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Biomedical subjects

I Nakashima

Publications and source records attributed to I Nakashima.

At least 73 records · Page 4Linked to original sources
PubMed1999

Human parvovirus B19 infection in multiple sclerosis.

The association of human parvovirus B19 (PVB19) infection with the development of several systemic autoimmune diseases has been confirmed in other studies. To determine if there is any association of PVB19 infection with multiple sclerosis (MS), we studied the prevalence of serum anti-PVB19 IgG and IgM by an enzyme-linked immunosorbent assay and PVB19-specific DNA in the cerebrospinal fluid (CSF) by the polymerase chain reaction method in a total of 46 patients during exacerbation or remission of MS. Anti-PVB19 IgG was detected in 65.8% of the patients' sera. The percentage was significantly higher than that in age-matched healthy control subjects (40%; p = 0.019), but was not higher in patients with other neurological diseases (50%; p = 0.16). There was no correlation between serum anti-PVB19 IgG status and antinuclear antibodies or oligoclonal IgG bands in CSF. Serum anti-PVB19 IgM and PVB19 DNA in CSF were consistently negative in the patients during exacerbation of MS. Although MS patients may be commonly infected with PVB19, our results suggest that there is no active PVB19 infection during exacerbation of MS.

Adolescent↗
PubMed1999

4-hydroxynonenal triggers an epidermal growth factor receptor-linked signal pathway for growth inhibition.

Lipid peroxidation has been implicated in the pathogenesis of various diseases. As a major product of membrane lipid peroxidation, 4-hydroxynonenal (HNE) appears after various kinds of oxidative stress, and is known to induce cell growth inhibition. We here analysed the HNE-mediated signal transduction cascade for the growth inhibition of human epidermoid carcinoma A431 cells. HNE dose-dependently induced phosphorylation of multiple cellular proteins including epidermal growth factor receptor (EGFR) in A431 cells, and rapidly upregulated the catalytic actions of EGFR for autophosphorylation and for phosphorylation of casein as an exogenous substrate. Immunoblot analysis by use of HNE-specific antibody demonstrated the binding of HNE to EGFR along with its activation. This binding, which did not induce cross-linking of EGFR, caused a capping of the receptor on the cell surface which mimicked the capping induced by EGF. Phosphorylation and activation of EGFR were followed by phosphorylation of adaptor protein Shc and activation of MAP kinase. Both genistein as a wide spectrum protein tyrosine kinase inhibitor and AG1478 as a specific EGFR tyrosine phosphorylation blocker inhibited activation of EGFR and MAP kinase by HNE. The same inhibitors prevented HNE-mediated growth inhibition, suggesting a close linkage between EGFR/MAP kinase activation and growth inhibition after exposure to HNE. Our results suggest that EGFR may be one of the primary targets of HNE for an oxidative stress-linked cell growth inhibition.

Aldehydes↗
PubMed1999

Decrease in multiple sclerosis with acute transverse myelitis in Japan.

Acute transverse myelitis (ATM) may be a manifestation of multiple sclerosis (MS) and was reported to be more common among Japanese MS patients than in Caucasian MS patients. Recently there are arguments whether clinical manifestations of MS may have changed. Therefore, we studied the frequency of ATM in MS and the clinical subtypes of MS in 86 clinically definite MS patients whose onsets were in 1970-1979, 1980-1989, and 1990-1998 in Sendai City, Japan. Fifty-six of the patients were women and 30 were men. Forty-four patients had the conventional form of MS (C-MS) commonly seen in Western countries, and 42 had optic-spinal or spinal forms of MS (OSS-MS). Twenty MS patients had ATM, and all of them were belong to optic-spinal form of MS. ATM was not seen in any cases of C-MS. The mean onset age (years) of the clinical subtypes was 25.5 in C-MS, 34.1 in OSS-MS without ATM, and 30.9 in OSS-MS with ATM. Among the patients whose onset of the disease was in 1970-1979, 60.0% of them were cases of OSS-MS with ATM, but such cases were markedly decreased to 5.3% in 1990-1998. In contrast, the frequency of C-MS increased to 63.2% in 1990-1998 compared with 20.0% in 1970-1979. Analysis of the data by the year of birth of the patients showed similar results. Our data suggest that the frequency of ATM in MS markedly decreased, and that of C-MS increased during the last 30 years in Sendai, Japan. Since the genetic background of Japanese has not changed, some exogenous factors, such as food, infectious microorganisms, and chemicals in our environment, may be responsible for the change.

Adult↗
PubMed1999

Therapeutic efficacy of transcranial magnetic stimulation for hereditary spinocerebellar degeneration.

