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Biomedical subjects

K Nagashima

Publications and source records attributed to K Nagashima.

At least 73 records · Page 4Linked to original sources
PubMed2001

[Anesthetic management for thoracoscopic bullae resection using epidural anesthesia].

We report the anesthetic management for elective thoracoscopic bullae resection (TBR) using high thoracic epidural (TE) anesthesia in awake patients. Pain and cough reflex caused by the surgical procedure could be controlled well with high TE anesthesia using 20-25 ml of 2% lidocaine. Respiratory and hemodynamic conditions remained stable during the surgical procedure. High TE anesthesia using a large dose of local anesthetic is thought to be suitable for TBR.

Adult↗
PubMed2001

[Clinical result of thermochemoradiotherapy for advanced head and neck cancer].

Since 1986, we have applied thermochemo (CDDP) therapy combined with radiotherapy to 18 patients with 25 advanced and/or recurrent head and neck cancers (thermochemoradiotherapy: TCR). In this report, the effects of TCR were compared with those of radiochemotherapy (RC) without hyperthermia for 22 patients with 27 cancers before 1985 in our department. Thermochemotherapy was performed twice a week, for a total of 8.8 times on average. Three kinds of heating system were used: a radiofrequency system, a microwave system, and a RF interstitial system. In the TCR group, 11 lesions (44.0%) showed a complete response (CR), 12 lesions (48.0%) a partial response (PR), and 2 lesions (8.0%) no change (NC). Therefore, the total response rate was 92.0%. After treatment with only RC, 5 lesions (18.5%) showed a CR, 12 lesions (44.5%) a PR, and 10 lesions (37.0%) NC, giving a total response rate of 63.0%. There was a significant difference in the CR and total response rate between these two groups. Furthermore, the 5-year cumulative local control and survival rates in the TCR group were 68.2% and 44.4%, and in the RC group were 22.2% and 18.2%, respectively. There was a significant difference in the local control rate between these two groups. In conclusion, thermochemoradiotherapy is an effective strategy for patients with advanced head and neck cancers.

Adult↗
PubMed2001

[A survey of 3,303 6th-year medical students from 36 universities concerning knowledge of resuscitation--more than 80% of medical students can not perform standard cardiopulmonary resuscitation?].

Questionnaires on knowledge of resuscitation were distributed to 3,303 6th-year medical school students from 36 universities. The questionnaire included 13 questions based on the 1992 guidelines for cardiopulmonary resuscitation. From the 13 questions, each student was instructed to select 6 questions concerning assessment of consciousness level, method for confirming respiration, method for securing the airway, method for confirming circulation, pressure points for cardiac massage, and the ratio of respiration and cardiac massage. If all of these six questions could not be answered correctly, it was considered that the student was not able to perform resuscitation according to the guidelines. At least one incorrect answer was given to the six questions by 84% of students, indicating that most medical students are not able to actually perform standard resuscitation. Possible reasons for these results may be the lack of desire on the part of students to master resuscitation, confusion over new findings concerning resuscitation and guideline, insufficient understanding of the difference between the guidelines and new findings by educators, and restricted teaching time for resuscitation. Possible ways to improve the situation include efforts to make students more responsible to master resuscitation, efforts to enhance students' desire to learn, adoption of more practical education, inclusion of such questions in graduation examinations and the national examination for a medical license, adherence by educators to the guidelines, and efforts by educators to make a clear distinction between the guidelines and new findings. With new guidelines for cardiopulmonary resuscitation due out in the year 2000, methods for teaching resuscitation should be reconsidered in order to ensure that all medical students can competently perform resuscitation.

Adult↗
PubMed2001

[Effects of lumbar sympathetic ganglion block in a patient with acquired lymphangioma].

A 70-year-old woman developed lymphangioma following surgery for cervical cancer and subsequent radiotherapy. The operation was performed 12 years ago, and a swelling of lower extremities was recognized 8 years ago. Her lower extremities became greatly edematous, and leakage of lymph to the groin was observed. We performed bilateral lumbar sympathetic ganglion block. After the block, lymphedema was relieved dramatically, and the leakage of the lymph to the groin was gradually reduced. We conclude that lumbar sympathetic ganglion block may be very effective in some patients with acquired lymphangioma.

