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Biomedical subjects

M Fujimoto

Publications and source records attributed to M Fujimoto.

At least 55 records · Page 3Linked to original sources

In situ detection of collisionless reconnection in the Earth's magnetotail.

Magnetic reconnection is the process by which magnetic field lines of opposite polarity reconfigure to a lower-energy state, with the release of magnetic energy to the surroundings. Reconnection at the Earth's dayside magnetopause and in the magnetotail allows the solar wind into the magnetosphere. It begins in a small 'diffusion region', where a kink in the newly reconnected lines produces jets of plasma away from the region. Although plasma jets from reconnection have previously been reported, the physical processes that underlie jet formation have remained poorly understood because of the scarcity of in situ observations of the minuscule diffusion region. Theoretically, both resistive and collisionless processes can initiate reconnection, but which process dominates in the magnetosphere is still debated. Here we report the serendipitous encounter of the Wind spacecraft with an active reconnection diffusion region, in which are detected key processes predicted by models of collisionless reconnection. The data therefore demonstrate that collisionless reconnection occurs in the magnetotail.

Journal Article↗

Interaction of hnRNP A2/B1 isoforms with telomeric ssDNA and the in vitro function.

Overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, especially of B1 has been reported as a useful marker to detect cancers in early stage, although the biological reason is not clear. A2/B1 proteins were previously reported to bind telomeric DNA repeats. Alternative splicing of A2/B1 gene produces abundant A2, less abundant B1, and testis-specific minor isoforms B0a and B0b. In this study, B1 and B0b that have the N-terminal 12 amino acid insertion were suggested to have higher affinities to telomeric single-stranded DNA (ssDNA) than A2 and B0a. Kinetic analyses using purified B1 and B0b indicated that they interact dynamically with a single array of telomeric repeats. Furthermore, functional assays demonstrated that B1 and B0b bind with telomeric repeats in a tandem fashion and protect them from a nuclease and promote telomerase activity. A2/B1 proteins, especially B1 and B0b, may function as telomeric ssDNA-binding proteins in cancer and reproductive cells.

Alternative Splicing↗

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation.

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1-deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin.Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.

Animals↗

Nondenaturing two-dimensional electrophoretic analysis of loop-sheet polymerization of serpin, squamous cell carcinoma antigen-2.

Two homologous serine proteinase inhibitors (serpins), squamous cell carcinoma (SCC) antigen-1 and -2 were separated by nondenaturing two-dimensional electrophoresis combined with immunostaining to acquire further information on these proteins under physiological conditions. Polymers of SCC antigen-2 were detected in cytosolic extracts prepared from tumor tissues. The polymer formation of SCC antigen-2 was apparently decreased and the SCC antigen-2-synthetic peptide binary complexes were newly formed by the addition of synthetic peptide with sequences corresponding to residues from P14 to P2 in the reactive center loop of SCC antigen-2. On the other hand, the incubation with synthetic peptides having the sequence of the reactive center loop of SCC antigen-1 or antithrombin had no effect on polymerization of SCC antigen-2. These data suggest that the polymerization of SCC antigen-2 may occur spontaneously in vivo by the loop-sheet mechanism of serpin.

Antigens, Neoplasm↗

Clinical significance of surfactant protein D as a serum marker for evaluating pulmonary fibrosis in patients with systemic sclerosis.

OBJECTIVE: To determine the clinical significance of surfactant protein D (SP-D), a useful marker for evaluating various lung diseases, in patients with systemic sclerosis (SSc) and to clarify any clinical significance between SP-D and KL-6, which is known to be correlated with pulmonary fibrosis (PF) in SSc patients. METHODS: We used a specific enzyme-linked immunosorbent assay to measure serum SP-D levels in 83 patients with SSc and 31 healthy control subjects. RESULTS: The serum levels of SP-D were significantly higher in patients with SSc than in healthy controls (mean +/- SD 81.9+/-59.2 versus 34.8+/-13.7 ng/ml). Serum SP-D levels in patients with diffuse cutaneous SSc were significantly higher than those in patients with limited cutaneous SSc (98.8+/-72.1 versus 66.8+/-40.0 ng/ml). Serum SP-D levels in patients with PF were significantly elevated compared with those in patients without PF (99.7+/-64.1 versus 65.3+/-49.4 ng/ml). Moreover, the incidences of decreased percentage diffusing capacity for carbon monoxide and decreased percentage vital capacity were also significantly greater in patients with elevated SP-D levels than in those with normal levels (67% versus 43% and 36% versus 17%, respectively). There was a significant positive correlation between serum levels of SP-D and KL-6. Serum SP-D and KL-6 levels showed almost the same sensitivities and specificities in the diagnosis of PF (68% versus 73% and 70% versus 74%, respectively). These two markers also predicted PF to almost the same degree (31% versus 33%, respectively). CONCLUSION: These results suggest that SP-D, as well as KL-6, may be a useful serum marker for evaluating PF in patients with SSc.

