequence Tags↗
Enhancing effect of electric stimulation on cytotoxicity of anticancer agents against rat and human glioma cells.
Electropermeabilization, or electroporation, has been used to deliver genes or drugs into the cytoplasm through micropores in the cell membrane caused by electric stimulation. The cytotoxic effect of a combination of anticancer agents with electric stimulation on rat C6 and human T98G glioma cells was examined in vitro. Electric pulses of 100 microsec square waves (eight cycles at 1 Hz) at various electric fields were delivered to C6 or T98G glioma cell suspensions in combination with several anticancer agents. Cell growth was evaluated 48-72 h after treatment. Measurement of cell lysis by electric stimulation was used to assess the optimum field strength for electroporation. Electric stimulation enhanced significantly the cytotoxicity of bleomycin to both C6 and T98G cells by more than 1000-fold using an electric field of 1750 V/cm for C6 cells and 1000 V/cm for T98G cells. The enhancement disappeared when bleomycin concentration was reduced to 100 pg/ml. The cytotoxicity of carboplatin was weakly but significantly enhanced by electric stimulation when a high dose of carboplatin was used. However, there was no enhancement of the cytotoxicity of nimustine hydrochloride (ACNU), etoposide, and vincristine. These results indicate that the combination of bleomycin and electroporation is the most potent candidate for electrochemotherapy in vivo.
Animals↗
Genetic analysis of SecA-SecY interaction required for spore development in Bacillus subtilis.
All spontaneous suppressor mutations obtained from a secA12 sporulation-defective mutant in Bacillus subtilis were localized in highly conserved membrane-spanning regions of SecY. The expression of early sporulation genes, kinA and spo0A encoding a histidine kinase and a transcription regulator for several sporulation genes, respectively, was restored in these suppressor mutants. These results indicate that the secretion function of translocase combined with Sec proteins is required for sporulation in B. subtilis.
ATP-Binding Cassette Transporters↗
Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase.
BACKGROUND: Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice. METHODS AND RESULTS: LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97+/-3 to 59+/-3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84+/-4 to 71+/-4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in Tg mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in Tg mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice. CONCLUSIONS: Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.
Animals↗
Cloning and DNA-binding properties of a tobacco Ethylene-Insensitive3 (EIN3) homolog.
Ethylene-Insensitive3 (EIN3) is a transcription factor that works in the ethylene signaling pathway in Arabidopsis. We isolated a tobacco cDNA encoding an EIN3 homolog as a sequence-specific DNA-binding protein. The encoded protein TEIL (tobaccoEIN3-like) shares 60% identity in amino acid sequence with EIN3. The DNA-binding domain was localized in the N-terminal half, which shows 92% identity in amino acid sequence with the corresponding region of EIN3, suggesting a conserved function in DNA-binding specificity. TEIL was indeed functionally similar to EIN3 because, like EIN3-overexpressing plants, transgenic Arabidopsis seedlings overexpressing TEIL cDNA exhibited constitutive triple response phenotypes. Random binding site selection analysis revealed that the consensus binding sequence for TEIL is AYGWAYCT, where Y and W represent A or C and A or T, respectively. A reporter plasmid containing the TEIL binding sites showed a 7- to 10-fold higher activation relative to that containing a mutated TEIL-binding sequence in tobacco protoplasts. A further 2- to 3-fold increase in activation was observed when a plasmid for TEIL overproduction was co-transfected, indicating that TEIL is a transcriptional activator. Moreover, nuclear extracts from ethylene-treated leaves showed an increase in DNA-binding activity specific to the TEIL-binding sequence, despite the level of the transcripts being unchanged. These observations suggest that TEIL functions as a transcription activator with a relatively redundant DNA-binding specificity, and its function may be regulated at least in part by modulation of the DNA-binding activity through ethylene signaling.
Amino Acid Sequence↗
Pollen immunotherapy inhibits T helper 1 and 2 cell responses, but suppression of T helper 2 cell response is a more important mechanism related to the clinical efficacy.
