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Biomedical subjects

Takashi Shimamoto

Publications and source records attributed to Takashi Shimamoto.

At least 19 recordsLinked to original sources
PubMed2003

BCL-2 antisense oligonucleotide genasense is active against imatinib-resistant BCR-ABL-positive cells.

PURPOSE: The near-universal emergence of imatinib resistance in patients with acute forms of Philadelphia chromosome-positive leukemia highlights the need for additional therapy to control this disease. G3139 (Genasense, oblimersen; Genta Inc.), a Bcl-2 antisense oligonucleotide, has been shown to down-regulate the Bcl-2 protein and induce apoptosis in myeloid leukemia cells from treated patients. We tested G3139 for its ability to inhibit BCR-ABL-mediated transformation in mice. EXPERIMENTAL DESIGN: Nude mice (n = 5/group) were transplanted s.c. with imatinib-resistant BCR-ABL-transformed TF-1 cells (BCR-ABL-TF-1-R cells). Mice with established tumors (0.1 g) were treated for 14 days with G3139 (7 mg/kg/day i.p.), or with the reverse-sequence control oligonucleotide G3622 (7 mg/kg/day i.p.) or with imatinib (50 mg/kg/day i.p.). RESULTS: Mice treated with G3622 or imatinib died within 10-12 weeks. Nearly all of the mice treated with G3139 survived for >6 months and had reduced tumor volume. Three of the 5 mice showed complete tumor regression. A transient decrease in Bcl-2 protein was observed that correlated with histological evidence of apoptosis. In addition, we harvested BCR-ABL-TF-1-R tumor cells from mice treated with G3139 or control G3622 (7 mg/kg/day i.p., 7 days). Cells were then cultured with the antileukemic agents imatinib, daunorubicin, 1-beta-D-arabinofuranosylcytosine, or etoposide. G3139 pretreatment resulted in enhanced induction of apoptosis by all of the agents. CONCLUSION: These results suggest that G3139 is a promising candidate for treatment of patients with imatinib-resistant Ph-positive leukemia, and that combination of G3139 and imatinib may be useful to circumvent clinically acquired imatinib resistance.

Animals↗
PubMed2003

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways.

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

Apoptosis↗
PubMed2003

Fat and protein intakes and risk of intraparenchymal hemorrhage among middle-aged Japanese.

The authors examined the relation between low intakes of saturated fat and animal protein and risk of intraparenchymal hemorrhage in a 14-year prospective study (ending in 1997) of 4,775 Japanese aged 40-69 years who undertook a single 24-hour dietary recall. Compared with the highest quartile of energy-adjusted saturated fat intake (median, 17 g/day), multivariate relative risks, after adjustment for age, sex, community, total energy intake, and known cardiovascular risk factors, were 0.77 (95% confidence interval (CI): 0.42, 1.42) for the second quartile (12 g/day), 0.66 (95% CI: 0.34, 1.25) for the third quartile (8 g/day), and 0.30 (95% CI: 0.12, 0.71) for the lowest quartile (5 g/day); p for trend = 0.005. An inverse relation was observed among both hypertensives and nonhypertensives; the respective relative risks with a one standard deviation increase in saturated fat intake (15.4 g/day) were 0.72 (95% CI: 0.52, 1.00) and 0.36 (95% CI: 0.14, 0.95). Intake of animal protein tended to correlate inversely with risk; the relative risk with a one standard deviation increase in animal protein intake (17.6 g/day) was 0.79 (95% CI: 0.61, 1.02); p = 0.07. Results are similar to those recently reported for US women and together help to explain the high rate of this stroke subtype in Asian countries, where intakes of these nutrients are low.

Adult↗
PubMed2003

Myeloid/natural killer cell precursor acute leukemia accompanied by homozygous protein C deficiency.

A patient with myeloid/natural killer (NK) cell precursor acute leukemia who was also homozygous for protein C deficiency was treated and showed a complete remission while he simultaneously received low molecular weight heparin. He presented with fever spikes, lymphadenopathy, and a bulky tumor of the anterior mediastinum. A bone marrow aspirate showed the infiltration of immature lymphoblastoid cells. The patient's diagnosis was determined to be myeloid/NK cell precursor acute leukemia by morphologic and immunophenotypic analysis (CD7(+)CD33(+)CD34(+)CD56(+)). The patient developed a thrombosis in his jugular vein on cannulation of the internal jugular vein. An examination of the serum levels and the activities of proteins C and S demonstrated a slight decrease in the protein C level but an undetectable protein C activity. The patient received the diagnosis of homozygous protein C deficiency, because both parents were found to have heterozygous protein C activity. Treatment of the patient's leukemia included induction chemotherapy (Ara-C and idarubicin) with concomitant administration of low molecular weight heparin for his homozygous protein C deficiency. He achieved a complete remission without expressing any thrombosis during the course of chemotherapy. To our knowledge, this is the first case ever described in which acute myeloid leukemia was complicated with homozygous protein C deficiency.

