High-dose ethosuximide for epilepsy in Angelman syndrome: implication of GABA(A) receptor subunit.
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Angelman Syndrome↗
Biomedical subjects
M Toyoshima
Publications and source records attributed to M Toyoshima.
Expression of three extracellular matrix degradative enzymes in bladder cancer.
The relationship between expression of extracellular matrix degradative enzymes, angiogenesis and survival of multistage bladder cancer was determined. Expression of 3 extracellular matrix degradative enzymes (metalloproteinase-2, -9 and heparanase) and microvessel formation were examined in 40 resected bladder cancer specimens by immunohistostochemic staining, and then the association of the enzyme expression with angiogenesis and various stages of cancer was investigated. Heparanase protein expression in muscular invasive or lymph-node metastatic cancer was significantly higher than in superficial or nonmetastatic cancer, respectively (69% vs. 8%, p < 0.001, and 80% vs. 40%, p = 0.028, respectively). Interestingly, heparanase was expressed at much higher levels than matrix metalloproteinase-2 and -9. The mean microvessel count in cancers with heparanase expression was significantly higher than that in cancers without heparanase expression (32.3 +/- 18.2 vs. 5.5 +/- 6.1, p = 0.0008). The microvessel formation was not associated with the expression of matrix metalloproteinase-2 and -9. The cancer-specific and overall survival rates of patients with heparanase expression were significantly lower than those of patients without it (p = 0.0001 and p = 0.0008, respectively). Multivariate analysis showed that heparanase expression was a significantly independent prognostic factor for both cancer-specific (p = 0.0047) and overall survival (p = 0.0200). Our study suggested that heparanase plays important roles in invasion, angiogenesis and metastasis of bladder cancer, and thus, this molecule could be a new molecule to inhibit invasion, angiogenesis and metastasis of bladder cancer. Moreover, our results indicate that expression of heparanase could be a new prognostic factor of this disease.
Adult↗
Wegener's granulomatosis responding to antituberculous drugs.
We present a case of Wegener's granulomatosis (WG) that responded to antituberculous drugs. A 44-year-old woman with multiple nodules on chest radiograph received a diagnosis of pulmonary tuberculosis because open-lung biopsy specimens showed caseous granulomas. Her chest shadows underwent repeated resolution after the start of antituberculous treatment, and relapse after the cessation of the drugs. Antineutrophil cytoplasmic antibody was positive (14 enzyme-linked immunosorbent assay units), and the second lung biopsy specimens showed necrotizing granulomas and vasculitis without pathogenic organisms. Thus, the patient received a diagnosis of WG and was successfully treated with trimethoprim/sulfamethoxazole 10 years after her initial evaluation. Antituberculous drugs were effective in this case of WG.
Adult↗
[Mitochondrial DNA T to G mutation 8993 in Leigh encephalopathy and organic aciduria].
We report a 10-month-old female infant with Leigh encephalopathy caused by a T to G mutation at nucleotide 8993 of mitochondrial DNA. Initial manifestations were diarrhea and pyrexia, followed by disturbance of consciousness. Blood chemistry showed lactic acidosis, and cranial T2 weighted magnetic resonance imaging demonstrated symmetric high-intensity areas in the basal ganglia, consistent with Leigh encephalopathy. Analysis of urinary organic acids revealed a increase of alpha-ketoglutamate. Derivatives of branched chain amino acids, which accumulate in maple syrup disease, were also increased. Lipoamide dehydrogenase (E3) deficiency was initially suspected; however, normal activity of pyruvate dehydrogenase complex excluded the diagnosis. The organic aciduria disappeared after two weeks. The CNS lesions in our case were observed more prominently in the floor of the bilateral frontal lobes than in the globus pallidus and putamen. In this case, mitochondrial DNA mutation may have caused organic aciduria and the atypical imaging findings.
DNA, Mitochondrial↗
Heparanase protein and gene expression in bladder cancer.
PURPOSE: We determined the association of heparanase protein and messenger (m)RNA expression with bladder cancer invasion and metastasis. MATERIALS AND METHODS: The expression of heparanase protein and mRNA was assessed by immunohistochemical staining and in situ hybridization, respectively, in 67 bladder cancer specimens resected at various stages of disease. To our knowledge this is the first systematic study of heparanase protein and mRNA expression in human bladder cancer. RESULTS: The expression of heparanase protein in muscular invasive bladder cancer was significantly higher than in superficial cancer (68% versus 19%, p = 0.0001). It was higher in the primary tumor of patients with lymph node metastatic cancer than those with nonmetastatic cancer (80% versus 37%, p = 0.0006). In high grade disease it was significantly higher than in low grade disease (79% versus 29%, p = 0.0001). The expression of heparanase mRNA was also significantly higher in stage pT3 or greater than in stage pT2 or less bladder cancer (96% versus 33%, p = 0.0003). In metastatic N+ cases it was significantly higher than in nonmetastatic bladder cancer (93% versus 46%, p = 0.0037). The heparanase gene and protein showed similar patterns of expression in bladder cancer. CONCLUSIONS: Our study implies that the expression of heparanase protein and mRNA is associated with bladder cancer invasion and metastasis, and heparanase may have a role in disease progression.