Antibodies, Antinuclear↗

A Hodgkin's disease cell line, KM-H2, shows biphenotypic features of dendritic cells and B cells.

The origin of Reed-Sternberg (RS) cells, the neoplastic cells of Hodgkin's disease, has long remained controversial. Dendritic cells (DCs) are highly specialized antigen-presenting cells that have the unique capacity to prime naive T cells, and they may be progenitors of RS cells in a population of Hodgkin's disease cells. In this study, the KM-H2 cell line, previously established from a patient with Hodgkin's disease of mixed cellularity, was reevaluated for its cellular derivation, particularly in terms of DCs. KM-H2 cells were demonstrated to carry the newly proposed DC-associated molecules fascin, CD83, and DEC-205, as well as costimulatory molecules such as CD40, CD80, and CD86. In addition, KM-H2 cells were shown to be able to potently stimulate peripheral blood T cells and to have the strong endocytotic activity of fluorescein isothiocyanate-dextran. On the other hand, KM-H2 cells were shown to have variable-diversity-joining recombination of the immunoglobulin H gene, although they did not express any subclasses of immunoglobulin and they were negative for CD79a and CD79b. In addition, KM-H2 cells produced the messenger RNA of the Pax-5 gene. These findings lead to a hypothesis that KM-H2 cells originated from the cells that had differentiated through the possible common DC-B-cell progenitors along the newly proposed pathway.

Adult↗

Expression profiling of cancer-related genes in human keratinocytes following non-lethal ultraviolet B irradiation.

Ultraviolet B irradiation initiates and promotes skin cancers, photo-aging, and immune suppression. In order to elucidate the effect of these processes at the level of gene expression, we used cDNA microarray technology to examine the effect of ultraviolet B irradiation on 588 cancer-related genes in human keratinocytes at 1, 6, and 24 h post-irradiation with a mildly cytotoxic dose of ultraviolet B (170 mJ/cm(2)). The viability of the irradiated keratinocytes was 75% at 24 h post-irradiation. Various cytokeratins and transcription factors were up-regulated within 1 h post-irradiation. After 6 h, expression of a variety of genes related to growth regulation (e.g. p21(WAF1), notch 4, and smoothened), apoptosis (e.g. caspase 10, hTRIP, and CRAF1), DNA repair (ERCC1, XRCC1), cytokines (e.g. IL-6, IL-13, TGF-beta, and endothelin 2), and cell adhesion (e.g. RhoE, and RhoGDI) were altered in human keratinocytes. These data suggest the changes in a cascade of gene expression in human keratinocytes occurring within 24 h after UVB exposure. Although the roles of these cellular genes after UVB-irradiation remain to be elucidated, microarray analysis may provide a new view of gene expression in epidermal keratinocytes following UVB exposure.

Apoptosis↗

Pharmacokinetics of cefcapene pivoxil and AS-924 in gastrectomized patients.

To investigate the effects of gastrectomy on the absorption of drugs, the blood concentrations of the active moieties, cefcapene (CCAP) and ceftizoxime (CTIZ), were determined in 36 gastrectomized patients after oral administration of cefcapene pivoxil (CCAP-PI) and AS-924, prodrug type cephem antibiotics with different solubility-profiles. In patients with gastrectomy, the C(max) and AUC for CCAP-PI whose solubility depended on the acidity of gastric juice, were lower than in the controls; whereas those for AS-924 were comparable with values in the control group. The T(max) was affected by the extent of gastrectomy; the T(max) value was the lowest in patients who had undergone total gastrectomy Roux-Y, followed by Billroth II and Billroth I procedure of subtotal gastrectomy. These results indicate the need to select drugs and to instruct gastrectomized patients regarding dosage and administration, taking the pharmacokinetics of drugs into consideration.