We applied transcranial magnetic stimulation (TMS) as a therapeutic approach for patients with spinocerebellar degeneration (SCD). The subjects were four familial SCD patients (three men and one woman) aged from 27 to 76 years old. They were genetically analysed as two spinocerebellar ataxia type 6 (SCA 6), one SCA 1, and one SCA 7. The durations of their illness ranged from 1 to 7 years. Ten consecutive magnetic pulses were delivered over the scalp corresponding to the right cerebellar hemisphere, the middle of the cerebellum and the left cerebellar hemisphere, respectively, every day for 21 days. In all patients, the time and the number of steps required for a 10 m walk examination were significantly decreased after TMS trial compared with those before TMS. The number of feasible steps in tandem gait test increased. The total length of tracing body balance for 30 seconds measured by gravinometer was significantly decreased. However, nystagmus, dysarthria or incoordination of the upper limbs did not change after TMS trial. It is of interest that the blood flow of the cerebellar hemisphere, putamen and pons were significantly increased during the TMS trial. Although we do not know the exact mechanism by which TMS improved the ataxic gait, we speculate the increase of blood flow in the cerebellum, putamen and pons takes part in the improvement. These findings suggest that TMS over the cerebellum may be an effective therapy for patients with SCD.

Adult↗
PubMed1999

Elevated plasma level of plasminogen activator inhibitor-1 (PAI-1) in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and one of the earliest changes in inflammatory focus involves the activation of vascular endothelial cells. We determined the plasma level of plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis and cell migration, in patients with MS. The level of plasma PAI-1 was significantly higher in active MS cases when compared to stable MS and controls. Plasma concentrations of tissue plasminogen activator, transforming growth factor beta-1, and lipoprotein-a remained normal in spite of disease activity. These results suggested that PAI-1 plasma levels are associated with MS disease activity and is a good marker for MS relapse.

Adult↗
PubMed1998

Level of HgCl2-mediated phosphorylation of intracellular proteins determines death of thymic T-lymphocytes with or without DNA fragmentation.

Exposure to Hg2+ at a wide range of concentrations (approximately 1-100 microM) more or less caused the death of murine thymic T-lymphocytes, and exposure to 1 microM but not 10 microM (or more) of Hg2- induced DNA fragmentation. Exposure of cells to Hg2+ caused phosphorylation of multiple cellular proteins at the tyrosine residue in a concentration-dependent manner. We found that not only the DNA fragmentation induced by 1 microM Hg2+ but also the cell death bypassing DNA fragmentation caused by 10 microM or more Hg2+ was partly inhibited by protein kinase inhibitors such as staurosporine and herbimycin A. This result suggested the involvement of a protein phosphorylation-linked signal in the mechanism of the Hg2+-mediated cell death with or without DNA fragmentation. Analysis of proteins by both one- and two-dimensional electrophoresis and immunoblot showed that a 52-kDa Shc protein was heavily phosphorylated by an early signal delivered by a high concentration of Hg2+, which also phosphorylated extracellular signal-regulated kinase 1 (ERK1; p44) and ERK2 (p42) of the mitogen-activated protein kinase (MAPK) family in a concentration- and time-dependent manner. The c-Jun amino terminal kinase (p54), which is a distant relative of the MAPK family, was also phosphorylated by the treatment with Hg2+. This eventually formed the signaling cascade that ended with a nuclear target by phosphorylating c-jun at the serine 73. This phosphorylation of c-jun was inhibited by staurosporine. These results suggest that a high level of Hg2+-mediated protein phosphorylation-linked signal induces rapid cell death bypassing DNA fragmentation, whereas a lower level induces cell death accompanying DNA fragmentation. This conclusion in turn implies that DNA fragmentation is not always a prerequisite for the signal transduction-dependent cell death of T-lymphocytes.

Animals↗
PubMed1998

Transgenic mouse model for skin malignant melanoma.

We report here on a novel metallothionein-I (MT)/ret transgenic mouse line in which skin melanosis, benign melanocytic tumor and malignant melanoma metastasizing to distant organs develop stepwise. The process of tumor development and its malignant transformation in this line may resemble that of the human giant congenital melanocytic nevus that is present at birth and that frequently gives rise to malignant melanoma during aging. We observed an increase in the expression level and activity of the ret transgene during the disease progression. That increase in transgene expression accompanied an activation of mitogen-activated protein kinases (MAPKs) and c-Jun as well as matrix metalloproteinases. These results suggest that progressive dysregulation of the expression level of the ret transgene might play a crucial role in the malignant transformation of melanocytic tumors developed in the MT/ret transgenic mouse line.

Animals↗
PubMed1998

Clinical and laboratory features of myelitis patients with anti-neutrophil cytoplasmic antibodies.

