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Biomedical subjects

M Honda

Publications and source records attributed to M Honda.

At least 73 records · Page 4Linked to original sources

De novo acute myeloid leukemia in the elderly; a consistent fraction of long-term survivors by standard-dose chemotherapy.

To clarify the characteristics of de novo acute myeloid leukemia (AML) among the elderly, we reviewed 112 patients over 60 years old (median age 72 years) who were treated at hospitals in Nagasaki Prefecture with a population of 1.5 million between 1987 and 1994. Reclassification of morphological diagnosis revealed that the proportion of M3 was lower but that of M6 and the incidence of cases with trilineage dysplasia (TLD), known as poor prognostic features, were higher in the elderly than in patients less than 60 years old. Similarly, chromosomal data showed a lower frequency of favorable karyotypes such as t(8;21) and t(15;17) in the elderly. The overall survival of all 112 patients was 10.3% at 5 years. Multivariate analysis indicated that good performance status (PS), low WBC at diagnosis, standard dose multi-drug chemotherapy and all-trans retinoic acid (ATRA) treatment for M3 patients, and morphological findings without TLD were significantly correlated with longer survival. Most of the long-term survivors were found among those who received standard dose therapy in this series, although no consensus has been established how to treat elderly AML patients. We propose that a prospective controlled trial is necessary to confirm the role of standard dose chemotherapy for elderly patients with de novo AML.

Acute Disease↗

Reversible posterior leukoencephalopathy in a patient with minimal-change nephrotic syndrome.

A 9-year-old boy with nephrotic syndrome was transferred to our hospital because of acute renal failure and disturbance of consciousness after high-dose methylprednisolone therapy. He developed severe headache, visual disturbance, and generalized seizures. Brain computed tomography (CT) scan revealed multiple, bilateral, low-density areas in the parieto-occipital lobes. Magnetic resonance imaging (MRI) disclosed a high signal intensity area on T2-weighted images and a low signal intensity area on T1-weighted images in the same lesion. Follow-up brain CT scan and MRI, 2 weeks after the first studies, showed complete resolution of the abnormal lesions, which suggested the diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS). Hypertension and high-dose methylprednisolone administration to the patient in the nephrotic state may be causes of this uncommon syndrome in this case. This is the first report of RPLS in nephrotic syndrome with hypertension not associated with cyclosporine administration.

Brain Diseases↗

Redox regulation of MAPK pathways and cardiac hypertrophy in adult rat cardiac myocyte.

OBJECTIVES: We analyzed the regulatory function of reactive oxygen species (ROS) on the hypertrophic signaling in adult rat cardiac myocytes: BACKGROUND: The ROS regulate mitogenic signal transduction in various cell types. In neonatal rat cardiac myocyte, antioxidants have been shown to inhibit cardiac hypertrophy, and ROS are suggested to modulate the hypertrophic signaling. However, the conclusion may not reflect the situation of mature heart, because of the different natures between neonatal and adult cardiac myocytes. METHODS: Cultured adult rat cardiac myocytes were stimulated with endothelin-1 (ET-1) or phenylephrine (PE), and intracellular ROS levels, the activities of mitogen-activated protein kinases (MAPKs; ERK, p38, and JNK), and 3H-phenylalanine incorporation were examined. We also examined the effects of antioxidant pretreatment of myocytes on MAPK activities and cardiac hypertrophy to analyze the modulatory function of redox state on MAPK-mediated hypertrophic signaling. RESULTS: The ROS levels in ET-1- or PE-stimulated myocytes were maximally increased at 5 min after stimulation. The origin of ROS appears to be from NADH/NADPH oxidase, because the increase in ROS was suppressed by pretreatment of myocytes with NADH/NADPH oxidase inhibitor diphenyleneiodonium. Extracellular signal-regulated kinase (ERK) activity was increased by the stimulation of ET-1 or PE. In contrast, p38 and c-Jun-N-terminal protein kinase (JNK) activities did not change after these stimulations. Antioxidant treatment of myocytes suppressed the increase in ROS and blocked ERK activation and the subsequent cardiac hypertrophy induced by these stimuli. CONCLUSIONS: These data demonstrate that ROS mediate signal transduction of cardiac hypertrophy induced by ET-1 or PE in adult rat cardiac myocytes.