Acute Disease↗
PubMed2003

Can eradication therapy for Helicobacter pylori really improve the thrombocytopenia in idiopathic thrombocytopenic purpura? Our experience and a literature review.

Helicobacter pylori has recently been postulated to play a role in the pathogenesis of autoimmune diseases, including idiopathic thrombocytopenic purpura (ITP). We investigated the prevalence of H pylori infection and the effects of its eradication in 61 patients with ITP. H pylori infection was found in 50 patients (83%), an incidence significantly higher than not only healthy volunteers in Japan (60%) but also subjects in other reported ITP series (approximately 43%-71%). In our study, the mean age of H pylori-positive ITP patients (58.0 years) was significantly higher than that of H pylori-negative ITP patients (40.5 years). Bacterium eradication efforts were performed in 29 infected ITP patients and succeeded in 27 patients (93%). The 29 patients with eradicated H pylori infections showed significant increases in platelet counts compared with patients with uneradicated infections or who were H pylori-negative. During the follow-up period (median, 11.0 months), 16 (55%) of 29 patients achieved a major or a minor response. The patients who achieved a major response had not received previous prednisolone therapy, suggesting a relationship between prednisolone therapy and the response to eradication efforts. The assessment of H pylori infection and its eradication should be attempted in cases of ITP, because this approach may be a good new strategy for treating some ITP patients, especially elderly Japanese patients. Some regional factors have been suggested as causes of H pylori-associated ITP.

Adolescent↗
PubMed2003

Determination of T-cell receptors of clonal CD8-positive T-cells in myelodysplastic syndrome with erythroid hypoplasia.

We determined T-cell receptor alpha-chain variable (TCRAV) and T-cell receptor beta-chain variable (TCRBV) region repertoires in peripheral bloods from patients with myelodysplastic syndrome (MDS) with erythroid hypoplasia. T-cells bearing TCR ADV14S1/BV5S2, AV21S1/BV21S4, and AV2S2/BV7S2 segments were markedly increased in three of four MDS patients, respectively. In addition, there was a positive relationship between the increase in the number of CD8-positive T-cells and the expression levels of these TCR transcripts. These findings suggest that CD8-positive T-cells monoclonally or oligoclonally expanded in the peripheral blood. We also determined the nucleotide and amino acid sequences of the complementarity-determining region 3 (CDR3) of TCR alpha- and beta-chains of the expanded T-cells. Unique sequences were detected in a high percentage of the respective CDR3 clones. The gene segment of the variable and joining regions, however, varied among the patients. The deduced amino acid sequences of CDR3 were heterogeneous among the patients, and there was no common motif. These results indicate there is monoclonal or oligoclonal proliferation of CD8-positive T-cells in MDS patients with erythroid hypoplasia, and suggest that these proliferating T-cells are responsible for the pathogenesis of the MDS entity.

Aged↗
PubMed2003

Cyclosporin A therapy for patients with myelodysplastic syndrome: multicenter pilot studies in Japan.

We examined the efficacy of cyclosporin A (CsA) in 50 patients with myelodysplastic syndrome (MDS) consisting from 47 of RA, 1 of RARS, and 2 of RAEB. These patients showed various marrow cell types including hypo-, normo-, and hypercellularity. Patients belonged to the following International Prognostic Scoring System (IPSS) risk groups: 4 of low, 41 of intermediate-1, and 5 of intermediate-2. The median CsA dose was 4.58mg/kg, and treatment responses were classified according to the International Working Group (IWG) criteria. Hematological improvement (HI) was observed in 30 (60%) patients, and all of them were belonged to RA. In the patients with RARS or RAEB, no efficacy was observed. Four (8%) of the responders achieved partial remission (PR) with granulocytes > or = 1500microl(-1), Hb>11g/dl and platelets > or = 100,000microl(-1). Higher response rate (53%) was shown in erythroid lineage (HI-E) compared to platelet (HI-P, 36%) or neutrophil lineage (HI-N, 35%). When we analyzed the correlation between the response to CsA therapy and the karyotype or HLA type, there were significantly more responders with good karyotype or DRB1*1501 than with intermediate/poor karyotypes or with other HLA types. These results indicate the usefulness of CsA therapy for MDS patients with any marrow cellularity, especially for erythroid lineage and patients with good karyotype or DRB1*1501.