Although perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are associated with vasculitic neuropathy, their association with central nervous system (CNS) disorders has not been studied except for one report on optic-spinal type of multiple sclerosis associated with serum pANCA. We examined pANCA in sera from 98 patients with various CNS disorders, such as 58 MS, 17 myelitis, 12 HTLV-1 associated myelopathy, and 11 other CNS diseases using indirect immunofluorescence methods. The results showed serum pANCA to be positive in five patients with a peculiar type of myelitis, including two with MS and three with etiology unknown myelitis. All of these ANCA-positive patients were women and had acute or subacute myelopathy with various severities. MRI revealed segmental swelling of the spinal cord with T2 hyperintensity in the acute stage of the disease. Marked pleocytosis (227.8+/-101/mm3) and elevated protein level (128.8+/-52 mg/dl) in CSF were noted. Four of the patients had anti-nuclear antibodies and two had previous histories of symptoms suggesting autoimmune disorders. In a search for target antigens of pANCA, myeloperoxidase reactivity was found in the sera from two myelitis patients. Clinical and laboratory features of myelitis patients with pANCA in the present study are different from those of typical MS patients. Further study will be needed to delineate the role of pANCA in the pathogenesis of a specific type of myelitis.

Adolescent↗
PubMed1998

Functional differences among multiple isoforms of guinea pig decay-accelerating factor.

Decay-accelerating factor (DAF, CD55) is a membrane inhibitor that protects host cells from the autologous C-mediated attack. The guinea pig homologue of DAF consists of multiple isoforms generated by alternative splicing from a single copy gene. These isoforms are mainly comprised of a glycosylphosphatidylinositol (GPI)-anchored form and a transmembrane form (TM) that is not present in human DAF. Both forms occur in at least three variations that differ in the length of the Ser/Thr-rich region (termed ST-a, ST-ab, and ST-abc). We have transfected cDNAs of the six major isoforms into Chinese hamster ovary cells, and their functional differences were evaluated in inhibition of C-mediated cytolysis and C3 deposition, using the transfectants expressing DAF at the same level on cell membranes. The degree of inhibition in both the classical and alternative pathways differed according to the length of the ST region in the order of abc > ab > a in both GPI and TM forms. When GPI and TM forms were compared, those with the ab or abc variation exhibited almost the same activity, whereas a-TM was less efficient than a-GPI. Although several isoforms are expressed constitutively in most of tissues, spermatozoa preferentially express the abc-GPI isoform, suggesting that this isoform offers effective protection to spermatozoa in the female genital tract.

Animals↗
PubMed1998

Microglial NO induces delayed neuronal death following acute injury in the striatum.

We have established a novel injury model in the central nervous system by a stereotaxic injection of ethanol into rat striatum to induce necrosis. With this model, we clarify a function of inducible nitric oxide synthase (iNOS) in a healing mechanism around a necrotic lesion. A semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that the iNOS mRNA arose at 6 h, peaked at 24 h, and declined to a lower level 48 h after an intrastriatal 5-microL ethanol injection. From in situ hybridization, this iNOS mRNA was expressed in the area surrounding the injury. By immunohistochemistry, mononuclear cells at this boundary area of necrosis were stained with anti-iNOS antibody on the first day after the injury. These cells turned out to be reactive microglia from the positive staining of GSA-I-B4, ED-1 and OX-42. Haematoxylin-eosin (HE) staining showed that neurons in this boundary area gradually disappear up to 5 days after the injury with an increment of microglial cells, and this area became cavernous. Nuclei of neurons in this area were stained positive by the terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick end-labelling (TUNEL) assay on the first day after the injury. These TUNEL-positive neurons gradually disappeared toward the third day, while microglial cells increased. L-Ng-nitro-arginine methylester (L-NAME), a competitive NOS inhibitor, administration diminished the elimination of neurons by microglia in this boundary area surrounding necrosis. Microglial NO may act as a neurotoxic agent to eliminate damaged neurons near the necrosis in the form of delayed neuronal death, and may reintegrate the neuronal circuits with functionally intact neurons.

Animals↗
PubMed1998

The herbal medicine Sho-saiko-to inhibits growth and metastasis of malignant melanoma primarily developed in ret-transgenic mice.