Animals↗

Production and pharmacologic modulation of the granulocyte-associated allergic responses to ovalbumin in murine skin models induced by injecting ovalbumin-specific Th1 or Th2 cells.

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Animals↗

Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour.

OBJECTIVE: To clarify the role of Rho small GTP-binding protein (Rho) in the progression of testicular germ cell tumour (GCT), by examining the expression levels of mRNAs of Rho genes in testicular GCT. PATIENTS AND METHODS: The mRNA levels of the RhoA, RhoB and RhoC genes were analysed in the surgical specimens of testicular GCT tissues from 45 consecutive Japanese patients, and in the corresponding unaffected tissue originating from the same patient, using reverse transcription-polymerase chain reaction. The expression levels in tumour tissues were compared with those in unaffected tissues and the relationship between their expression levels in tumours and tumour stage evaluated. The expression levels of mRNAs of the Rho genes were also evaluated between tumours with seminoma only, and mixed tumours with seminoma and nonseminoma. RESULTS: The mRNA levels of RhoA were greater in tumour tissues than in unaffected tissues of the resected testis (P < 0.01); the mRNAs of RhoB and RhoC were not detected in either tissue. The increase in RhoA mRNA levels was related to tumour stage (P < 0.05). The mRNA levels of RhoA in seminomatous and nonseminomatous areas where both were present were higher than those in tumours with seminoma only (P < 0.05). CONCLUSIONS: These results suggest that RhoA is involved in testicular germinal epithelial carcinogenesis and progression in testicular GCT, indicating that RhoA may be a useful prognostic marker for progression in testicular GCT.

Adolescent↗

Differential gene expression between chronic hepatitis B and C hepatic lesion.

BACKGROUND & AIMS: Complementary DNA (cDNA) microarray technology allows simultaneous expression analysis of hundreds to thousands of genes. We applied the cDNA microarray technique to clarify gene expression profiles in chronic viral hepatitis tissue lesions. METHODS: We made cDNA microarrays consisting of 1080 human cDNAs and analyzed gene expression using labeled cDNAs prepared from 6 normal, 12 chronic hepatitis B, and 14 chronic hepatitis C liver tissues. Relative expression ratios of individual genes were obtained by comparing hybridization of Cy5-labeled cDNAs from chronic hepatitis lesions and Cy3-labeled cDNA from normal liver tissue. RESULTS: Hierarchical clustering analysis of the gene expression profiles in 26 patients showed that the patients were clustered into 2 groups with respect to similarities in differentially expressed genes. Hepatitis B and C virus infection, but not age, sex, or histology of hepatitis, were significant factors determining clustering (P < 0.05). In hepatitis B tissue lesions, genes involved in inflammation were predominant, whereas in hepatitis C, expression of anti-inflammatory response genes was relatively dominant. CONCLUSIONS: These findings shed new light on the possible differential molecular mechanisms in the pathogenesis of hepatitis caused by hepatitis B virus and hepatitis C virus infection, from which hepatocellular carcinoma frequently develops.

Adult↗

alpha-fetoprotein-producing hepatoma cell lines share common expression profiles of genes in various categories demonstrated by cDNA microarray analysis.