OBJECTIVES: To investigate the allergen-induced IgE synthesis and cytokine production by peripheral blood mononuclear cells from patients with seasonal allergic rhinitis due to Japanese cedar (Cryptomeria japonica) pollens and to elucidate the immunological mechanisms related to the clinical efficacy of immunotherapy (IT) for seasonal allergic rhinitis. DESIGN: This study included 51 patients with seasonal allergic rhinitis due to the pollen and 8 nonatopic healthy volunteers (nonatopic group). Thirty-nine patients had been undergoing IT using the pollen extracts for various lengths of time (IT group). The remaining 12 patients had never been treated with IT (untreated group). Peripheral blood mononuclear cells (3.3 x 10(6) cells per milliliter) from each individual were cultured with Cry j 1, 4.17 microg/mL. After 96 hours, culture supernatants were harvested to determine the concentrations of IgE, interleukin (IL) 5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). RESULTS: The levels of IgE (P = .02), IL-5 (P<.01), and TNF-alpha (P = .05) were significantly higher in the untreated group than in the nonatopic group. The levels of IFN-gamma did not differ significantly between the untreated and the nonatopic groups (P = .19). The levels of IgE, IL-5, and IFN-gamma, but not of TNF-alpha, were inversely correlated with the duration (in years) of IT, and none of the levels of IgE (P = .74), IL-5 (P = .15), IFN-gamma (P = .61), and TNF-alpha (P = .55) differed significantly between the nonatopic group and those who had been treated with IT for 10 years or more. The levels of IL-5 were significantly lower in the good responders than in the poor responders to IT (P<.001), whereas the levels of total IgE (P = .20), IFN-gamma (P = .16), and TNF-alpha (P = .14) did not differ significantly between them. CONCLUSION: The mechanisms responsible for the clinical efficacy of pollen IT are principally related to the tolerance or anergy of T helper 2 cells.
Adult↗
Allergen-induced mRNA expression of IL-5, but not of IL-4 and IFN-gamma, in peripheral blood mononuclear cells is a key feature of clinical manifestation of seasonal allergic rhinitis.
OBJECTIVES: To investigate the allergen-induced messenger RNA (mRNA) expression of interleukin (IL) 4, IL-5 and interferon gamma (IFN-gamma) in peripheral blood mononuclear cells from individuals sensitized by Japanese cedar (Cryptomeria japonica) pollens, and to elucidate the clinical role of IL-4, IL-5, and IFN-gamma in the allergen sensitization and clinical manifestation of allergic disorders. DESIGN: This study included 30 patients sensitized to the pollen and 14 nonatopic healthy volunteers. Peripheral blood mononuclear cells (1.0 x 10(6) cells/mL) of each individual were cultured at 37 degrees C for 24 hours in the presence of 10 microg/mL of Cry j 1, a major allergen of the pollens. Total cellular RNA was extracted from the peripheral blood mononuclear cells, and IL-4, IL-5, and IFN-gamma mRNA expression was determined with a reverse transcriptase polymerase chain reaction. RESULTS: From the results of a survey of symptom diary cards and interviews regarding nasal symptoms during the pollen season in 1998, we found that 20 patients (symptomatic group), but not 10 patients (asymptomatic group), had typical symptoms of seasonal allergic rhinitis. Interleukin 4 mRNA was not expressed in the nonatopic subjects but was expressed in 9 asymptomatic patients and in 17 symptomatic patients. Interleukin 5 mRNA was exclusively expressed in the symptomatic patients. Interferon gamma mRNA expression did not differ significantly among the nonatopic subjects, asymptomatic patients, and symptomatic patients. CONCLUSIONS: This study has clearly highlighted an interesting and new concept that IL-4 is implicated in allergen sensitization but not in clinical manifestation, and that IL-5 may not be a feature of atopy in itself but seems to be a hallmark of clinical manifestation of ongoing atopic diseases.
Adolescent↗
Mitogen-activated protein kinases and wound stress.