Sho-saiko-to is the most popular herbal medicine in Japan. We investigated the anti-tumor and anti-metastatic effects of Sho-saiko-to and its chemically defined ingredients on the primary skin melanoma that developed in a metallothionein-I (MT)/ret transgenic mouse line and on a melanoma cell line (Mel-ret), which was derived from a primary tumor developed in a MT/ret transgenic mouse. In vitro, Sho-saiko-to suppressed the growth of Mel-ret cells more strongly than any single ingredient of Sho-saiko-to, although baicalin as one of several ingredients tested also suppressed it significantly. In vivo, Sho-saiko-to (i) significantly (p < 0.02) prolonged the onset of tumor development (1.5 mo), (ii) definitely retarded the transition to malignancy, (iii) significantly decreased the incidence of distant metastasis to brain (p < 0.002), kidney (p < 0.05), and liver (p < 0.05) at the malignant stage, and (iv) significantly (p < 0.02) prolonged life span (2.6 mo). Moreover, Sho-saiko-to and baicalin down-regulated the matrix metalloproteinase-2 and -9 expression levels, and upregulated their inhibitor expression level in both the primary tumors and Mel-ret cells. In conclusion, Sho-saiko-to displayed anti-tumor and anti-metastatic effects on melanoma with regulation of the balance of matrix metalloproteinase and tissue inhibitor of the matrix metalloproteinase levels.

Animals↗
PubMed1998

Induction of apoptosis and tyrosine phosphorylation of cellular proteins in T cells and non-T cells by stimulation with concanavalin A.

A high concentration (30 microg/ml or more) of Con A caused the death of not only thymocytes but also splenic cells of BALB/c mice, whereas a moderate concentration (3 microg/ml) of Con A induced proliferation of these cells. A high concentration of Con A also induced the death of splenic cells of athymic BALB/c-nu/nu mice and the bone marrow cells of BALB/c mice which mainly consist of non-T cells. However, any concentration (1-30 microg/ml) of Con A failed to induce the proliferation of these cells. Specific binding of tetrameric Con A to mannose-containing receptors was required for the induction of cell death. DNA fragmentation was observed by both laser flow cytometry and electrophoresis in Con A-stimulated T cells and non-T cells. This indicated that the mechanism of induction of apoptosis with Con A is not necessarily TCR-dependent. Con A induced tyrosine phosphorylation of a number of proteins in various types of cells. Interestingly, phosphorylation of the 40 kDa protein developed only in the thymocytes and spleen cells that contain T cells, whereas phosphorylation of the 80 and 120 kDa proteins appeared in both T cells and non-T cells. These results suggested that the Con A-induced apoptosis of T cells and non-T cells involves different but possibly mutually related protein tyrosine phosphorylation-linked signals.

Animals↗
PubMed1998

Evidence of potential regulation by interleukin-4 of the soluble intercellular adhesion molecule 1 level in patients with seasonal allergic rhinitis under provocation by a small amount of natural allergen.

Interleukin-4 (IL-4) and intercellular adhesion molecule 1 (ICAM-1) are assumed to be involved in the pathogenesis of allergic disease. In this study, we examined the potential link between IL-4 and soluble ICAM-1 (sICAM-1) levels in patients with allergic rhinitis. The levels of sICAM-1 and IL-4 in sera and in nasal epithelial lining fluids (ELF) from 12 patients with Japanese cedar pollinosis were measured preseason through postseason, and the results were compared with those from 7 healthy subjects. In sera from the allergic subjects, the levels of sICAM- 1 were upregulated during the early part of the season and downregulated during the middle of the season, with upregulation of the IL-4 levels. Moreover, a negative correlation was found between the serum sICAM-1 levels and serum IL-4 levels during the middle (r = -.80) and late (r = -.73) parts of the season. In ELF from allergic subjects, the levels of sICAM-1 were significantly upregulated during the early and middle parts of the season, and began to be downregulated during the late part of the season, with upregulation of the levels of IL-4. In conclusion, IL-4 possibly acts as a potential suppressor of sICAM-1 in the pathogenesis of seasonal allergic rhinitis, at least under provocation by a small amount of natural allergen.

Adult↗
PubMed1998

The herbal medicine sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas-mediated apoptosis and arresting cell cycle through downregulation of cyclin dependent kinases.

The anti-tumor effect and its mechanism of the herbal medicine sho-saiko-to were investigated on a murine malignant melanoma cell line (Mel-ret). Sho-saiko-to induced apoptotic cell death of Mel-ret cells with a definite increase of cell surface Fas antigen and Fas ligand (FasL). Sho-saiko-to arrested Mel-ret cells in G1 phase by decreasing the expression of cyclin-dependent kinase (cdk) 4 and its homologue cdk6. Kinase activities of cdk4 and cdk6 were identified to be downregulated by sho-saiko-to. Ingredient analysis revealed that baicalin is likely the main active constituent in the upregulation of Fas antigen and Fas ligand, while glycyrrhizin is the main constituent in the inhibition of cdks.

Animals↗