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Biomedical subjects

K Nagashima

Publications and source records attributed to K Nagashima.

At least 19 recordsLinked to original sources
PubMed1999

Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus.

We investigated a role of chemokines in thymocyte trafficking. Genes encoding stromal cell-derived factor-1 and its receptor CXCR4 were detected in the cortex by in situ hybridization. Early immigrant cells did not express CXCR4, whereas their descendant CD44+CD25+CD4-CD8- cells did. CXCR4 expression was down-modulated when CD4+CD8+ double-positive cells became CD4+CD8- or CD4-CD8+ single-positive (SP) cells. Positively selected CD69+CD3intermediate cells gained CCR4, of which ligand, thymus activation-regulated chemokine, was expressed in the medulla. At the next developmental stage, CD69-CD3high cells lost CCR4 but gained CCR7. These results suggest that thymocytes use different chemokines along with their development. Blockade of chemokine receptor-mediated signaling by pertussis toxin perturbed the normal distribution of SP cells and resulted in the accumulation of SP cells in the cortex. Thus, a pertussis toxin-sensitive event controls the trafficking of SP cells across the corticomedullary junction.

Animals↗
PubMed1999

Analysis of human lymphotropic T-cell virus type II-like particle production by recombinant baculovirus-infected insect cells.

The molecular processes involved in retrovirus assembly and budding formation remain poorly understood. The gag-pro-pol genes of human lymphotropic T-cell virus type II (HTLV-II) are translated into Gag, Gag-Pro, or Gag-Pro-Pol by frameshift events. In the present study, we investigated the roles of the gag, pro, and pol regions of HTLV-II in viral particle formation using recombinant baculoviruses. In this study we could successfully produce mature HTLV-II viral particles containing core structures using a construct expressing the entire gag-pro-pol region. We also investigated the role of the pol region in particle formation. Deletion of the pol region affects viral particle assembly or release very little, indicating that the gag-pro region is sufficient for viral particle formation and maturation. Expression of the Gag proteins alone or Gag proteins with inactivated viral proteases (Pro) resulted in the formation of viral particles; however, these particles did not contain core structures. These results suggest the intracellular expression of Gag with Pro of HTLV-II is essential for the production of mature virus particles, whereas that of Pol is not.

Animals↗
PubMed1999

Augmented expression of macrophage migration inhibitory factor (MIF) in the telencephalon of the developing rat brain.

Macrophage migration inhibitory factor (MIF) has been characterized as a proinflammatory cytokine, hormone, and immunomodulator. We previously demonstrated the distribution of MIF in the adult rat brain and revealed its expression in neurons as well as glial cells. In this study, we investigated the localization of MIF in the developing rat brain from embryonic day (ED) 13 to ED19, and after birth from postnatal day (PD) 1 to PD28 using both immunohistochemistry and in situ hybridization. On ED16, the signals of MIF mRNA were high in the ventricular, subventricular, and intermediate zones of the telencephalon, in which 'neuropoietic' progenitor cells proliferate and migrate from the ventricular zone to the superficial layer in the cerebral cortex. The mRNA expression was detected throughout the postnatal period, and intense signals of the transcript were seen in the ventricle and in layers I, II and III of the cerebral cortex at PD5. Similarly, positive staining of MIF protein was seen in the ventricular zone by immunohistochemical analysis, although the positively stained area appeared to be smaller than the mRNA expression. Taken together, these results suggest that the increase in MIF mRNA in the developing brain reflects the growth and maturation of neurons and glial cells.

Animals↗
PubMed1999

Adult Leigh syndrome with mitochondrial DNA mutation at 8993.

Adult onset Leigh syndrome with a nucleotide (nt) 8993 mutation in mitochondrial (mt) DNA is reported. A 43-year-old woman with a 6-year-history of insulin-resistant diabetes mellitus developed muscular weakness, intractable nausea and vomiting, and anemia. These were followed vertigo, blindness, and deafness with nystagmus. Magnetic resonance imaging (MRI) revealed abnormal high intensities in the bilateral medial regions of the thalamus and periaqueductal gray matters. Autopsy disclosed well-demarcated necrotizing lesions with prominent capillaries in the areas detected by MRI, which were sufficiently diagnostic for Leigh syndrome. MtDNA analysis performed on DNAs extracted from formalin-fixed tissues including liver, heart, brain, muscle, kidney and pancreas showed a T-->G mutation at nt 8993. This is the first case of adult Leigh syndrome demonstrating on mtDNA mutations.

Adult↗
PubMed1999

Allelic variations of the D2 dopamine receptor gene in children with idiopathic short stature.