Liver carcinogenesis is a multistep process involving various genetic alterations. cDNA microarray containing 1,080 elements (930 unique genes) was used to comprehensively analyze the genetic alterations in hepatoma cell lines, and clustering analysis was used to analyze the relatedness of the gene-expression profiles. Among 7 hepatoma cell lines analyzed, 5-alpha-fetoprotein (AFP)-producing hepatoma cell lines (HepG2, Huh7, Hep3B, PLC/PRF/5, and Huh6) were shown to have common gene-expression profiles compared with those of AFP-negative hepatoma cell lines (HLE and SK-Hep1) and cancer cell lines of nonhepatocyte origin (HeLa and KMBC). Furthermore, HepG2, Huh7, and Hep3B had higher expressions of AFP and shared a common gene-expression profile even when compared with other AFP-producing cells. Analysis of the genes with a common expression profile among these 3 AFP-positive cells revealed 254 genes across various categories. We found that 18 of these genes consistently showed altered levels of expression (more than 3-fold changes) in the 3 AFP-producing hepatoma cell lines (11 up-regulated and 7 down-regulated). In these 18 genes, 5 genes, including that for AFP, were previously reported to be involved in HCC and 6 genes involved only in other types of cancer. Our study showed that AFP-producing hepatoma cell lines shared a distinct expression profile of genes in various categories. An understanding of a causal relationship of this particular expression profile of genes to AFP-positive and AFP-negative hepatocellular carcinoma (HCC) may contribute to more rational therapy in future.

Carcinoma, Hepatocellular↗

Identification of differentially expressed genes in hepatocellular carcinoma with cDNA microarrays.

Genes expressed in hepatocellular carcinoma (HCC) were analyzed using cDNA microarrays to clarify gene abnormalities in HCC. mRNA was extracted from cancerous and noncancerous tissues of 10 patients with HCC, cDNA labeled with Cy5 and Cy3 fluorescence was prepared, and it was hybridized for each patient with a cDNA microarray consisting of 1,080 elements (930 unique genes). The mRNA expression rate of each element in HCC was evaluated using the level of mRNA expression in noncancerous tissue in each patient as a reference. The expression of 10 genes was enhanced 2 times or more in HCC cancerous tissue compared with noncancerous tissue in 5 or more of the 10 patients. In contrast, 9 genes were expressed at half the level or less in HCC cancerous tissue compared with noncancerous tissue. When hierarchical clustering was performed to identify genes related to clinical phenotypes of the patients, 22 genes showed changes associated with the degree of differentiation of HCC. Thirteen of these genes were transcriptional factors or tissue-specific expression proteins related to cell differentiation or development. Our present analysis clarified a number of genes that characterize HCC. This information based on examination of clinical samples is considered to be useful for clarification of the mechanism of hepatocarcinogenesis and the diagnosis and treatment of HCC.

Adult↗

Detection of hepatitis C virus in the bile and bile duct epithelial cells of hepatitis C virus-infected patients.

The pathobiology of hepatitis C virus (HCV) in the biliary system has not been clarified yet, although bile duct damage is a histological finding characteristic of chronic hepatitis C. In this study, we examined whether HCV infects bile ducts and is released into the bile. Twelve patients positive for serum HCV antibody were examined in this study, and eight were seropositive for HCV RNA by polymerase chain reaction (PCR). For those who underwent abdominal surgery, the bile was aspirated from the gall bladders by fine needle puncture. Five underwent wedge liver biopsy. Series of saline-diluted bile were assayed for HCV RNA by PCR to determine the HCV RNA titers. To examine HCV expression in the biliary system, the liver specimens were immunostained using monoclonal antibodies to the HCV proteins. HCV RNA was detected in the bile of 5 patients with high serum HCV RNA load (> or = 2.5 Meq/mL). Comparison of viral loads between serum and bile revealed that the HCV RNA level in the bile was as high as that in serum. Furthermore, immunohistological study showed that bile duct epithelial cells were infected with HCV. In contrast, HCV was not found in either the bile or bile duct of patients seronegative for HCV RNA or with low serum HCV load (< or = 1.1 Meq/mL). These findings suggest that the biliary system is involved in the pathobiology of HCV and that the bile is as highly infectious as the serum.

Aged↗

Isolated diffuse mesangial sclerosis and Wilms tumor suppressor gene.

