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Biomedical subjects

M Hirano

Publications and source records attributed to M Hirano.

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

Leber's hereditary optic neuropathy mitochondrial DNA mutations in normal-tension glaucoma.

BACKGROUND: in Leber's hereditary optic neuropathy, increased optic nerve cupping has been reported by several authors. Recently, a mitochondrial DNA (mtDNA) mutation at nucleotide 11778 typically associated with Leber's hereditary optic neuropathy (LHON) was identified in a patient treated for glaucoma but lacking typical signs of LHON. The question arises: should all normal-tension glaucoma patients be further evaluated for LHON? METHODS: we screened 54 unselected patients with normal-tension glaucoma (age range 20-96 years, 16 men and 38 women) for the primary mtDNA LHON mutations at nucleotides 3460, 11778 and 14484. RESULTS: none of the patients harboured the mtDNA mutations at nucleotides 3460, 11778 or 14484 (95% confidence intervals for each mutation ranged from 0% to 5.3%). CONCLUSIONS: primary LHON mtDNA mutations are rare or absent in unselected normal-tension glaucoma patients. Therefore, unselected normal-tension glaucoma patients should not be screened for these mutations. It is probable that only normal-tension glaucoma patients with atypical features (rapid progression, early deep central scotoma, pallor of neuroretinal rim, elevated disc, peripapillary teleangiectasia) or a positive family history of visual loss compatible with a matrilinear transmission should be further evaluated.

Adult↗
PubMed2001

Development of a time-resolved fluorometric method for observing hybridization in living cells using fluorescence resonance energy transfer.

We previously showed that a specific kind of mRNA (c-fos) was detected in a living cell under a microscope by introducing two fluorescently labeled oligodeoxynucleotides, each labeled with donor or acceptor, into the cytoplasm, making them hybridize to adjacent locations on c-fos mRNA, and taking images of fluorescence resonance energy transfer (FRET) (A. Tsuji, H. Koshimoto, Y. Sato, M. Hirano. Y. Sei-Iida, S. Kondo, and K. Ishibashi, 2000, Biophys. J. 78:3260-3274). On the formed hybrid, the distance between donor and acceptor becomes close and FRET occurs. To observe small numbers of mRNA in living cells using this method, it is required that FRET fluorescence of hybrid must be distinguished from fluorescence of excess amounts of non-hybridizing probes and from cell autofluorescence. To meet these requirements, we developed a time-resolved method using acceptor fluorescence decays. When a combination of a donor having longer fluorescence lifetime and an acceptor having shorter lifetime is used, the measured fluorescence decays of acceptors under FRET becomes slower than the acceptor fluorescence decay with direct excitation. A combination of Bodipy493/503 and Cy5 was selected as donor and acceptor. When the formed hybrid had a configuration where the target RNA has no single-strand part between the two fluorophores, the acceptor fluorescence of hybrid had a sufficiently longer delay to detect fluorescence of hybrid in the presence of excess amounts of non-hybridizing probes. Spatial separation of 10-12 bases between two fluorophores on the hybrid is also required. The decay is also much slower than cell autofluorescence, and smaller numbers of hybrid were detected with less interference of cell autofluorescence in the cytoplasm of living cells under a time-resolved fluorescence microscope with a time-gated function equipped camera. The present method will be useful when observing induced expressions of mRNA in living cells.

3T3 Cells↗
PubMed2001

MNGIE: from nuclear DNA to mitochondrial DNA.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a unique autosomal recessive disorder with mitochondrial DNA alterations. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Muscle biopsies typically reveal mitochondrial abnormalities including ragged-red fibers and focal cytochrome c oxidase deficiency. Analysis of mitochondrial DNA in skeletal muscle shows partial depletion, multiple deletions, or both. To identify the cause of MNGIE, we mapped the disease locus to chromosome 22q13.32-qter. Within this region, we identified the gene encoding thymidine phosphorylase as the MNGIE gene. We have identified homozygous or compound-heterozygous thymidine phosphorylase gene mutations in 35 MNGIE patients (21 families) from diverse ethnic groups, including: Ashkenazi Jewish, Western European, Jamaican, Hispanic, and Japanese. We confirmed pathogenicity of the mutations by a spectrophotometric assay of thymidine phosphorylase activity with peripheral leukocytes of 15 MNGIE patients. Thymidine phosphorylase enzymatic activity was severely reduced, thus enabling us to conclude that the loss-of-function mutations in thymidine phosphorylase gene cause MNGIE. Thymidine phosphorylase catabolizes thymidine to thymine. In agreement with this notion, we noted that plasma thymidine level is increased more than 20-fold in MNGIE patients compared to controls. Therefore, we have hypothesized that increased thymidine causes mitochondrial nucleotide pool imbalance which, in turn, leads to motochondrial DNA alterations, via a mitochondria-specific thymidine salvage pathway. The identification of the MNGIE gene has allowed us to classify MNGIE as a disease of nucleoside dysmetabolism. We may be entering a new era of research on mitochondrial nucleoside metabolism.