One of the most severe environmental stresses that plants encounter during their life cycle is wounding. Plants respond to wound stress by activating a set of genes that encode proteins involved in healing injured tissues. In recent years, mitogen-activated protein kinases have been implicated to be key signal molecules in the initial signal transduction pathways that mediate this stress to expression of genes.
Adaptation, Physiological↗
Characterization of the gammac chain among 27 unrelated Japanese patients with X-linked severe combined immunodeficiency (X-SCID).
X-linked severe combined immunodeficiency (X-SCID) is a rare fatal disease that is caused by mutations in the gene encoding the gammac chain. In this study, 27 unrelated Japanese patients with X-SCID were examined in terms of their genetic mutations and surface expression of the gammac chain. Among 25 patients examined, excluding two patients with large deletions, 23 different mutations were identified in the IL2RG gene, including 10 novel mutations. One patient bearing an extracellular mutation and all three of the patients bearing intracellular mutations after exon 7 expressed the gammac chain on the cell surface. Overall, 84% of patients lacked surface expression of the gammac chain leading to a diagnosis of X-SCID.
Antibodies, Monoclonal↗
Beta 1-integrin-mediated cell signaling in T lymphocytes.
beta1-integrins play crucial roles in a variety of cell processes such as adhesion, migration, proliferation, and differentiation of lymphocytes. For understanding the molecular mechanisms of these various biological effects, it may be particularly important to analyze cell signaling through the beta1-integrins. Our previous study had shown that PLC-gamma, pp125FAK (focal adhesion kinase), pp105, paxillin, p59fyn, p56lck and ERK1/2 are phosphorylated in their tyrosine residues upon engagement of beta1-integrins. We identified pp105 as Cas (Crk-associated substrate)-related protein and successfully cloned its cDNA. pp105 is a Cas homologue predominantly expressed in the cells of lymphoid lineage, which led us to designate it as Cas-L. Like p130Cas, Cas-L contains a single SH3 domain and multiple SH2 binding sites (YXXP motif), which is suggested to bind SH2 domains of Crk, Nck, and SHPTP2. Subsequent studies revealed that pp125FAK binds Cas-L on its SH3 domain and phosphorylates its tyrosine residues upon beta1-integrin stimulation. Since Cas-L is preferentially expressed in lymphocytes, it is conceivable that Cas-L plays an important role in lymphocyte-specific signals. We have shown that Cas-L is involved in the T-cell receptor (TCR)/CD3 signaling pathway as well as the beta1-integrin signaling pathway. Cas-L is transiently phosphorylated following CD3 cross-linking, and tyrosine-phosphorylated Cas-L binds to Crk and C3G. Furthermore, a Cas-L mutant (Cas-LDeltaSH3), which lacks the binding site for FAK, is still tyrosine-phosphorylated upon CD3 cross-linking, but not upon beta1-integrin cross-linking, suggesting that FAK is not involved in CD3-dependent Cas-L phosphorylation. Finally, we have identified a crucial role of Cas-L in beta1-integrin-mediated T-cell co-stimulation. beta1-integrins have known to provide a co-stimulus for TCR/CD3-driven interleukin-2 production and proliferation of peripheral T-cells. We have found that this co-stimulatory pathway is impaired in the Jurkat T-cell line, and that the expression level of Cas-L is reduced in Jurkat cells compared with peripheral T-cells. The transfection of Cas-L cDNA into Jurkat cells restored the beta1-integrin-mediated co-stimulation, while the transfection of Cas-LDeltaSH3 mutant failed to do so, showing a contrast to the case with CD3-mediated signaling. These results indicate that Cas-L plays a key role through the association and phosphorylation by FAK in the beta1-integrin-mediated T-cell co-stimulation. Taken together, Cas-L might be the bi-modal docking protein that assembles the signals through beta1-integrins and TCR/CD3, and participates in a variety of T-cell functions.
Animals↗
Circadian and senescence-enhanced expression of a tobacco cysteine protease gene.