Diffuse mesangial sclerosis is a rare renal disease, occurring either in isolation or as part of Denys-Drash syndrome. Denys-Drash syndrome originates from mutations of the Wilms tumor suppressor gene (WT1 ). We describe the presence of WT1 mutations in 7 Japanese children with isolated diffuse mesangial sclerosis.

Female↗

Structural analysis of the sugar chains of human urinary thrombomodulin.

The sugar chains of human urinary thrombomodulin were studied. N- and O-linked sugar chains were simultaneously liberated by hydrazinolysis followed by N-acetylation and were tagged with 2-aminopyridine. Then the structures of the N- and O-linked pyridylamino (PA-) sugar chains were analyzed by two-dimensional sugar mapping combined with exoglycosidase digestion. The major N-linked sugar chains of human urinary thrombomodulin were found to be monosialo- and disialofucosylbiantennary chains, while the major O-linked sugar chain was +/-Siaalpha2-3Galbeta1-3(+/-Siaalpha2-6)GalNAc. Thrombomodulin also contained the reported structure SO4-3GlcAbeta1-3Galbeta1-3(+/-Siaalpha2-6)Galbeta1-4Xyl [H. Wakabayashi, S. Natsuka, T. Mega, N. Otsuki, M. Isaji, M. Naotsuka, S. Koyama, T. Kanamori, K. Sakai, and S. Hase (1999) J. Biol. Chem. 274, 5436-5442]. In addition to these sugar chains, a single Glc was linked to Ser 287.

Acetylation↗

Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo.

OBJECTIVE: To assess the in-vivo action on the renal microvasculature of the calcium antagonists nifedipine (L-type blocker), efonidipine (L/T-type blocker), and mibefradil (predominant T-type blocker). DESIGN: An intravital needle-type charge-coupled device (CCD) camera videomicroscope was introduced to visualize the renal microcirculation directly in vivo. METHODS: In anesthetized mongrel dogs, nifedipine (0.01-1 mg/kg per min), efonidipine (0.033-0.33 mg/kg per min), or mibefradil (0.01-1 mg/kg per min) was infused intravenously after the insertion of a CCD probe into the kidney. Renal microvascular responses to calcium antagonists were directly evaluated, with concomitant observation of renal clearance. RESULTS: Each calcium antagonist caused modest vasodepressor action without affecting heart rate. Nifedipine (1 mg/kg per min, n = 9) increased renal plasma flow (RPF) (14 +/- 4%, P < 0.05) and glomerular filtration rate (GFR) (19 +/- 5%, P < 0.05), and tended to increase the filtration fraction (5 +/- 2% increment, P = 0.07). Efonidipine (0.33 mg/kg per min, n = 9), however, had no effect on filtration fraction, with 14 +/- 6% increments in RPF (P < 0.05) and 14 +/- 7% increments in GFR (P = 0.08). Rather, mibefradil (1 mg/kg per min, n = 9) elicited 6 +/- 2% decreases in filtration fraction (P < 0.05), with slight increments in RPF (6 +/- 3%) and no changes in GFR. In direct in-vivo microvasculature observations, nifedipine caused predominant (22 +/- 2%) dilatation of afferent arterioles (from 15.5 +/- 0.4 to 18.9 +/- 0.4 microm, n = 5), compared with that of efferent arterioles (10 +/- 2%; from 11.0 +/- 0.4 to 12.1 +/- 0.3 microm). In contrast, efonidipine caused a similar magnitude of vasodilatation (16 +/- 4%) compared with 18 +/- 2%; n = 6), and mibefradil caused greater dilatation of efferent arterioles (20 +/- 4%, n = 7) than that of afferent arterioles (13 +/- 4%). CONCLUSIONS: There exists marked heterogeneity in action of nifedipine, efonidipine and mibefradil on the renal microvascular in canine kidneys in vivo. Furthermore, our current observations suggest an important contribution of T-type calcium channel activity to efferent arteriolar tone in vivo.