Adult↗
[Percutaneous radiofrequency ablation for metastatic lung tumors--a case report].
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Aged↗
Genomic organization and chromosome localization of the newly identified human heparanase gene.
Heparanase (HPSE), which we have recently isolated, is an endo-beta-D-glucuronidase capable of cleaving heparan sulfate and has been implicated in inflammation and tumor angiogenesis and metastasis. In this report, the genomic organization and chromosome localization of the human heparanase gene is described. Polymerase chain reaction, subcloning and DNA sequencing analysis of a bacterial artificial chromosome (BAC) clone revealed that the 3.7 kb human heparanase cDNA is spread over about 50 kb and contains 14 exons and 13 introns. The heparanase gene is expressed as two mRNA species containing the same open reading frame, HPSE 1a (5 kb) (GenBank Data Library under accession number: AF155510); and HPSE 1b (1.7 kb) (GenBank Data Library under accession number: AF144325), generated by alternative splicing. The HPSE 1a-form contains all 14 exons, whereas in the HPSE 1b-form the first and fourteenth exons (5'- and 3'-untranslated region) have been spliced out. All splice sites conform to the GT-AG rule, except for the splice donor site of intron 13 (which is GA instead of GT), and the splice acceptor of intron 13 (which is GG instead of AG). Fluorescence in situ hybridization and radiation hybrid mapping suggest that the heparanase gene is located on human chromosome 4q22. This report regarding the structure of the human heparanase gene will aid in understanding the genetic contribution of this gene to normal physiology as well as to disease states. A possible involvement of heparanase in neuronal degeneration is discussed.
Alternative Splicing↗
Flexible synthesis and biological activity of uronic acid-type gem-diamine 1-N-iminosugars: a new family of glycosidase inhibitors.
An efficient and flexible synthetic route to four gem-diamine 1-N-iminosugars of uronic acid-type (D-glucuronic, D-mannuronic, L-iduronic, and L-guluronic acid), a new family of glycosidase inhibitor, from l-galactono-1,4-lactone have been developed in an enantiodivergent fashion through a sequence involving as the key steps (a) the formation of gem-diamine 1-N-iminopyranose ring by the Mitsunobu reaction of an aminal and (b) the introduction of a carboxylic acid group by the Wittig reaction of a ketone, hydroboration and oxidation, and the Sharpless oxidation. D-Glucuronic and D-mannuronic acid-type 1-N-iminosugars, (3S,4R,5R, 6R)- and (3S,4R,5R,6S)-4, 5-dihydroxy-6-trifluoroacetamido-3-piperidinecarboxylic acid, were proven to be potent inhibitors for beta-D-glucuronidase (IC(50) 6.5 x 10(-)(8)M) and to affect human heparanase (endo-beta-glucuronidase).
Animals↗
Minimally invasive lung and pleural biopsies using 2-mm and standard thoracoscopic equipment.
Videoendoscopic surgery is commonly used to obtain a definitive diagnosis in a patient with pleural lesions or pulmonary infiltration of unknown etiology. We have performed minimally invasive pleural and lung biopsies, using 2-mm mini-videoscopic instruments supported by standard thoracoscopy via one 11.5-mm port, in 10 patients. These involved 8 patients with diffuse pulmonary infiltration, and two with diffuse pleural thickening. They underwent thoracoscopic pulmonary wedge resection and pleural biopsy using one 11.5-mm port and two or three 2-mm mini-ports. The mean operating time was 37 minutes. This procedure was successful in establishing a definitive diagnosis in each patient. Complications included subacute acceleration in pulmonary infiltration in one patient. No patient complained of pain or discomfort at the 2 mm-thoraco port sites. Healing of this port site resulted in excellent cosmesis. Mini-videoscopic surgery supported by standard thoracoscopic equipment can be used to perform lung or pleural biopsy less invasively than standard thoracoscopic approach.
Aged↗
Antigen uptake and subsequent cell kinetics in bronchus-associated lymphoid tissue.