Chromosomes, Human, Pair 22↗
PubMed2001

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

Amino Acid Sequence↗
PubMed2001

Correlation between HHV-6 infection and skin rash after allogeneic bone marrow transplantation.

We investigated whether a causal relationship exists between human herpesvirus 6 (HHV-6) and skin rash resembling acute graft-versus-host disease (GVHD) following bone marrow transplantation (BMT). Isolation of HHV-6 was used to monitor active HHV-6 infection in this study. We analyzed 25 episodes of skin rash in 22 recipients. All recipients were seropositive for HHV-6 before BMT. The onset of skin rash started prior to 30 days post transplantation (group A) in 15 of 25 cases, but after that (group B) in the remaining 10 cases. Twenty-five skin tissue samples were obtained from 22 recipients. The HHV-6 genome was detected in four of 15 skin samples from group A, but not detected in those from group B. HHV-6 was isolated from 11 of 22 recipients around 2 to 3 weeks after BMT (range 14 to 28 days after BMT). HHV-6 was isolated at a time between 10 days before and after the onset of skin rash (skin rash-related viremia) in nine cases in group A. Meanwhile, no skin rash-related viremia was observed in group B. Of the four recipients with positive detection of HHV-6 genome in their skin tissue (group A), two had HHV-6 viremia at the same time. The association between the timing of HHV-6 infection and the onset of skin rash was analyzed statistically. HHV-6 viremia (skin rash-related viremia) was found in nine of 15 (60%) cases in group A, compared with none of 10 (0%) cases in group B. This difference was statistically significant (P = 0.008). Moreover, HHV-6 infection (skin rash-related viremia and/or positive detection of HHV-6 DNA in skin tissue) was demonstrated in 11 of 15 (73.3%) cases in group A, compared with none of 10 (0%) cases in group B (P = 0.001). Thus, this study suggests that HHV-6 may be involved in the development of skin rash in the first month after allogeneic BMT.

Adolescent↗
PubMed2001

Serum nm23-H1 protein as a prognostic factor for indolent non-Hodgkin's lymphoma.

Standard chemotherapy has been ineffective for improving the poor 10-year survival rate of patients with indolent lymphoma. However, a wider choice of therapeutic modalities has become recently available, including immunotherapy with monoclonal antibodies and allogeneic peripheral blood stem cell transplantation. Accordingly, a sensitive prognostic indicator is required to identify high-risk patients and to help design new therapeutic approaches for them. We previously reported that the serum nm23-H1 protein level was an independent prognostic factor for aggressive lymphoma. The present study was performed to assess the clinical implications of this protein on indolent lymphoma and whether it can be used to classify the aggressiveness of the disease in order to assist in the individualization of therapy. A total of 130 patients with indolent lymphoma were enrolled in this multicenter study. The serum nm23-H1 protein level was significantly higher in patients with indolent lymphoma than in a normal control group. In addition, indolent lymphoma patients with higher nm23-H1 levels had worse overall and progression-free survival rate than those with lower nm23-H1 levels. Therefore, nm23-H1 in serum may be useful for identifying a distinct group of patients at high risk.

Adolescent↗
PubMed2001

Solitary fibrous tumor in the mental region.

Solitary fibrous tumor (SFT) is a rare, benign, soft tissue tumor that most commonly occurs in the pleura; however, it has recently been described in other sites of the body. To date, eight examples of oral SFT have been reported. This paper is a description of the first case of an SFT occurring as a soft tissue tumor in the mental region. Histologically, the tumor was composed predominantly of rather uniform spindle-shaped fibroblastic cells arranged in vague fascicles or in a haphazard fashion, intermingled with abundant collagen fibers. Immunohistochemically, the tumor cells were positive for CD34 and vimentin, and weakly positive for muscle actin and alpha-smooth muscle actin. The diagnosis of SFT may be difficult as this tumor shares a number of histological features with other soft tissue tumors. Awareness of its occurrence in the oral cavity is important so that confusion with other spindle cell neoplasms can be avoided.