Animals↗

Reduced expression of syndecan-1 affects metastatic potential and clinical outcome in patients with colorectal cancer.

Syndecan-1 is a transmembrane heparansulfate proteoglycan which regulates cell-to-cell or cell-to-extracellular matrix interactions and may influence malignant cell behavior. We investigated the alterations of syndecan-1 expressions in colorectal cancers and analyzed the relationship between histological and clinical characteristics. Syndecan-1 protein expression in colorectal cancer tissues was investigated with immunohistochemical staining of resected specimens. In situ hybridization was performed using syndecan-1 riboprobe to confirm the transcriptional signals. Syndecan-1 mRNA expression in cancer cell lines cultured with or without methylation inhibitor was also analyzed by quantitative PCR. Out of 105 specimens tested, less than 25% of tumor cells were stained with anti-syndecan-1 monoclonal antibody in 36 (34.3%). In situ hybridization showed a similar staining profile to that of immunohistochemistry. Syndecan-1 mRNA expression was increased by the methylation inhibitor 5-aza-2'-deoxycytidine, suggesting that the hypermethylation is involved in the suppression of syndecan-1 expression. Clinically, the incidence of metastasis to lymphnode or liver in patients with syndecan-1-negative tumors was significantly high. Among T1 colorectal cancers displaying a primary invasive phase, lymphnode metastasis, undifferentiated characters and 'budding' of cancer cells were more common in syndecan-1-negative tumors. The survival rate in patients with syndecan-1-negative tumors was decreased significantly in a stage-independent manner. These results suggest that the reduction of syndecan-1 expression in colorectal cancer cells, which is supposed to be regulated at the transcription level, is closely related to invasive character. The evaluation of syndecan-1 expression in colorectal cancer may allow prediction of patients' survival after surgery.

Adenocarcinoma↗

Dynamic articulatory model based on multidimensional invariant-feature task representation.

A dynamic model of articulatory movements is introduced. The research presented herein focuses on the method of representing the phonemic tasks, i.e., phoneme-specific articulatory targets. Phonemic tasks in our model are formally defined using invariant features of articulatory posture. The invariant features used in the model are characterized by the linear transformation of articulatory variables and found using a statistical analysis of measured articulatory movements, in which the articulatory features with minimum variability are taken to be the invariant features. Articulatory movements making vocal-tract constrictions or relative movements among articulators reflecting task-sharing structures are typical examples of the features found to have low variability. In the trajectory formation of articulatory movements, the dimension number of the phonemic task is set at a smaller value than that of articulatory variables. Consequently, the kinematic states of the articulators are partly constrained at given time instants by a sequence of phonemic tasks, and there remain unconstrained degrees of freedom of articulatory variables. Articulatory movements are determined so that they simultaneously satisfy given phonemic tasks and dynamic smoothness constraints. The dynamic smoothness constraints coupled with the underspecified phonemic targets allow our model to explain contextual articulatory variability using context-independent phonemic tasks. Finally, the capability of the model for predicting actual articulatory movements is quantitatively investigated using empirical articulatory data.

Adult↗

Generation of articulatory movements by using a kinematic triphone model.

The method described here predicts the trajectories of articulatory movements for continuous speech by using a kinematic triphone model and the minimum-acceleration model. The kinematic triphone model, which is constructed from articulatory data obtained from experiments using an electro-magnetic articulographic system, is characterized by three kinematic features of a triphone and by the intervals between two successive phonemes in the triphone. After a kinematic feature of a phoneme in a given sentence is extracted, the minimum-acceleration trajectory that coincides with the extremum of the time integral of the squared magnitude of the articulator acceleration is formulated. The calculation of the minimum acceleration requires only linear computation. The method predicts both the qualitative features and the quantitative details of experimentally observed articulation.

Adult↗

Maximal and submaximal forces of slow fibers in human soleus after bed rest.