Adolescent↗
PubMed2003

Immunosuppressive treatments for myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders, while, immunological abnormalities are frequently observed in patients with MDS. Several reports revealed that about 10% of MDS patients have clinical autoimmune disorders like skin vasculitis, rheumatic disease, or autoimmune hemolytic anemia. Furthermore, serological immunological abnormalities like hyper- or hypogammaglobulinemia, positivities of antinuclear antibody, positivities of direct Coombs test, or inverted CD4/8 ratios were found in 18-65% of patients with MDS. Recently immunosuppressive therapies including prednisolone, antithymocyte globulin, and cyclosporin A (CsA) are used to treat cytopenia in some patients with MDS. We examined the efficacy of CsA in 50 patients with MDS. Hematologic improvement was observed in 30 (60%) patients especially for erythroid lineage. There were significantly more responders with good karyotype or DRB1*1501 than with intermediate/poor karyotypes or with other HLA types. MDS with erythroid hypoplasia is a rare form of MDS, and has not yet been clearly defined. We reported four patients with MDS with erythroid hypoplasia who had morphological evidence of myelodysplasia and low percentage of erythroid precursors. Rearrangements of the TCR-beta and -gamma genes were seen in these patients using Southern blot and PCR analysis. Also they had skewed TCR usages using TCR repertoire analysis. Their anemia drastically improved with CsA therapy. We have to establish the clinical usefulness of immunosuppressive therapy in MDS patients and simple tools for revealing T-cell mediated myelosuppression in the individual patients for decision-making.

Autoimmune Diseases↗
PubMed2003

Smoking raises the risk of total and ischemic strokes in hypertensive men.

To examine the relation between cigarette smoking and risk of stroke and coronary heart disease among Japanese, we conducted a 14-year prospective study of 3,626 men aged 40-69, initially free from history of stroke and coronary heart disease. We identified 257 strokes (75 hemorrhagic and 173 ischemic strokes) and 100 coronary heart disease events. When we adjusted for age and other cardiovascular risk factors, a significant excess risk among current smokers of > 20 cigarettes/day vs. never-smokers was found for total stroke (relative risk (RR) = 1.6 (95% confidence interval (CI), 1.1-2.4)). The excess risk of total stroke was particularly evident among hypertensives (RR = 2.3 (1.2-4.4)). The multivariate RR of ischemic stroke was 1.6 (1.0-2.5) for total subjects, and 2.2 (1.0-5.0) among hypertensives. Significant excess risks among current smokers of > 20 cigarettes/day vs. never-smokers were also found for coronary heart disease (RR = 4.6 (1.6-12.9)) and total cardiovascular disease (1.9 (1.3-2.7)). The estimated proportion of the events attributable to current smoking was 30 (95% CI, 11-44)% for total stroke and 34 (5-54)% for coronary heart disease. In conclusion, current smoking of > 20 cigarettes per day increased the risk of both total stroke and ischemic stroke among Japanese middle-aged men, and particularly among middle-aged hypertensive men.

Adult↗
PubMed2003

Ankle-arm blood pressure index and cardiovascular risk factors in elderly Japanese men.

Low ankle-arm systolic blood pressure index (AAI) correlates with various cardiovascular risk factors and with risk of subsequent coronary heart disease and stroke in Western countries. However, few epidemiological data are available among Japanese, in whom the reported prevalence of peripheral artery disease is low. We examined the relationship between AAI and cardiovascular risk factors among 1,219 men aged 60 to 79 years in two Japanese communities in 1999 and 2000. The prevalence of AAI<0.90 was 5% in both communities. Hypertension, major ECG abnormality, current smoking, and history of stroke were associated with two- to four-fold higher prevalence of AAI<0.90. One-standard deviation increments of body mass index and high density lipoprotein-cholesterol levels were associated with 60% and 40% lower prevalence of AAI<0.90, respectively. Although the prevalence of low AAI in Japanese elderly men is lower than that reported in the Unites States and European studies, similar correlations of low AAI with cardiovascular risk factors were observed among different ethnic groups. Low AAI is suggested to be a predictor for stroke among Japanese men, which should be confirmed by a prospective study.

Age Distribution↗
PubMed2003

Improvement in Japanese clinical laboratory measurements of total cholesterol and HDL-cholesterol by the US Cholesterol Reference Method Laboratory Network.