The D2 dopamine receptor (DRD2) plays a major role in growth hormone (GH) secretion. Recent reports indicate that Taq I A DRD2 gene alleles (A1 and A2) are related to the function of DRD2. Idiopathic short stature (ISS) is defined as short stature without accompanying malnutrition, chronic disease, and endocrinological disorders. However, some reports suggest that ISS is associated with a mild disturbance of GH secretion. In this study, we examined the notion that allelic variants of the DRD2 are associated with ISS. We studied 55 children with ISS aged 8.4 (SD 2.9) years; (group I) and 104 age-matched children of normal stature (group II). Informed consent was obtained from each child's parent or guardian. Genomic DNAs were extracted from peripheral mononuclear cells and amplified by polymerase chain reaction (PCR). The PCR products were digested by Taq1 and resolved by electrophoresis. The frequency of the A1 allel was significantly higher in group I (0.42) than in group II (0.26). The insulin-like growth factor (IGF)-I ratio (the ratio of the individual level to the normal mean value according to age at our laboratory center) was significantly lower in group I than in group II. When group I was subdivided into group A (with the A1 allele) and group B (with only the A2 allele), group A had a significantly lower peak GH response to the l-dopa test, lower levels of IGF-I, and retarded bone maturation. These findings indicate that polymorphism of the DRD2 gene may be one genetic factor that affects body height in childhood, acting through the hypothalamus (GH-releasing hormone)--pituitary (GH)--IGF-I axis.

Alleles↗
PubMed1999

Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarbox ylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury.

CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).

Animals↗
PubMed1999

Glial cell line-derived neurotrophic factor protects against delayed neuronal death after transient forebrain ischemia in rats.

Glial cell line-derived neurotrophic factor, a member of the transforming growth factor-beta superfamily, is a potent neurotrophic factor, which has a variety of biological activities that affect several types of neurons in both the central and peripheral nervous systems. In this study, we examined the effects of glial cell line-derived neurotrophic factor on delayed neuronal death in the hippocampal CA1 region of rats after transient forebrain ischemia. In the control rats pretreated with the vehicle, transient forebrain ischemia-induced delayed neuronal death in the hippocampal CA1 region was observed seven days after reperfusion. Pretreatment with glial cell line-derived neurotrophic factor (1.0 microg), which was directly microinjected into the right hippocampal CA1 region, gave significant protection against the delayed hippocampal neuronal death. On the contralateral side of the hippocampus, which was not injected with glial cell line-derived neurotrophic factor, delayed neuronal death similar to that seen in vehicle-treated control animals was observed. Intracerebroventricular glial cell line-derived neurotrophic factor (2.5 microg) injection also protected against delayed neuronal death. In addition, pretreatment with glial cell line-derived neurotrophic factor gave significant protection against apoptotic cell death induced by brain ischemia in the hippocampal CA1 region, as determined by in situ staining for DNA fragmentation. These findings suggest that glial cell line-derived neurotrophic factor plays an important role in delayed neuronal death induced by brain ischemia.

Animals↗
PubMed1999

Dysplastic gangliocytoma (Lhermitte-Duclos disease) associated with Cowden disease: report of a case and review of the literature for the genetic relationship between the two diseases.

We report a case of dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease, LDD). The patient also had cutaneous and mucosal hamartomas, adenomatous goiter, bilateral breast tumors, and gastrointestinal polyposis, indicating the diagnosis of Cowden disease (CD), the familial hamartoma syndrome. This was a rare sporadic case without any family history of CD, though CD is considered to be an autosomal dominant hereditary disease. Based on a thorough review of the previously reported cases, it is reasonable to consider that CD is inherited in autosomal dominant fashion through a CD gene (PTEN) containing a germline mutation, and that the occurrence of LDD is predicted on an additional somatic hit on the remaining normal CD allele or another unknown gene.

Adult↗
PubMed1999

Mechanism for the posture-specific plasma volume increase after a single intense exercise protocol.

To test the hypothesis that exercise-induced hypervolemia is a posture-dependent process, we measured plasma volume, plasma albumin content, and renal function in seven healthy subjects for 22 h after single upright (Up) or supine (Sup) intense (85% peak oxygen consumption rate) exercise. This posture was maintained for 5 h after exercise. Plasma volume decreased during exercise but returned to control levels by 5 h of recovery in both postures. By 22 h of recovery, plasma volume increased 2.4 +/- 0.8 ml/kg in Up but decreased 2.1 +/- 0.8 ml/kg in Sup. The plasma volume expansion in Up was accompanied by an increase in plasma albumin content (0.11 +/- 0.04 g/kg; P < 0.05). Plasma albumin content was unchanged in Sup. Urine volume and sodium clearance were lower in Up than Sup (P < 0.05) by 5 h of recovery. These data suggest that increased plasma albumin content contributes to the acute phase of exercise-induced hypervolemia. More importantly, the mechanism by which exercise influences the distribution of albumin between extra- and intravascular stores after exercise is altered by posture and is unknown. We speculate that factors associated with postural changes (e.g., central venous pressure) modify the increase in plasma albumin content and the plasma volume expansion after exercise.