The effects of 2 and 4 mo of bed rest, with or without exercise countermeasures, on the contractile properties of slow fibers in the human soleus muscle were examined. Mean fiber diameters were 8 and 36% smaller after 2 and 4 mo of bed rest, respectively, than the pre-bed rest level. Maximum tetanic force (P(o)), maximum activated force (F(max)) per cross-sectional area (CSA), and the common-logarithm value of free Ca(2+) concentration required for half-maximal activation (pCa(50)) also decreased after 2 and 4 mo of bed rest. In contrast, maximum unloaded shortening velocity (V(o)) was increased after 2 and 4 mo of bed rest. After 1 mo of recovery, fiber diameters, P(o), F(max) per CSA (P > 0.05), and pCa(50) were increased and V(o) decreased toward pre-bed rest levels. Effects of knee extension/flexion exercise by wearing an anti-G Penguin suit for 10 h daily, and the effects of loading or unloading of the plantar flexors with (Penguin-1) or without (Penguin-2) placing the elastic loading elements of the suit, respectively, were investigated during ~2 mo of bed rest. In the Penguin-1 group, mean fiber diameter, P(o), F(max) per CSA, V(o), and pCa(50) were similar before and after bed rest. However, the responses of fiber size and contractile properties to bed rest were not prevented in the Penguin-2 group, although the degree of the changes was less than those induced by bed rest without any countermeasure. These results indicate that long-term bed rest results in reductions of fiber size, force-generation capacity, and Ca(2+) sensitivity, and enhancement of shortening velocity in slow fibers of the soleus. The data indicate that continuous mechanical loading on muscle, such as stretching of muscle, is an effective countermeasure for the prevention of muscular adaptations to gravitational unloading.

Adult↗

Effect of long-term, low-dose acyclovir suppressive therapy on susceptibility to acyclovir and frequency of acyclovir resistance of herpes simplex virus type 2.

We have examined the susceptibility to acyclovir and frequency of acyclovir-resistant viruses in herpes simplex virus type (HSV) 2 clones isolated directly from genital lesions of 11 patients who had taken suppressive therapy (200 mg/day) for 1-9 years and 15 patients naive to acyclovir. Suppressive therapy significantly reduced the incidence of recurrence and the severity of the skin lesions. HSV samples from genital lesions were directly inoculated into Vero cells, and viral clones were isolated in the absence and presence of 10 microg/ml acyclovir. Five-hundred-and-ninety-two clones, isolated in the absence of acyclovir, were subjected to the acyclovir susceptibility test, and 155 clones isolated in the presence of acyclovir were analysed for the mechanisms of resistance to acyclovir. There were no significant differences in the susceptibility to acyclovir, the frequency of acyclovir-resistant virus and the ratio of thymidine kinase-deficient viruses in acyclovir-resistant viruses between the two groups. The frequency of acyclovir-resistant clones was about three per 10000 plaque forming units (PFU), and genital lesions contained up to 3x10(6) PFU of replicating virus in the specimens from the patients with genital herpes with or without acyclovir-suppressive therapy. Thus, the low dose of acyclovir suppressive therapy did not affect the susceptibility to acyclovir or increase the frequency of acyclovir-resistant viruses in the genital lesions.

Acyclovir↗

Method for recording spinal reflexes in mice: effects of thyrotropin-releasing hormone, DOI, tolperisone and baclofen on monosynaptic spinal reflex potentials.

Mice were used to record the spinal reflex potentials and to examine the effects of some drugs upon them. In anesthetized mice, laminectomy was performed in the lumbo-sacral region, and monosynaptic reflex potential (MSR) and polysynaptic reflex potential were recorded from the L5 ventral root after stimulation of the L5 dorsal root. Thyrotropin-releasing hormone (TRH) and 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) produced transient and long-lasting increases in the MSR amplitude, respectively. Tolperisone hydrochloride and baclofen produced transient and long-lasting MSR depressions, respectively. These results show that mice can be used to record spinal reflex potentials, and that it may be possible to study the spinal cord function of mutant and knockout mice using this method.

Amphetamines↗