Actins↗
PubMed2001

Familial occurrence of adiposis dolorosa.

Adiposis dolorosa is a rare condition characterized by multiple painful lipomas. We describe two typically affected siblings who were found to have at least 5 affected first-degree relatives in two generations. Manifestations were remarkably variable, ranging from complete disability to solitary asymptomatic tumors. Review of histopathologic findings did not reveal any features that might distinguish the tumors from common sporadic lipomas. Mutational analysis excluded the 8344 A to G mitochondrial mutation seen in other patients with multiple lipomas. Adiposis dolorosa may be an extreme manifestation of the more common condition of familial multiple lipomas. Further work is needed to define the genetic basis of these conditions.

Adiposis Dolorosa↗
PubMed2001

Bruton's tyrosine kinase is required for signaling the CD79b-mediated pro-B to pre-B cell transition.

Formation of the pre-BCR complex is a critical check point during B cell development and induces the transition of pro-B to pre-B cells. CD79b (Igbeta) is a signaling component in the pre-BCR complex, since differentiation to the pre-B phenotype is induced by cross-linking the CD79b expressed on developmentally arrested pro-B cells from recombination-activating gene (RAG)-2-deficient mice. Bruton's tyrosine kinase (BTK) plays important roles in B cell development. However, its molecular mechanisms in early B cell development are not fully understood. To examine whether BTK functions in CD79b-mediated signaling for the pro-B/pre-B transition, we utilized RAG2/BTK double-knockout (DKO) mice. Pro-B cells from RAG2/BTK-DKO mice did not differentiate into pre-B cells following CD79b cross-linking, although tyrosine phosphorylation of cellular proteins including Erk1/2 and phospholipase C-gamma2 was induced in the same manner as RAG2-KO mice. BTK is phosphorylated after cross-linking of CD79b on RAG2-deficient pro-B cells. These findings suggest that BTK-dependent pathways downstream of CD79b are critical for the pro-B/pre-B transition and BTK-independent signaling pathways are also activated via the pre-BCR complex.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2001

Mitochondria and the heart.

Since the identification of the first pathogenic mutations of mitochondrial DNA in 1988, a plethora of information about human mitochondrial diseases has been brought to light. Not surprisingly, many of these disorders affect the myocardium, because this tissue relies heavily upon oxidative metabolism. This review focuses on disorders of the respiratory chain, the only area of mammalian cellular metabolism under the control of two genomes, nuclear and mitochondrial. Consequently, defects of aerobic synthesis of adenosine triphosphate (ATP) can be due to mutations of either genome. We describe genetic mitochondrial cardiomyopathies and briefly review mouse models and the mitochondrial theory of presbycardia.

Animals↗
PubMed2001

Five quantitative trait loci affecting 4-nitroquinoline 1-oxide-induced tongue cancer in the rat.

In our previous study, Dark-Agouti (DA) rats were found to be highly susceptible to 4-nitroquinoline 1-oxide (4NQO)-induced tongue carcinoma (TC), whereas Wistar / Furth (WF) rats were barely susceptible. Interval mapping analysis of reciprocal backcross rats showed two quantitative trait loci (QTL) on rat chromosomes (RNO) 1 and 19. In the present study, a composite interval mapping analysis was applied to 4NQO-induced TC in 130 (DA x WF) F2 rats, demonstrating five independent QTL, Tongue squamous cell carcinoma 1 - 5 (Tscc1 - 5), responsible for phenotypic differences in the size and number of TCs in the two strains. Two of these QTL were mapped on RNO1, and the others were mapped on RNO4, 14, and 19. The DA allele at these loci consistently yielded semidominant susceptibility to TC. Out of the five loci detected in this F2 generation, Tscc1 and 2 were identical to Stc1 and Rtc1 described in our previous study, but the other three were novel. We propose a new nomenclature consistent with their function. Genome-wide screening of the F2 progeny also suggested the presence of three additional QTL on RNO5, 6, and 10. The possible roles of these loci in tongue carcinogenesis are discussed.

4-Nitroquinoline-1-oxide↗
PubMed2001

Thyroarytenoid muscle: functional subunits based on morphology and muscle fiber typing in cats.