Adult↗
PubMed1999

Role of serum leptin in the regulation of weight gain in early infancy.

We investigated the changes in the serum leptin concentration from birth to 30 days of age in order to determine the effects of leptin in early infancy. Twenty-seven Japanese term infants (12 boys and 15 girls) were examined. The serum leptin concentration at 3-6 days of age was significantly lower than that in cord blood (p < 0.0001) and was significantly higher at 30 days than at 3-6 days (p < 0.0001). The serum leptin concentration did not differ with gender or nutrition. The body weight gain and the magnitude of leptin rise that occurred between 3-6 and 30 days of age showed a significant positive correlation (r = 0.79; p < 0.0001). These changes in leptin levels suggest that leptin plays an important role in the regulation of weight gain in early infancy.

Aging↗
PubMed1999

The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells.

ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. The KATP channels in pancreatic beta-cells are thought to be critical in the regulation of glucose-induced and sulfonylurea-induced insulin secretion. Until recently, however, the molecular structure of the KATP channel was not known. Cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the sulfonylurea receptors (SUR1 and SUR2) has clarified the molecular structure of KATP channels. The pancreatic beta-cell KATP channel comprises two subunits: a Kir6.2 subunit and an SUR1 subunit. Molecular biological and molecular genetic studies have provided insights into the physiological and pathophysiological roles of the pancreatic beta-cell KATP channel in insulin secretion.

ATP-Binding Cassette Transporters↗
PubMed1998

Acceleration of apoptotic cell death after the cleavage of Bcl-XL protein by caspase-3-like proteases.

Interleukin-2 (IL-2)-dependent T cell clone CTLL-2 underwent apoptosis by deprivation of IL-2 from culture medium. The decrease in the anti-apoptotic Bcl-XL protein level was observed during apoptosis after IL-2 withdrawal. We found that Bcl-XL protein was cleaved to produce two 18 kDa fragments during CTLL-2 cell apoptosis. When the activation of caspases was suppressed by overexpressing human Bcl-2 protein or by the addition of caspase inhibitors, cleavage of Bcl-XL protein was suppressed in vivo. Bcl-XL protein cleavage by incubation with apoptosed CTLL-2 cell lysate was suppressed by the caspase-3/CPP32-specific tetrapeptide inhibitor in vitro. Therefore, caspase-3/CPP32-like proteases were activated and involved in the cleavage of Bcl-XL protein during CTLL-2 cell apoptosis. We found that Bcl-XL protein was cleaved by caspase-3/CPP32 at two sites in the loop domain (i.e., HLAD61/S and SSLD76/A). The transfection of the carboxy-terminal 18 kDa Bcl-XL fragment increased the sensitivity to apoptosis. These results indicate that caspase-3/CPP32-like proteases cleaved anti-apoptotic Bcl-XL protein and resulted in accelerated apoptotic cell death.

Animals↗
PubMed1998

Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice.

ATP-sensitive K+ (KATP) channels regulate many cellular functions by linking cell metabolism to membrane potential. We have generated KATP channel-deficient mice by genetic disruption of Kir6.2, which forms the K+ ion-selective pore of the channel. The homozygous mice (Kir6.2(-/-)) lack KATP channel activity. Although the resting membrane potential and basal intracellular calcium concentrations ([Ca2+]i) of pancreatic beta cells in Kir6.2(-/-) are significantly higher than those in control mice (Kir6.2(+/+)), neither glucose at high concentrations nor the sulfonylurea tolbutamide elicits a rise in [Ca2+]i, and no significant insulin secretion in response to either glucose or tolbutamide is found in Kir6.2(-/-), as assessed by perifusion and batch incubation of pancreatic islets. Despite the defect in glucose-induced insulin secretion, Kir6.2(-/-) show only mild impairment in glucose tolerance. The glucose-lowering effect of insulin, as assessed by an insulin tolerance test, is increased significantly in Kir6.2(-/-), which could protect Kir6.2(-/-) from developing hyperglycemia. Our data indicate that the KATP channel in pancreatic beta cells is a key regulator of both glucose- and sulfonylurea-induced insulin secretion and suggest also that the KATP channel in skeletal muscle might be involved in insulin action.

Animals↗
PubMed1998

Sustained release dosage of thyrotropin-releasing hormone improves experimental Japanese encephalitis virus-induced parkinsonism in rats.