OBJECTIVE: Bronchus-associated lymphoid tissue (BALT) plays an important role in the immunological defence of airways. However, the mechanisms of BALT development, antigen sampling, and subsequent cell kinetics remain unclear. To clarify these chronological processes, we used a Pseudomonas aeruginosa-exposed mouse model. METHODOLOGY: In BALB/c and C57BL/6 mice, BALT development was induced by inhalation of heat-killed P. aeruginosa after sensitization with subcutaneous injection of P. aeruginosa in the presence of Freund's complete adjuvant. Subsequently, we chronologically killed these mice who had inhaled PKH26-labelled P. aeruginosa and examined bacterial transport using fluorescence microscopy. The distribution of interleukin-4-positive cells and interferon-gamma-positive cells was studied immunohistochemically. RESULTS: The degree of BALT hyperplasia was greater in sensitized mice than in non-sensitized mice and in BALB/c mice than in C57BL/6 mice. PKH26-labelled bacteria were found in BALT earlier in sensitized mice than in non-sensitized mice. Immunohistochemical studies revealed that interleukin-4-positive cells predominated over interferon-gamma-positive cells in the peripheral areas of lymphoid follicles. CONCLUSION: These results indicate that administered antigens are actively transported into BALT and that sensitized Th2 lymphocytes play an important role in forming and maintaining BALT.
Animals↗
[Testicular sarcoidosis].
We report a rare case of testicular sarcoidosis. A 68-year-old man was admitted for detailed examination of uveitis and swelling of the testes. A chest X-ray film and computed tomographic scans disclosed ground-glass shadows in the lower fields of both lungs with mediastinal lymphadenopathy. Ga scintigram showed pronounced accumulations in the testes, hilum, and mediastinum. Transbronchial lung and testicular biopsy specimens demonstrated noncaseating epithelioid granulomas, thus confirming the diagnosis of sarcoidosis with testicular involvement. The patient was followed up without systemic steroids. A review of the world literature found only 12 reported cases of clinically evident testicular sarcoidosis.
Aged↗
[Human heparanase: roles in invasion and metastasis of cancer].
Heparanase, which is an extracellular matrix degradative enzyme, degrades heparan sulfate and heparan sulfate proteoglycans, which are chief components of extracellular matrix and vascular basement membrane. The gene structure of this enzyme was recently determined. The biological functions of this enzyme in vivo were as follows: 1) this enzyme accelerates cancer cell invasion and metastasis though the degradation of vascular basement membrane and extracellular matrix by cancer cells; 2) this enzyme releases and activates heparin-binding growth factors such as bFGF and VEGF from heparan sulfate proteoglycans, and induces angiogenesis; 3) the degradative products of heparan sulfate proteoglycans by this enzyme suppress the biological function of activated T-lymphocytes. Therefore, heparanase is thought to be a favorable molecule for acceleration of cancer invasion and metastasis. The expression of heparanase is strongly correlated with the metastasis of melanoma and fibrosarcoma. Thus, heparanase may play important roles in invasion and metastasis of cancer.
Animals↗
Human heparanase. Purification, characterization, cloning, and expression.
Heparan sulfate and heparan sulfate proteoglycans are present in the extracellular matrix as well as on the external cell surface. They bind various molecules such as growth factors and cytokines and modulate the biological functions of binding proteins. Heparan sulfate proteoglycans are also important structural components of the basement membrane. Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan sulfate and has been implicated in inflammation and tumor angiogenesis and metastasis. In this study, we report the purification of a human heparanase from an SV40-transformed embryonic fibroblast cell line WI38/VA13 by four sequential column chromatographies. The activity was measured by high speed gel permeation chromatography of the degradation products of fluorescein isothiocyanate-labeled heparan sulfate. The enzyme was purified to homogeneity, yielding a peptide with an apparent molecular mass of 50 kDa when analyzed by SDS-polyacrylamide gel electrophoresis. Using the amino acid sequences of the N-terminal and internal heparanase peptides, a cDNA coding for human heparanase was cloned. NIH3T3 and COS-7 cells stably transfected with pBK-CMV expression vectors containing the heparanase cDNA showed high heparanase activities. The homology search revealed that no homologous protein had been reported.
Amino Acid Sequence↗
Cellular senescence of angiofibroma stroma cells from patients with tuberous sclerosis.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, mental retardation and hamartomatous lesions in multiple organs. It has been shown that the genes responsible for TSC, TSC1 and TSC2, act as tumor suppressors, but the mechanism of hamartomatous growth in several tissues is not completely understood. The TSC hamartomas are essentially benign and they rarely progress to malignant tumors. In this report, we cultured the angiofibroma stroma cells of three adult TSC patients and compared these cells with normal skin fibroblasts for their proliferative capacity, cell morphology and mitotic cycle using a stain for microtubules and the expression of the senescent associated beta-galactosidase (SA beta-Gal). Cultured angiofibroma stroma cells from TSC patients displayed several characteristics observed in human senescent fibroblasts; a low proliferative capacity, an increase in cell size, increased binucleated cells in association with abnormal cytokinesis and increased SA beta-Gal positives. Growth of facial angiofibromas in TSC may be caused by a gain in enhanced sensitivity toward some of the potential mitogens and forced multiplication without loss of the cellular senescent program; this may be the reason why TSC hamartomas rarely progress to malignancy and why the growths are limited to a finite size.