Using parvalbumin immunohistochemistry to determine the distribution of muscle fiber types in the feline thyroarytenoid muscle (TA), we clearly distinguished the vocalis (with predominance of "slow" type 1 fibers) from the external TA (in which "fast" type 2 fibers predominated, especially in its rostral part). Reconstruction of serial frontal sections of the TA allowed the stereoscopic study of each division. The existence of a rudimentary laryngeal ventricle separating the true and false vocal folds in cats was demonstrated anatomically and histologically, and its relationships to each division of the TA were established. Our results suggest that the vocalis, fitted for enduring activities, is suited for voice control. The fast, rostral part of the external TA seems suited to laryngeal sphincteric demands, while its caudal counterpart may act in both functions. The anatomic individualization of the divisions of the TA may suggest that they play distinct physiological roles and may imply that they should not be considered a single functional unit.

Animals↗
PubMed2001

Stellate cells in the human vocal fold.

Cells have been discovered that are star-like in appearance and that actively synthesize extracellular matrices in the human adult vocal fold mucosa. These cells have no nomenclature and are thus designated as vocal fold stellate cells (VFSC) in this study. Light and electron microscopic investigation of VFSC in the human vocal fold mucosa was carried out on excised human adult larynges. A comparison between VFSC and conventional fibroblasts was made. The results are summarized as follows. 1) The VFSC are distributed in human adult maculae flavae. 2) The VFSC are irregular and stellate in shape, possessing slender cytoplasmic processes. 3) Lipid droplets are present in the cytoplasm. 4) The VFSC have a small nucleus-cytoplasm ratio and well-developed rough endoplasmic reticulum, suggesting active protein synthesis in these cells. 5) No basal lamina is present, and filaments can be seen in the cytoplasm. 6) The VFSC show strong cytoplasm staining with periodic acid-Schiff stain and type III collagen. 7) The VFSC actively synthesize collagenous fibers, including reticular fibers, as well as other extracellular matrices, such as elastic fibers and glycosaminoglycan (hyaluronic acid). 8) The VFSC, first demonstrated in this study, actively synthesize extracellular matrices in the human adult vocal fold mucosa under normal conditions. 9) The VFSC participate in the metabolism of the extracellular matrices essential for the viscoelastic properties of the lamina propria of the human adult vocal fold mucosa as a vibrating tissue.

Aged↗
PubMed2001

Fine structure of the human newborn and infant vocal fold mucosae.

This study was carried out to determine the fine structure of the membranous portion of the human newborn and infant vocal fold mucosae and to clarify how the human vocal fold mucosa begins to grow after birth. Light and electron microscopic observations were made on the vocal fold mucosae excised from human newborn and infant larynges. Our findings are summarized as follows. 1) Reinke's space of the newborn vocal fold is a loose structure composed of ground substance and sparse fibers. 2) Ground substance is abundant and glycoproteins (fibronectin) are present in the lamina propria. 3) In the maculae flavae of newborn vocal folds, fibroblasts begin to form collagenous, reticular, and elastic fibers. 4) In the infant maculae flavae, fibroblasts are activated to become stellate in shape and synthesize extracellular matrices such as collagenous and reticular fibers. 5) After birth, the collagenous and reticular fibers synthesized in the maculae flavae extend toward the middle of the membranous portion of the vocal fold mucosa. 6) Glycoprotein (fibronectin) determines the orientation of collagenous and reticular fiber deposition. 7) Glycoprotein (fibronectin) decreases with the increase of the fibrous components in Reinke's space. 8) Elastic fibers increase after collagenous and reticular fibers appear in Reinke's space. 9) Much hyaluronic acid (glycosaminoglycan) is actively produced in the infant maculae flavae. 10) The collagenous and reticular fibers serve as stabilizing scaffolds for the other extracellular matrices, such as elastic fibers and glycosaminoglycan. During infancy, the extracellular matrices synthesized in the maculae flavae appear in the membranous portion of the vocal fold, each at a different time, so as to initiate the 3-dimensional formation of the vocal fold mucosa.

Extracellular Matrix↗
PubMed2001

[Significance of pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) in advanced gastric cancers].