Aged↗

Synthesis and structure-activity relationships of potent and orally active sulfonamide ETB selective antagonists.

The synthesis and structure activity relationships of a series of N-pyrimidinyl benzenesulfonamides as ETB selective antagonists are described. N-Isoxazolyl benzenesulfonamide 1a, previously reported, (1) was selected as a lead compound, and isosteric replacement of the isoxazole ring of 1a with a pyrimidine ring led to the discovery of the highly potent ETB selective antagonist 6e with oral bioavailability. Modification of the terminal aldehyde group at the 6-position of the pyrimidine ring was investigated, and malonate 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Compound 6e showed ETB antagonistic activity on in vivo evaluation.

Aldehydes↗

SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo.

Suppressor of cytokine signaling-1 (SOCS-1), also known as STAT-induced STAT inhibitor-1 (SSI-1), is a negative feedback molecule for cytokine signaling, and its in vivo deletion induces fulminant hepatitis. However, elimination of the STAT1 or STAT6 gene or deletion of NKT cells substantially prevented severe hepatitis in SOCS-1-deficient mice, while administration of IFN-gamma and IL-4 accelerated its development. SOCS-1 deficiency not only sustained IFN-gamma/IL-4 signaling but also eliminated the cross-inhibitory action of IFN-gamma on IL-4 signaling. These results suggest that SOCS-1 deficiency-induced persistent activation of STAT1 and STAT6, which would be inhibited by SOCS-1 under normal conditions, may induce abnormal activation of NKT cells, thus leading to lethal pathological changes in SOCS-1-deficient mice.

Animals↗

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT): initial aims and impact of the family history of type 1 diabetes mellitus in Japanese children.

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) was established in July 1994 with the chief aim to improve the quality of therapy for type 1 diabetes in children, an entity far less common in Japan than in Europe. We proposed four initial research topics: (i) to determine the current status of medical care and glycemic control in Japanese children with type 1 diabetes mellitus; (ii) to standardize the measurement of hemoglobin A1c; (iii) to establish a registry of a large cohort of patients in order to enable prospective studies to improve the quality of therapy for children with type 1 diabetes in Japan; and (iv) to enable participants of the JSGIT to hold a workshop twice annually. We registered a total of 736 patients from 45 hospitals throughout Japan. Intervention via insulin treatment was instituted after 2 yr for those patients whose hemoglobin A1c level was more than 8.1%. The proportion of patients receiving multiple insulin injections increased after intervention; however, average hemoglobin A1c in females remained significantly higher than in males. We identified two forms of diabetes in Japanese children: a rapidly progressive form and a more slowly progressive form. There was a significantly higher prevalence of a family history of diabetes in first-degree relatives in the slowly progressive form. These preliminary findings are the result of the first collaborative study of childhood diabetes in Japan.

Journal Article↗

Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloid beta protein-induced neuronal cell death.

1. The accumulation of amyloid beta protein (Abeta) in the brain is a characteristic feature of Alzheimer's disease (AD). Clinical trials of AD patients with nonsteroidal anti-inflammatory drugs (NSAIDs) indicate a clinical benefit. NSAIDs are presumed to act by suppressing inhibiting chronic inflammation in the brain of AD patients. 2. In the present study, we investigated effects of S-2474 on Abeta-induced cell death in primary cultures of rat cortical neurons. 3. S-2474 is a novel NSAID, which inhibits cyclo-oxygenase-2 (COX-2) and contains the di-tert-butylphenol antioxidant moiety. S-2474 significantly prevented neurons from Abeta(25 - 35)- and Abeta(1 - 40)-induced cell death. S-2474 ameliorated Abeta-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA completely. 4. Prior to cell death, Abeta(25 - 35) generated prostaglandin D(2) (PGD(2)) and free radicals from neurons. PGD(2) is a product of cyclo-oxygenase (COX), and caused neuronal cell death. 5. S-2474 significantly inhibited the Abeta(25 - 35)-induced generation of PGD(2) and free radicals. 6. The present cortical cultures contained little non-neuronal cells, indicating that S-2474 affected neuronal survival directly, but not indirectly via non-neuronal cells. Both an inhibitory effect of COX-2 and an antioxidant effect might contribute to the neuroprotective effects of S-2474. 7. In conclusion, S-2474 exhibits protective effects against neurotoxicity of Abeta. Furthermore, the present study suggests that S-2474 may possess therapeutic potential for AD via ameliorating degeneration in neurons as well as suppressing chronic inflammation in non-neuronal cells.