Aged↗
PubMed2001

New rat model for attention deficit hyperactive disorder (ADHD).

PURPOSE: In a strain of the Long-Evans Cinnamon (LEC) rats, we found spontaneously hyperactive animals designated as "wiggling," and established a congenic wiggling (Wig) rat by transferring the gene from the LEC to the Wistar King-Aptekman/Hokkaido (WKAH) strain. We evaluated the feasibility of the Wig rat for an animal model of human attention deficit hyperactive disorder (ADHD). METHODS: Mode of inheritance was examined by use of linkage analyses. Motor activity, behavior, and working memory were assessed by use of electric digital counters, open field test, and Y-maze and water-maze tests. RESULTS: The abnormal behavior, including hyperactivity, was transmitted in autosomal recessive mode. Diurnal and nocturnal motor activity of 12- to 14-week-old Wig rats was markedly higher than that of controls, and this hyperactivity was more prominent during nighttime than daytime. Ambulation in the open-field test was significantly increased in Wig rats, but rearing was decreased in Wig rats, compared with controls. Results of the Y-maze tests indicated that spontaneous alternation behavior was significantly impaired in Wig rats, although there was no difference in the total arm entries. The water-maze test could not be performed because, when exposed to water, Wig rats panicked and almost drowned. CONCLUSIONS: Wig rats are hyperactive and have impaired working memory and impulsive behavior, as assessed by the motor activity and open-field tests and the Y-maze test, and these abnormalities are transmitted by a single gene with Mendelian pattern. Wig rats represent an excellent animal model of human ADHD.

Animals↗
PubMed2000

Deficiencies of hippocampal Zn and ZnT3 accelerate brain aging of Rat.

We examined the link of hippocampal Zn to the functional impairments with aging using senescence-accelerated mouse prone 10 (SAMP10) with deficits in learning and memory. Zn in hippocampal mossy fiber pathway was less distributed in aged SAMP10 than that in the age-matched control. Furthermore, expression of Zn transporter 3, ZnT3, which plays to accumulate Zn in synaptic vesicles in the mossy fiber pathway, was markedly reduced in the hippocampal region even in young SAMP10. Moreover, excessive presynaptic release of glutamate as well as glycine and expression of glial fibrillary acidic protein, a marker of neuronal cell injury, were observed in the hippocampus of aged SAMP10 compared to the control. The present results suggest that age-dependent deficiencies of Zn in synaptic vesicles of the mossy fiber pathway induced by low expression of ZnT3 cause glutamatergic excitotoxicity in the hippocampal neurons and the deterioration of learning and memory in SAMP10.

Aging↗
PubMed2000

Neuronal circuitries involved in thermoregulation.

The body temperature of homeothermic animals is regulated by systems that utilize multiple behavioral and autonomic effector responses. In the last few years, new approaches have brought us new information and new ideas about neuronal interconnections in the thermoregulatory network. Studies utilizing chemical stimulation of the preoptic area revealed both heat loss and production responses are controlled by warm-sensitive neurons. These neurons send excitatory efferent signals for the heat loss and inhibitory efferent signals for the heat production. The warm-sensitive neurons are separated and work independently to control these two opposing responses. Recent electrophysiological analysis have identified some neurons sending axons directly to the spinal cord for thermoregulatory effector control. Included are midbrain reticulospinal neurons for shivering and premotor neurons in the medulla oblongata for skin vasomotor control. As for the afferent side of the thermoregulatory network, the vagus nerve is recently paid much attention, which would convey signals for peripheral infection to the brain and be responsible for the induction of fever. The vagus nerve may also participate in thermoregulation in afebrile conditions, because some substances such as cholecyctokinin and leptin activate the vagus nerve. Although the functional role for this response is still obscure, the vagus may transfer nutritional and/or metabolic signals to the brain, affecting metabolism and body temperature.

Animals↗
PubMed2000

Japanese encephalitis virus up-regulates expression of macrophage migration inhibitory factor (MIF) mRNA in the mouse brain.