BACKGROUND: Accurate and precise measurements of total cholesterol (TC) and HDL-cholesterol (HDL-C) are necessary for effective diagnosis and treatment of lipid disorders. We studied the impact of TC certification and HDL-C evaluation in Japanese clinical laboratories to standardize their measurements. METHODS: We selected 78 laboratories participated at least twice for TC and 46 laboratories participated twice for HDL-C in the standardization protocols developed by the Cholesterol Reference Method Laboratory Network (CRMLN). We compared the initial and subsequent results using the performance guidelines established by US National Cholesterol Education Program (NCEP). RESULTS: For TC, mean percentage bias of all participants was -0.93% and -0.49% for the initial and second rounds, respectively. Mean within-sample CV was 0.72% and 0.69% for the initial and second rounds, respectively. For HDL-C, mean percentage bias of all participants was -1.86% and -0.06% for the initial and second events, respectively. Mean among-run CV was 1.56% and 1.58% for the initial and second events, respectively. CONCLUSIONS: TC accuracy in the second round than the initial round tended to improvement although statistically not significant, however in the five years follow-up, mean absolute percentage bias was reduced over time. HDL-C accuracy was statistically improved in the second event than the initial event. The precision for both TC and HDL-C did not change. This study shows CRMLN protocols contribute effectively to improvement of TC and HDL-C performance.

Certification↗
PubMed2003

[A follow-up study on mental and physical function function among stroke patients: comparisons between admission and discharge status in a rehabilitation-specialized hospital].

PURPOSE: To assess results of a 5 year-follow-up, in terms of disability, depression, quality of life, and social network in cases of stroke patients. This report deal with results at admission and discharge (in average, from 2.5 to 6 months of the onset) in a rehabilitation-specialzed hospital. OBJECT AND METHOD: The subjects were 87 stroke patients hospitalized in the Ibaraki Prefectural University Hospital. They were 64 men and 23 women, and their age were between 42 and 79 with an average of 59 years. Systematic evaluation for mental and physical functions was conducted at admission and discharge, and it is intended that the evaluation will be repeated 1, 2, 3 and 5 years from the stroke onset. RESULTS: There were substantial improvements in motor functions, general intelligence, and the status of dementia during the hospitalization. Activities of daily living and degrees of job execution and satisfactory were also improved. The prevalence of depression remained 40%, and the acceptance of limb paralysis or reduced quality of life did not change. Social network scores declined. DISCUSSION: Lack of improvement of depressive status and quality of life, and deterioration social network may increase the rist of major difficulties after discharge of stoke patients. Prevention programs at hospital may be necessary to cope with these potential problems.

Activities of Daily Living↗
PubMed2002

Trends in the incidence of coronary heart disease and stroke and the prevalence of cardiovascular risk factors among Japanese men from 1963 to 1994.

PURPOSE: To determine trends in the incidence of cardiovascular disease in Japan, we examined observational data on coronary heart disease, stroke, and cardiovascular risk factors among urban Japanese working men. SUBJECTS AND METHODS: The surveyed population included all male employees aged 40 to 59 years who worked for eight industrial companies in Osaka, the second largest metropolitan city in Japan. Surveillance for cardiovascular disease and risk factors was conducted from 1963 to 1994. RESULTS: The age-adjusted incidence of coronary heart disease increased from 0.4 per 1000 person-years during 1963 to 1970, to 1.5 per 1000 person-years during 1979 to 1986, and then plateaued until 1987 to 1994 (P for trend = 0.002), whereas the incidence of stroke declined from 1.2 per 1,000 person-years during 1971 to 1978, to 0.6 per 1,000 person-years in 1987 to 1994 (P for trend = 0.02). The age-adjusted mean (+/- SD) total cholesterol level, which was 4.87 +/- 2.88 mmol/L during 1963 to 1966, increased to 5.11 +/- 0.62 mmol/L during 1982 to 1983 (P <0.001), and 5.09 +/- 0.75 mmol/L during 1990 to 1991. Both mean systolic and diastolic blood pressures increased by 1 mm Hg between the periods of 1966 to 1967 and 1982 to 1983, and declined below the 1966 to 1967 levels during 1990 to 1991. The prevalence of smoking declined from 72% during 1975 to 1976, to 58% during 1990 to 1991 (P for trend <0.001). CONCLUSION: Although these findings were limited to urban middle-aged men, the increase in serum cholesterol is likely to attenuate the reduction in future rates of coronary heart disease in Japan that would have been expected to result from the declining prevalence of smoking.

Adult↗
PubMed2002

One-year community-based education program for hypercholesterolemia in middle-aged Japanese: a long-term outcome at 8-year follow-up.