A cDNA clone encoding a cysteine protease was isolated from a tobacco cDNA library, utilizing as a probe a PCR fragment obtained from degenerated primers based on the conserved sequences of plant cysteine protease genes. A putative protein encoded by the clone NTCP-23 had an amino acid sequence with significant similarities to those of plant senescence-associated cysteine proteases and mammalian cathepsin H. Northern blot analysis showed that NTCP-23 mRNA is expressed in all organs and the mRNA and protein expression is enhanced during natural senescence. We propose that NTCP-23 is responsible for amino acid remobilization especially in senescencing leaves. Furthermore, it was found that the mRNA expression follows a circadian rhythm and is reduced by continuous darkness, wounding and hypersensitive reaction (HR). NTCP-23 is the first cysteine protease whose mRNA expression has been shown to be temporarily reduced by wounding.
Amino Acid Sequence↗
A prospective study of interferon therapy modified by pre-treatment viral load in cirrhotic patients. Tokyo-Chiba Hepatitis Research Group.
BACKGROUND/AIMS: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. METHODS: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with "low" viral load (< or = 10(5.8) copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with "high" viral load (< or = 10(6.3) copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1,404 MU). RESULTS: HCV-RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with "low" viral load, in contrast to 14% in patients with "high" viral load. Sustained virological response was found in 40% of patients with "low" viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with "high" viral load. Viral eradication was found in approximately 50% of patients having a low virus load (< or = 10(4.3) copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. CONCLUSIONS: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12-month course of intensive IFN therapy. This result indicates that there is a certain cut-off level of HCV RNA load which can not be eradicated.
Adult↗
Allergen induced mRNA expression of interleukin-5, but not of interleukin-4 and interferon-gamma, in peripheral blood mononuclear cells obtained before the pollen season predicts the clinical efficacy of immunotherapy for seasonal allergic rhinitis.
The primary aim of this study was to investigate whether the allergen-induced synthesis of cytokines by peripheral blood mononuclear cells (PBMCs) obtained immediately before the pollen season could predict the clinical efficacy of immunotherapy during the following pollen season. PBMCs (1.0 x 106 cells/ml) were obtained from 17 nonatopic subjects and from 60 patients receiving immunotherapy for seasonal allergic rhinitis (caused by Japanese cedar pollens) immediately before the pollen season of 1998, and were cultured for 24 h in the presence of 10 mg/ml of Cry j 1, a major allergen of Japanese cedar pollens, at 37 degrees C in a fully humidified 5% CO2 atmosphere. Total cellular RNA was extracted from the PBMCs, and the allergen-induced interleukin (IL)-4, IL-5 and interferon-gamma (IFN-gamma) mRNA expression was determined using a reverse transcription-polymerase chain reaction. According to the nasal symptoms during the pollen season of 1998, the 60 patients on immunotherapy were divided into 36 good responders (who had no nasal symptoms and no requirement for rescue medications) and 24 poor responders who needed rescue medications to control nasal symptoms. Neither IL-4 mRNA nor IL-5 mRNA was expressed in any of the 17 nonatopic individuals. By contrast, IL-4 mRNA was expressed in 26 good responders and in 22 poor responders, and IL-5 mRNA was expressed in eight good responders (22.2%) and in 23 poor responders (95.8%). IFN-gamma mRNA was expressed in four nonatopic subjects, in nine good responders and in seven poor responders. The expression of IFN-gamma did not differ significantly among the nonatopic subjects, the good responders and the poor responders. The mRNA expression of IL-5 (P < 0.0001), but not of IL-4 (P = 0.0999) and IFN-gamma (P = 0. 7713), differed significantly between the good and poor responders. Therefore, our study has highlighted that positive expression of IL-5 mRNA in PBMCs sampled immediately before the pollen season could be predictive of a poor clinical outcome of immunotherapy during the following pollen season and that the down-regulation of IL-5 mRNA expression in PBMCs could be an important mechanism of pollen immunotherapy related to the clinical efficacy.
Actins↗