Adult↗
Biased T cell receptor Vbeta gene expression in bronchoalveolar lavage fluid from Japanese patients with sarcoidosis.
OBJECTIVE: Sarcoidosis is believed to be one of the T cell-mediated granulomatous diseases with unknown aetiology. We attempt to search for the causative T cell clones of sarcoidosis. METHODS: We study T cell receptor beta-chain variable region (Vbeta) repertoire in peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) from patients with sarcoidosis, using semi-quantitative reverse transcriptase-polymerase chain reaction method. The expression of 22 kinds of Vbeta genes is examined in 17 patients with sarcoidosis and nine normal subjects. RESULTS: Compared with control subjects, the group with sarcoidosis exhibits significantly high expressions of the Vbeta2 (P < 0.005, Wilcoxon's test) and Vbeta6 (P = 0.005) genes in BALF. In each BALF sample, the Vbeta2 (P < 0.01, chi2 test) and Vbeta6 (P < 0.01) genes were overexpressed (> 2 SD above the mean value for each Vbeta observed in control subjects) in 11 and 10 of 17 patients with sarcoidosis, respectively. Furthermore, the amino acid sequences of Vbeta6+ complementarity determining region 3 were conserved in one of three patients. There is, however, no disposition of Vbeta gene usage in PB from patients with sarcoidosis compared with control subjects. CONCLUSIONS: The T lymphocytes with Vbeta2 and/or Vbeta6 are associated with the pathogenesis of sarcoidosis. The possibility exists that these T lymphocytes might be capable of recognizing the restricted antigens, thereby inducing oligoclonal expansion.
Adult↗
Reversal of multidrug resistance by kopsiflorine isolated from Kopsia dasyrachis.
Kopsiflorine, an indole alkaloid of the aspidofractinine-type isolated from Kopsia dasyrachis, was examined for its effect in enhancing drug cytotoxicity in multidrug-resistant tumor cells. The cytotoxicity of vincristine was enhanced in a concentration-dependent manner by kopsiflorine in drug-resistant KB cells (VJ-300). Kopsiflorine alone had no effect on the growth of drug sensitive or resistant cells, but the intracellular accumulation of vincristine was enhanced by kopsiflorine in VJ-300 cells. Kopsiflorine (10 micrograms/ml) significantly inhibited the binding of [3H]azidopine to P-glycoprotein in VJ-300 cells. The results suggest that kopsiflorine interacts directly with P-glycoprotein and inhibits the efflux of antitumor agents in drug-resistant cells.
Drug Resistance, Multiple↗
Somatic cell mutation induced by sunlight in Drosophila.
There is ample epidemiological evidence showing that sunlight can cause skin cancer in the human. In experimental studies, simulated sunlight or UV lamps are used for demonstrating carcinogenesis and other biological effects. Little studies, however, have been performed using natural sunlight itself. In this work, we have examined the mutagenicity of natural sunlight in Drosophila. The Drosophila wing spot test is useful to detect somatic cell mutations. Third instar larvae in petri dishes were exposed to sunlight (ultraviolet region with < 290 nm wavelength cut off by a plastic cover) in the yard of Okayama University campus (north latitude: 34 degrees 39', east longitude: 133 degrees 55'). The sunlight was mutagenic in Drosophila larvae and produced pyrimidine dimers in their DNA. In the observed mutagenicity, there was dependence on the exposure period and UV fluence. During the two-year monitoring, the highest induction of mutant spot observed was 1.98 total spots/wing on June 25, 1998, and the lowest was 0.64 on December 29, 1998, while non-exposure spontaneous spots were 0.29 and 0.32 on these days, respectively. Thus, solar radiation was mutagenic both in summer and in winter.
Animals↗
[A case of pulmonary alveolar proteinosis presenting with peripheral infiltrates].
We report a case of pulmonary alveolar proteinosis (PAP). A 39-year-old asymptomatic woman was admitted to our hospital because of abnormal shadows on chest X-ray films. Chest X-ray films revealed peripheral infiltrates in both lungs. Computed tomographic examination showed patchy peripheral ground-glass attenuation, concentrated subpleurally. Bronchoalveolar lavage fluid was clear. Because transbronchial lung biopsy findings were inconclusive, a VATS-biopsy was performed. The specimens demonstrated accumulation of proteinaceous materials within alveolar spaces. The patient was given a diagnosis of PAP. Although the distribution of radiographic shadows varies in patients with PAP, perihilar or centralized shadows usually predominate. In our patient, subpleural areas of the lung were affected almost exclusively.
Adult↗