To examine a long-term effect of community-based education program for hypercholesterolemia and an effect modification by apolipoprotein E polymorphism, we conducted a 1-year randomized clinical trial with 8 year-follow-up. One hundred four persons aged 40-64 years who had serum total cholesterol levels between 6.21 and 7.73 mmol/l (240 and 299 mg/dl) in 1988-89 cardiovascular risk surveys were enrolled in the trial. The intervention group (n=51, 82% for women) attended eight education classes in 1 year, while the control group (n=53, 85% for women) attended only two classes. Both groups were invited to the subsequent annual surveys. The mean serum cholesterol was 0.24-0.26 mmol/l less in the intervention than in the control group at both 6 month and 1 year (P=0.03, each) while the proportion of subjects using hypolipidemic agents was 0 and 6% in both groups, respectively. During 8-year follow-up, the probability of using hypolipidemic agents and/or total cholesterol > or =7.76 mmol/l was 51% in the education group and 69% in the control group; the risk ratio in the intervention vs control groups was 0.62 (95% CI: 0.36-1.06). When stratified by the apolipoprotein E polymorphism examined for 78% of the subjects, the risk ratio was 0.61 (0.31-1.18) among subjects without e4 allele (n=59) and 0.55 (0.14-2.14) among those with e4 allele (n=22). The intervention group had reduced intake of egg, fish egg, butter, mayonnaise and fatty meat compared to the control group at 6-month, 1- and 8-year follow-up. In conclusion, our community-based program was effective in reducing serum total cholesterol levels non-pharmacologically during the first year, and also reduced the likelihood of progressive worsening of hypercholesterolemia during the subsequent 8 years, regardless of the apolipoprotein E polymorphism.

Adult↗
PubMed2002

Determinants of platelet aggregation in 50-70-year-old men from three Japanese communities.

To investigate the association of lifestyle and constitutional variables with platelet aggregation, we examined the platelet aggregation, serum fatty acid composition, alcohol intake, smoking, and dietary intake of seafood and soybean estimated by a 1-week dietary record in 448 males aged 50-70 in three rural Japanese communities: Ikawa, Akita prefecture (northeast coast), Noichi, Kochi prefecture (southwest coast), and Kyowa, Ibaraki prefecture (central inland). Platelet aggregatory threshold index (PATI) was used to determine the minimum concentration of adenosine 5'-diphosphate (ADP) that caused a non-reversible aggregation of platelets. Intake of seafood and n3-polyunsaturated fatty acid and ingestion of ethanol were higher in the northeast coastal community than in the other two communities. Mean platelet and white blood cell counts were lower in northeast coastal community than in the other two communities. The geometric mean PATI was higher (i.e. platelet aggregation was lower) in the northeast coastal community than the other two communities. Within the entire sample, platelet aggregation correlated inversely with serum level of n3-polyunsaturated fatty acids and gamma-glutamyl transpeptidase, an index of alcohol consumption, and positively with platelet and white blood cell counts. Platelet aggregation tended to correlate positively with serum arachidonic acid. There was no correlation between smoking and platelet aggregation. Our results suggest that seafood intake and moderate alcohol consumption reduce platelet aggregation.

Aged↗
PubMed2002

The relation of anger expression with blood pressure levels and hypertension in rural and urban Japanese communities.

OBJECTIVE: To examine the relation of anger expression with blood pressure and hypertension among Japanese. DESIGN: A cross-sectional study. METHODS: Subjects were 4374 men and women aged 30-74 years from rural and urban communities. Anger expression was estimated using the anger-out and anger-in scores of the Spielberger Anger Expression Scale. Multiple linear regression analyses were performed to estimate the associations of anger expression scores with blood pressure. Proportions of hypertensives among the tertiles of anger expression scores and the relative odds of hypertension for low versus high tertiles of anger expression scales were calculated using logistic regression models. RESULTS: The anger-out score was inversely associated with systolic and diastolic blood pressure levels for men; a four-point (one standard deviation) lower anger-out score was associated with 1.6 mmHg [95% confidence interval (CI), 0.6-2.6] greater systolic blood pressure and 0.6 mmHg (95% CI, -0.03 to 1.2) greater diastolic pressure after adjustment for age, body mass index, alcohol intake, smoking category, and parental history of hypertension. The adjusted relative odds of hypertension for low versus high tertiles of anger-out was 1.60 (95% CI, 1.19-2.15). These inverse associations were more evident among men with low coping behavior than among those with high coping behavior. For women, the anger-out score was not associated with blood pressure. There was no relation between the anger-in score and either blood pressure or hypertension in either men or women. CONCLUSIONS: This study suggests that Japanese men who do not express their anger, especially when they have low coping behavior, may have an increased risk of high blood pressure.

Adult↗