Macrophage migration inhibitory factor (MIF) is known as a proinflammatory cytokine, glucocorticoid-induced immunomodulator, and pituitary hormone, and contributes to broad-spectrum immune and inflammatory response. To investigate the expression of MIF in the central nervous system in an event of viral infection, we evaluated MIF mRNA expression in the mouse brain infected with Japanese encephalitis virus (JEV). In situ hybridization revealed that MIF mRNA expression was significantly up-regulated in the whole brain by intracranial JEV inoculation at 2 days post-inoculation (d.p.i.). Neurons as well as glial cells expressed MIF transcripts in which some of these cells were co-labeled by double staining for JEV antigens and MIF mRNA. At 4 d.p.i., when typical symptoms of encephalitis were observed, JEV antigen-positive cells were much increased in parallel with enhanced MIF mRNA, consistent with the results of Northern blot analysis. Reverse transcription-polymerase chain reaction showed that MIF mRNA was minimally changed at 1 d.p.i. in comparison with that at 0 d.p.i., but markedly up-regulated after 2 d.p.i. and sustained up to 4 d.p.i. On the other hand, a significant increase of tumor necrosis factor (TNF)-alpha mRNA was observed after only 3 d.p.i. These data suggest the possibility that MIF is involved in virus-induced encephalitis with regard to not only immune responses in the early stage, but also the exacerbation of inflammation in concert with TNF-alpha in the late stages. This is the first evidence demonstrating that MIF is up-regulated in the case of virus-induced encephalitis, which should contribute to the further understanding of the pathological mechanism of JEV-induced encephalitis.

Animals↗
PubMed2000

Expression of Ets-1 angiogenesis-related protein in gastric cancer.

The Ets-1 transcription factor plays important roles in invasiveness and angiogenesis. Using automated immunodetection, we investigated Ets-1 expression and tumor microvessel density (MVD) in relation to the clinical significance of gastric cancer. The MVD of Ets-1-positive tumors was higher than that of Ets-1-negative tumors, but the difference was insignificant. The survival rate of patients with high-MVD tumors was significantly poorer than those with low-MVD tumors, and the survival rate of patients with Ets-1-positive tumors was significantly poorer than that of those with negative ones. These results indicate that Ets-1 expression is a useful marker for predicting the outcome for patients with gastric cancer.

Adenocarcinoma↗
PubMed2000

The Na+-driven Cl-/HCO3- exchanger. Cloning, tissue distribution, and functional characterization.

The Na(+)-driven Cl(-)/HCO(3)(-) exchanger is an important regulator of intracellular pH in various cells, but its molecular basis has not been determined. We show here the primary structure, tissue distribution, and functional characterization of Na(+)-driven chloride/bicarbonate exchanger (designated NCBE) cloned from the insulin-secreting cell line MIN6 cDNA library. The NCBE protein consists of 1088 amino acids having 74, 72, and 55% amino acid identity to the human skeletal muscle, rat smooth muscle, and human kidney sodium bicarbonate cotransporter, respectively. The protein has 10 putative membrane-spanning regions. NCBE mRNA is expressed at high levels in the brain and the mouse insulinoma cell line MIN6 and at low levels in the pituitary, testis, kidney, and ileum. Functional analyses of the NCBE protein expressed in Xenopus laevis oocytes and HEK293 cells demonstrate that it transports extracellular Na(+) and HCO(3)(-) into cells in exchange for intracellular Cl(-) and H(+), thus raising the intracellular pH. Thus, we conclude that NCBE is a Na(+)-driven Cl(-)/HCO(3)(-) exchanger that regulates intracellular pH in native cells.

Animals↗
PubMed2000

CalDAG-GEFIII activation of Ras, R-ras, and Rap1.