Amyloid beta-Peptides↗

Disruption of MSSP, c-myc single-strand binding protein, leads to embryonic lethality in some homozygous mice.

BACKGROUND: MSSP, c-myc single-strand binding protein, works as a factor for DNA replication, transcription, apoptosis induction, and myc/ras cooperative transformation. The cDNAs encoding four of the family proteins, MSSP-1, MSSP-2, Scr2 and Scr3, were cloned. These proteins possess two copies of putative RNA binding domains, RNP-A and RNP-B, and these RNA binding domains have been suggested to be indispensable to the functions of MSSP. RESULTS: To elucidate its role in vivo, we generated Mssp knockout mice by homologous recombination in embryonic stem cells. Although intercrossing of Mssp+/- mice gave rise to mice homozygous to the mutant Mssp allele (Mssp-/-) and the Mssp-/- mice, once born, did not display an overt phenotype, the ratio of littermates born among Mssp+/+, Mssp+/- and Mssp-/- mice was 1 : 1.6 : 0.5, which is not a typical Mendelian ratio. When E2.5 embryos from the pregnant mice were cultured in vitro for 5 days, the inner cell mass and trophoblast giant cells in wild-type (Mssp+/+) E2.5 embryos developed normally. However, Mssp-/- E2.5 embryos displayed significant defects in growth and development. Since Mssp was expressed in uterine gland-transported glycogen, we evaluated the hormonal state of wild-type and Mssp-/- mice. The progesterone concentration of Mssp-/- mice was decrease to 6.5% of that of wild-type mice at E2.5. CONCLUSIONS: These results suggest that the deletion of the mssp gene results in both the growth defect in the embryo and the hormonal defect in adult female mouse. The embryonic defect and a decreased concentration of progesterone in female mice reflect a development defect of the pre-implantation embryo in Mssp-/- mice, thereby leading to embryonic lethality.

Animals↗

Adult T-cell lymphoma involving the leptomeninges associated with a spinal cord schwannoma.

Adult T-cell lymphoma (ATL-L) developing initially in the meninges is rare. An autopsy case of ATL-L with an acute onset of meningitis and generalized lymphadenopathy in association with a cervical cord schwannoma is reported here. A 78-year-old woman with sensori-motor weakness of both arms over a 1-year period, developed febrile episodes and drowsiness with neck stiffness. Lumbar puncture revealed an increased protein content (161 mg/dL) and increased cell count (463/3) consisting of 99% of lymphocytes which contained atypical lymphocytes with multilobulated nuclei ('flower cells'), which are characteristic of ATL-L. Viral titers were positive only for HTLV-I antibodies (serum X 640: CSF X 16). Biopsy of an enlarged retroperitoneal lymph node revealed malignant lymphoma of the T-cell type. Brain MRI was negative, whereas an intradural extramedullary mass was found at the C4 level. With a diagnosis of ATL-L stage IV, chemotherapy was commenced, which was effective in reducing the generalized lymphadenopathy as well as the cervical mass and restoring the CSF findings to normality. The cervical cord mass was verified to be a solitary schwannoma, and ATL-L involvement was found not only in the leptomeninges, but also within the cervical cord schwannoma.

Aged↗

Early rehabilitation effect for traumatic spinal cord injury.