Thyrotropin-releasing hormone (TRH) has been reported to have some possibilities toward the treatment of affective CNS disorders. However, long term treatments with daily injections are often required. Effects of TRH-SR (sustained release microspheres of TRH) which is encapsulated in copoly (dl-lactic/glycolic acid) using an in-water drying method were investigated in experimental Japanese encephalitis virus (JEV)-induced post-encephalitic parkinsonism rats by a pole test and high performance liquid chromatography (HPLC) with an electrochemical detector (ECD). We have already reported that in adult Fischer rats killed 12 weeks after infection with JEV at the age of 13 days a marked decrease of tyrosine hydroxylase-positive neurons was found in the bilateral substantia nigra. TRH-SR (3 mg/kg per 2 weeks, 4 times injections, subcutaneous [s.c.]) improved bradykinesia observed in the JEV-induced parkinsonism rats. Dopamine (DA) concentrations in the JEV-infected rats were profoundly reduced in the striatum as compared with controls. TRH-SR (3 mg/kg, once, s.c.) increased DA in the striatum 7 days after the injection. Although the pathomechanism of post-encephalitic parkinsonism is different from that of Parkinson's disease and TRH possesses a variety of CNS effects as well, these results suggest that TRH-SR play a possible role in the treatment of Parkinson's disease in addition to post-encephalitic parkinsonism as a supportive drug of L-DOPA.

Animals↗
PubMed1998

The HIV-inactivating protein, cyanovirin-N, does not block gp120-mediated virus-to-cell binding.

Concentrations of the potent, HIV(human immunodeficiency virus) inactivating protein, cyanovirin-N (CV-N), which completely inhibit HIV-1 infectivity, do not block the binding of soluble CD4-receptor (sCD4) to HIV-1 lysates nor the attachment of intact HIV-1 virions to several target T-cell lines. Furthermore, in contrast to the known disassociative effects of sCD4 on viral envelope glycoproteins, treatment of HIVRF with high concentrations of CV-N results in complete viral inactivation but without apparent shedding of gp120 or other ultrastructural changes. These results are consistent with the view that the virucidal effects of CV-N result from interference with step(s) in the fusion process subsequent to the initial binding of the virus to target cells.

Anti-HIV Agents↗
PubMed1998

Identification of macrophage migration inhibitory factor mRNA expression in neural cells of the rat brain by in situ hybridization.

Macrophage migration inhibitory factor (MIF) has been rediscovered as a hormone and immunomodulator as well as a proinflammatory cytokine. We investigated the expression of MIF protein and mRNA in the rat brain using optimized immunohistochemistry and in situ hybridization, respectively. By immunohistochemical analysis, we found that MIF protein was present in the epithelial cells of the choroid plexus and ependymal cells as well as astrocyte-like cells in the cerebral white matter and cortex. Tissue sections double-stained for glial fibrillary acidic protein (GFAP) and MIF revealed the presence of MIF protein in astrocytes, whereas this protein was scarcely identified in the neurons by staining using an anti-MIF antibody. We also measured the MIF content in the cerebrospinal fluid, which was 15.5 +/- 2.5 ng/ml (mean +/- SEM), comparable to the serum MIF value. In contrast, expression of MIF mRNA was found not only in astrocytes but also in neurons by the in situ hybridization technique. These results suggest that MIF plays a pivotal role as an immunomodulatory cytokine for inflammatory reactions and immune responses in the whole central nervous system.

Animals↗
PubMed1998

Reactivation of herpes simplex virus type 1 in patients with Bell's palsy.

Reactivation of herpes simplex virus type 1 (HSV-1) has been implicated in the pathogenesis of idiopathic peripheral facial palsy (Bell's palsy). The present study used the polymerase chain reaction (PCR) to analyze the saliva of patients with Bell's palsy for the presence of shed HSV-1. The study involved 47 patients with Bell's palsy, 24 patients with Ramsay Hunt syndrome, and 16 healthy HSV-seropositive volunteers. HSV-1 DNA was not detected in the saliva samples from HSV-seronegative patients. The prevalence of shed HSV-1 in patients with Bell's palsy (50%) was significantly higher than that in healthy volunteers (19%, p<0.05). When saliva samples were tested within 7 days after the onset of palsy, the prevalence of shed HSV-1 in patients with Bell's palsy (40%) was significantly higher than that in patients with Ramsay Hunt syndrome (7%, p<0.05). Furthermore, HSV-1 usually became undetectable by the second week after the onset of Bell's palsy when HSV-1 was detected during the acute phase of the disease. These findings strongly suggest that reactivation of HSV-1 is involved in the pathogenesis Bell's palsy, and indicate that PCR is a useful tool for early diagnosis of HSV-1 reactivation in patients with Bell's palsy.

Antibodies, Viral↗