We characterized a novel guanine nucleotide exchange factor (GEF) for Ras family G proteins that is highly homologous to CalDAG-GEFI, a GEF for Rap1 and R-Ras, and to RasGRP/CalDAG-GEFII, a GEF for Ras and R-Ras. This novel GEF, referred to as CalDAG-GEFIII, increased the GTP/GDP ratio of Ha-Ras, R-Ras, and Rap1 in 293T cells. CalDAG-GEFIII promoted the guanine nucleotide exchange of Ha-Ras, R-Ras, and Rap1 in vitro also, indicating that CalDAG-GEFIII exhibited the widest substrate specificity among the known GEFs for Ras family G proteins. Expression of CalDAG-GEFIII was detected in the glial cells of the brain and the glomerular mesangial cells of the kidney by in situ hybridization. CalDAG-GEFIII activated ERK/MAPK most efficiently, followed by CalDAG-GEFII and CalDAG-GEFI in 293T cells. JNK activation was most prominent in cells expressing CalDAG-GEFII, followed by CalDAG-GEFIII and CalDAG-GEFI. Expression of CalDAG-GEFIII induced neuronal differentiation of PC12 cells and anchorage-independent growth of Rat1A cells less efficiently than did CalDAG-GEFII. Thus, co-activation of Rap1 by CalDAG-GEFIII apparently attenuated Ras-MAPK-dependent neuronal differentiation and cellular transformation. Altogether, CalDAG-GEFIII activated a broad range of Ras family G proteins and exhibited a biological activity different from that of either CalDAG-GEFI or CalDAG-GEFII.

Animals↗
PubMed2000

Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3.

We studied the regulation of three closely related members of Ras family G proteins, R-Ras, TC21 (also known as R-Ras2), and M-Ras (R-Ras3). Guanine nucleotide exchange of R-Ras and TC21 was promoted by RasGRF, C3G, CalDAG-GEFI, CalDAG-GEFII (RasGRP), and CalDAG-GEFIII both in 293T cells and in vitro. By contrast, guanine nucleotide exchange of M-Ras was promoted by the guanine nucleotide exchange factors (GEFs) for the classical Ras (Ha-, K-, and N-), including mSos, RasGRF, CalDAG-GEFII, and CalDAG-GEFIII. GTPase-activating proteins (GAPs) for Ras, Gap1(m), p120 GAP, and NF-1 stimulated all of the R-Ras, TC21, and M-Ras proteins, whereas R-Ras GAP stimulated R-Ras and TC21 but not M-Ras. We did not find any remarkable difference in the subcellular localization of R-Ras, TC21, or M-Ras when these were expressed with a green fluorescent protein tag in 293T cells and MDCK cells. In conclusion, TC21 and R-Ras were regulated by the same GEFs and GAPs, whereas M-Ras was regulated as the classical Ras.

Amino Acid Sequence↗
PubMed2000

Transcriptional activation of JC virus by human T-lymphotropic virus type I Tax protein in human neuronal cell lines.

Polyomavirus JC (JCV) causes the human demyelinating disease, progressive multifocal leukoencephalopathy (PML). The recent demonstration of cases of PML in association with human T-lymphotropic virus type I (HTLV-I) infection prompted us to examine whether the HTLV-I-encoded regulatory protein Tax activates JCV transcription. By employing a dual luciferase assay, we initially found that the expression of Tax activated the transcriptional potential of both early and late promoters of JCV in human neuronal but not in non-neuronal cells. We subsequently analyzed the mechanism of Tax-induced activation of the JCV promoter in neuronal cells with the following results: 1) the JCV promoter that lacks the NF-kappaB-binding motif could not be activated by Tax; 2) the overexpression of IkappaBalpha abolished Tax-induced transcriptional activation of the JCV promoter; 3) a Tax mutant (M22) lacking the potential for activation via the NF-kappaB pathway did not activate the JCV promoter. Furthermore, Tax enhances the gene expression of JCV T antigen and VP1. We examined mechanisms of the cell-specific activation of the JCV promoter by Tax. Electrophoretic mobility shift assay demonstrated the presence of Tax-bound protein(s) that were specifically present in non-neuronal cells. This study is the first demonstration of the activation of JCV promoter by HTLV-I Tax in an NF-kappaB-dependent manner.

Base Sequence↗
PubMed2000

Genotoxic and functional consequences of transplacental zidovudine exposure in fetal monkey brain mitochondria.