OBJECTIVE: To determine the natural course of traumatic spinal cord injury (SCI) and the effect of early rehabilitation on it. DESIGN: A retrospective, multicenter study. SETTING: Sixteen Rosai hospitals and 1 medical school. PARTICIPANTS: One hundred twenty-three SCI patients (104 men, 19 women; mean age, 48.8 +/- 17.7yr) enrolled. INTERVENTIONS: Dividing the subjects into an early rehabilitation group and a delayed group; differences were ensured by international classification of SCI. MAIN OUTCOME MEASURES: Using the American Spinal Injury Association (ASIA) classifications, the motor recovery rate (MRR) was defined as (ASIA motor score at discharge - ASIA motor score at admission)/(100 - ASIA motor score at admission). The regression lines for FIM instrument score and ASIA motor score were determined for 6 subgroups (early or delayed tetraplegia, central cord injury, paraplegia) by the MRR staging. The regression lines for physical or cognitive FIM score and ASIA motor score were also determined for 6 subgroups. RESULTS: Three stages were obtained: acute stage: 2 weeks postinjury; recovery stage: 2 weeks to 6 months postinjury; and chronic stage: more than 6 months postinjury. Regression lines showed that rehabilitation improved physical functional independence for ASIA motor score, especially in the early rehabilitation subgroups. There was no correlation between cognitive FIM score and ASIA motor score in 6 subgroups. CONCLUSION: Early SCI rehabilitation contributes to good physical activities of daily living for motor function.

Activities of Daily Living↗

Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist.

The pharmacologic properties of a novel nonpeptide endothelin (ET) receptor antagonist, S-1255 ([R]-[+]-2-[benzo(1,3)dioxol-5-yl]-6-isopropyl-4-[4-methoxyphenyl]-2H-chromene-3-carboxylic acid), was studied. [3H]S-1255 specifically bound to porcine aortic smooth muscle membranes expressing only ET(A) receptors with a Kd value of 0.39 nM. [3H]S-1255 binding was potently inhibited by ET-1 and selective ET(A) or ET(A)/ET(B) receptor antagonists, such as L-749329, SB209670, bosentan, and BQ-123, but the inhibitory effect of ET-3 and the selective ET(B) receptor antagonist, BQ-788, on the binding was weak. These inhibitory effects on [3H]S-1255 binding correlated well with those on [125I]ET-1 binding. S-1255 inhibited ET(A) receptor- and ET(B) receptor-mediated contractions in isolated rabbit femoral and pulmonary arteries with pA2 values of 8.8 and 6.3, respectively. The pA2 value of S-1255 for ET(B) receptor-mediated relaxation in isolated rabbit mesenteric artery was 7.4. Oral administration of S-1255 (0.3-10 mg/kg) caused dose-dependent inhibition of the pressor response to exogenous ET-1 (0.1 nmol/kg) in conscious normotensive rats, which was similar to that produced by intravenous administration (1 and 3 mg/kg). S-1255 (10 and 30 mg/kg, p.o.) significantly reduced blood pressure in deoxycorticosterone acetate-salt hypertensive rats from 6 h after administration, and the hypotensive effects were sustained up to 24-48 h. These results suggest that S-1255 is a highly potent and orally active ET(A) receptor antagonist.

Animals↗

Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: Recent evidence strongly suggests that endothelins (ETs) play an important role in the regulation of blood-brain barrier (BBB) functions. The aim of the present study was to evaluate the role of ETs on edema formation and BBB permeability change after cerebral ischemia/reperfusion. METHODS: We examined the brain tissue ET-1 content and evaluated the time and dose response of the therapeutic effects of the specific ET type A receptor (ET(A)) antagonist, S-0139, on brain edema formation, development of infarction, and disruption of BBB after 1 hour of middle cerebral artery occlusion (MCAO) in rats. RESULTS: After 1-hour MCAO and reperfusion, the brain ET-1 content did not change during the first 3 hours, increased at 6 hours, and rose almost continuously over 48 hours in the ischemic region as well as in the ischemic rim. Rats infused with S-0139 (0.03 to 1.0 mg/kg per hour) during reperfusion showed dose-dependent and significant attenuation of the increase in brain water content 24 hours after reperfusion. When the infusion of S-0139 was begun after 10 minutes and 1 hour of reperfusion, the brain edema formation and infarct size were significantly attenuated. Furthermore, posttreatment with S-0139 significantly attenuated the increased Evans blue dye-quantified albumin extravasation and improved the mortality of animals after cerebral ischemia/reperfusion. CONCLUSIONS: Our data demonstrate that infusion with S-0139, an ET(A) antagonist, results in significant reduction of brain injury and plasma extravasation after transient MCAO. Thus, ETs may contribute to cerebral ischemia/reperfusion injury at least partly by increasing the BBB permeability via ET(A)s.

Animals↗