We measured pyrimidine nucleoside phosphorylase (PyNPase), a known angiogenetic factor, and dihydropyrimidine dehydrogenase (DPD) in advanced gastric cancers. PyNPase was expressed in cytoplasm of the cancer cells and surrounding interstitial cells. The levels of PyNPase and DPD were significantly higher in cancer tissue. With respect to tumor factors, the level of PyNPase was significantly higher in cases positive for venous invasion. We divided patients into two groups, with high and low activities of IAP and MMP-9. The level of PyNPase was significantly higher in the high IAP activity group. A correlation was suggested between the level of PyNPase and the activity of IAP. 5'-Deoxy-5-fluorouridine (5'-DFUR) is transformed into 5-FU by PyNPase and manifests antitumor effects. DPD is a rate-limiting enzyme in the process of degradation of 5-FU. In the present study, the level of PyNPase/DPD was significantly higher in cancer tissue. PyNPase/DPD suggests not only the malignant potential of the tumor but also the efficiency of chemotherapy using 5-FU, especially 5'-DFUR.

Aged↗
PubMed2001

[Early phase II clinical trial of amrubicin hydrochloride in patients with malignant lymphoma].

An early phase II multi-center collaborative study of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, was conducted for malignant lymphoma at 12 institutions nationwide. A total of 41 patients were enrolled in this study between January 1988 and October 1990. Of these, 36 patients, six patients with Hodgkin's disease (HD) and 30 patients with non-Hodgkin's lymphoma (NHL), were eligible for the study. The starting dose of amrubicin hydrochloride was 100 mg/m2 (body surface area) and it was administered once every three weeks, in principle. The efficacy was assessed for 34 patients, excluding two patients: one who has not been followed up adequately and the other violated the dosing schedule (once per week). The overall response rates (CR + PR) were 50.0% (3/6) for HD and 42.9% (12/28) for NHL. Furthermore, a relatively high response rate was noted in 8 (36.4%) of 22 NHL patients who had been treated with other anthracycline derivatives prior to the trial. The safety of amrubicin hydrochloride was assessed for 36 eligible patients. Leukopenia (grade 3 or higher) and thrombocytopenia were noted in 21 patients (58.3%) and 10 patients (27.8%), respectively. Anorexia, nausea/vomiting, fever, alopecia, decrease in hemoglobin and elevations of GOT and GPT levels were observed with a relatively high frequency. Other than myelosuppression, the following adverse reactions (grade 3 or higher) occurred during the course of the trial: diarrhea (two patients), alopecia (two patients), stomatitis (one patient), anorexia (one patient), nausea/vomiting (one patient) and fever (one patient). In conclusion, these results indicate that amrubicin hydrochloride is effective in the treatment of patients with malignant lymphoma.

Aged↗
PubMed2001

[Late phase II clinical study of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, for malignant lymphoma].

A late phase II clinical trial of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, was conducted at 14 institutions nationwide, in patients with non-Hodgkin's lymphoma. In this multi-center collaborative study, doxorubicin hydrochloride was replaced by amrubicin hydrochloride in CHOP therapy, a standard regimen for non-Hodgkin's lymphoma consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisolone. A total of 39 patients were enrolled in this study between January 1996 and March 1998. Among them, 37 patients were eligible for this study. The study drugs were administered to patients with non-Hodgkin's lymphoma according to the following schedule: amrubicin hydrochloride (100 mg/m2, body surface area), cyclophosphamide (750 mg/m2) and vincristine sulfate (1.4 mg/m2, a maximal dose of 2.0 mg/body) were administered intravenously on day one, while prednisolone (60 mg/m2/day) was administered orally on days 1 to 5. This cycle of treatment was repeated every three weeks in principle. The efficacy and safety were assessed for 37 eligible patients. The combined rate for CR + CRu was 70.3% (26/37) and the overall response rate (CR + CRu + PR) was 86.5% (32/37). demonstrating that amrubicin hydrochloride was very effective in the treatment of non-Hodgkin's lymphoma. The most frequent adverse reactions that occurred during the study were myelosuppressions: leukopenia and neutropenia, 100% (37/37); and decreases in hemoglobin levels, 81.1% (30/37). Thrombocytopenia, elevations of serum GOT and GPT levels, anorexia, nausea/vomitting, fever, stomatitis and alopecia were also observed. Although leukopenia and neutropenia of grade 3 or higher were noted in 89.2% (33/37) and 94.6% (35/37), respectively, they were controllable by administrations of G-CSF or solely by follow-up observations. One patient developed intestinal paralysis (grade 4) and another developed hematemesis. In conclusion, these results indicate that amrubicin hydrochloride is an effective agent as a component of combination chemotherapy for non-Hodgkin's lymphoma.

Aged↗