Mitochondrial toxicity was assessed in the brains of developing Erythrocebus patas monkey fetuses exposed in utero to the nucleoside analogue drug zidovudine (3'-azido-3'deoxythymidine or AZT). Pregnant E. patas monkeys were given 0 (n = 5), 10 (n = 3), and 40 (n = 3) mg of AZT/day, equivalent to 21 and 86% of the human daily dose, for the last half (about 10 weeks) of gestation. Mitochondria were isolated from fetal cerebrum and cerebellum at birth and mitochondrial morphology was examined in these tissues by transmission electron microscopy (TEM). Oxidative phosphorylation (OXPHOS) enzyme specific activities were measured spectrophotometrically. Mitochondrial DNA (mtDNA) integrity and quantity were determined by Southern blot and slot blot analysis. In the cerebral mitochondria, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (complex I) specific activity decreased by 25% in monkeys treated with 40 mg of AZT/day compared with unexposed monkeys (p > or = .05). At the same AZT dose in the cerebral mitochondria, succinate dehydrogenase (complex II) and cytochrome c reductase (complex IV)-specific activities showed dose-dependent increases (p > or = .05), compared with those in controls. In the cerebellum, no difference was seen in mitochondrial OXPHOS enzyme activities between unexposed and exposed fetuses. Furthermore, TEM demonstrated no difference in mitochondrial morphology in frontal cerebrum or cerebellum from unexposed and exposed fetuses, and all fetuses had similar amounts of mtDNA in both tissues. Cerebral mtDNA degradation was noted in the highest AZT dosage group, whereas mtDNA from cerebellum was uneffected. Thus, in fetal patas monkeys given a human equivalent daily dose of AZT during the last half of pregnancy, mitochondria in the fetal cerebrum appear to sustain moderate damage, while the fetal cerebellum mitochondria were not effected.

Animals↗
PubMed2000

The von Hippel-Lindau tumor suppressor targets to mitochondria.

Subcellular localization of von Hippel-Lindau (VHL) tumor suppressor may clarify its role in tumorigenesis. In rat kidney, we observed a granular cytoplasmic immunostaining of VHL, as seen in human tissues. The green fluorescent protein (GFP)-tagged VHL also appeared as cytoplasmic granules in vitro and was colocalized with a mitochondrion-selective dye. Immunogold electron microscopy localized VHL specifically to the mitochondrion. Mitochondria retaining GFP-VHL fusion protein, mimicking an insertional VHL mutant, displayed abnormal phenotypes. Among these, small mitochondria have been observed in clear cell renal carcinomas known to have frequent VHL alterations. Thus, VHL may contribute to tumorigenesis through mitochondria-based action.

Animals↗
PubMed2000

Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3'-azido-3'-deoxythymidine.

3'-azido-3'-deoxythymidine (AZT) is given to pregnant women positive for the human immunodeficiency virus type 1 (HIV-1) to reduce maternal-fetal viral transmission. To explore fetal mitochondrial consequences of this exposure, pregnant Erythrocebus patas monkeys were given daily doses of 1.5 mg (21% of the human daily dose) and 6.0 mg (86% of the human daily dose) of AZT/kg body weight (bw), for the second half of gestation. At term, electron microscopy of fetal cardiac and skeletal muscle showed abnormal and disrupted sarcomeres with myofibrillar loss. Some abnormally shaped mitochondria with disrupted cristae were observed in skeletal muscle myocytes. Oxidative phosphorylation (OXPHOS) enzyme assays showed dose-dependent alterations. At the human-equivalent dose of AZT (6 mg of AZT/kg bw), there was an approximately 85% decrease in the specific activity of NADH dehydrogenase (complex I) and three- to sixfold increases in specific activities of succinate dehydrogenase (complex II) and cytochrome-c oxidase (complex IV). Furthermore, a dose-dependent depletion of mitochondrial DNA levels was observed in both tissues. The data demonstrate that transplacental AZT exposure causes cardiac and skeletal muscle mitochondrial myopathy in the patas monkey fetus.

Animals↗
PubMed2000

Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720: effect of monotherapy and combined treatment with conventional drugs.

BACKGROUND: The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS: Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS: The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS: FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.

Animals↗