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Takashi Shimamoto

Publications and source records attributed to Takashi Shimamoto.

At least 37 records · Page 2Linked to original sources
PubMed2004

Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese.

BACKGROUND: To date, no prospective studies have examined the association between serum homocysteine levels and the risk of stroke and stroke subtypes in Asian populations. METHODS AND RESULTS: A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11 846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for the other two communities. By the end of 2000, we identified 150 incident strokes, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Serum total homocysteine levels were measured by high-performance liquid chromatography. Compared with control subjects, total (n=150), hemorrhagic (n=52), and ischemic (n=98) strokes had higher geometric mean values of total homocysteine and higher proportions of homocysteine > or =11.0 micromol/L. The multivariate odds ratios (95% CI) for highest (> or =11.0 micromol/L) versus lowest quartiles (<7.0 micromol/L) of homocysteine after adjustment for body mass index, smoking, alcohol intake, hypertension, serum total cholesterol, and other cardiovascular risk factors were 2.99 (1.51 to 5.93) for total stroke, 3.89 (1.60 to 9.46) for ischemic stroke, 3.36 (1.27 to 8.90) for lacunar infarction, and 1.63 (0.44 to 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5-micromol/L increase in homocysteine were 1.40 (1.09 to 1.80), 1.52 (1.07 to 2.14), 1.48 (1.01 to 2.18), and 1.10 (0.76 to 1.59). The excess risk of total and ischemic strokes did not vary significantly according to sex, age, smoking status, or hypertensive status. CONCLUSIONS: High total homocysteine concentrations were associated with the increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women.

Adult↗
PubMed2004

Alpha-adducin G460W polymorphism, urinary sodium excretion, and blood pressure in community-based samples.

BACKGROUND: There is limited evidence on the gene-environmental interaction among alpha-adducin G460W gene polymorphism, sodium intake, and blood pressure (BP) levels in a general population. One hypothesis is that the association between G460W polymorphism and BP is more evident among persons with higher sodium intake than those with lower sodium intake. METHODS: We conducted a population-based cross-sectional study of 2823 men and women aged 30 to 74 years in a Japanese rural community to examine the association of the alpha-adducin G460W polymorphism with BP levels stratified by salt intake, as estimated by 24-h urine collection and dietary questionnaire. RESULTS: There was no difference in systolic or diastolic BP levels among the GG, GW, and WW groups for women, but for men, mean systolic BP tended to be higher in the WW group than in the GG group. When we stratified men according to sodium excretion/intake, mean systolic BP was significantly higher in the WW group than in the GG group among men with higher urinary sodium excretion (138.8 v 133.6 mm Hg, P =.02) and tended to be higher among men with higher previous sodium intake. No genetic association was found among women or among men with lower urinary sodium excretion or lower sodium intake. CONCLUSIONS: The alpha-adducin WW genotype was associated with higher systolic BP among men with a higher sodium intake.

Adult↗
PubMed2004

Urinary cyclic GMP excretion and blood pressure levels in a general population.

Dysfunction of the nitric oxide (NO) system is potentially involved in the development of hypertension, but only limited data are currently available from experimental or clinical studies. We investigated cross-sectionally the relation between urinary excretion of cyclic guanosine 3',5'-monophosphate (cyclic GMP), a second messenger of NO, and hypertension in a general population sample of Japanese men and women. The samples comprised 1541 subjects (788 men and 753 women) aged 40-79 years who participated in cardiovascular risk surveys between 1997 and 2002 and underwent a 24h urine collection. Urinary excretion of cyclic GMP was measured using a 125I-labeled cyclic GMP radioimmunoassay, and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). Urinary cyclic GMP excretion was 66.0+/-62.0nmol/mmol creatinine (mean+/-S.D.). Compared with normal blood pressure individuals, the multivariate-adjusted mean value of urinary cyclic GMP excretion was significantly higher in people with moderate hypertension, but not higher in severe hypertension. Among subjects with hypertensive end-organ damage, we observed reduced urinary cyclic GMP excretion in severe hypertension and no increased excretion in moderate hypertension, compared with normal blood pressure. Although we had the limited number of subjects with severe hypertension (n=15), our data suggest that NO bioactivity may be increase in the early stage of hypertension but decreased in severe hypertension with end-organ damage.

Adult↗
PubMed2004

Prevalence and correlates of carotid atherosclerosis among elderly Japanese men.

We determined intima-media thickness (IMT) and diameter of carotid artery and estimated their correlations with cardiovascular risk factors in 1129 men aged 60-74 years, who participated in a cardiovascular risk survey in three Japanese communities. The multivariate odds ratios (95% confidence interval) for the maximum IMT > or = 1.1 mm in the common carotid artery (CCA) were 1.3 (1.1-1.5) per 4 years of age, 1.8 (1.4-2.5) for hypertension, 1.4 (1.2-1.7) for a 34.4 mg/dl increase in serum total cholesterol, 0.7 (0.6-0.8) for a 14.7 mg/dl increase in serum HDL-cholesterol, and 2.4 (1.1-5.0) for history of stroke, while the maximum IMT > or = 1.5mm in the internal carotid artery (ICA) were 1.6 (1.4-1.8) per 4 years of age, 1.9 (1.5-2.4) for hypertension, 1.6 (1.2-2.1) for current smoking, and 3.5 (1.6-7.6) for history of stroke. Age, height, hypertension, current smoking, ethanol intake and history of coronary heart disease were independent determinants of both the outer and inner CCA diameter. Maximum IMT correlated positively with the outer diameter and inversely with the inner diameter in the CCA. Carotid atherosclerosis suggests to be a risk factor for stroke among Japanese elderly men, although future prospective studies are required to confirm this finding.

Age Factors↗
PubMed2004

Association of lymphocyte sub-populations with clustered features of metabolic syndrome in middle-aged Japanese men.

To examine the relationship between altered cellular immune status and clustered features of the metabolic syndrome, we measured body mass index (BMI), serum concentrations of high-density lipoprotein-cholesterol, triglycerides, fasting plasma glucose, and blood pressure levels as well as differential leukocyte counts and lymphocyte sub-populations among 439 apparently healthy Japanese men aged 35-60 years. The components of the metabolic syndrome were defined based on the following criteria: BMI >/=25.0 kg/m(2), fasting plasma glucose >/=6.11 mmol/l, systolic blood pressure >/=130 mmHg and/or diastolic blood pressure >/=85 mmHg, high-density lipoprotein (HDL)-cholesterol <1.03 mmol/l, and fasting triglyceride >/=1.69 mmol/l. Counts of total leukocyte, total lymphocyte, CD3 + T cell, CD4 + T cell, and CD4 + CD45RO + T cell significantly correlated with the number of components of the metabolic syndrome (0, 1, 2, and 3+) after adjustment for age and smoking status. These findings were more evident among smokers than among non-smokers. The counts of total leukocytes, total lymphocytes and more specifically memory (CD4 + CD45RO + T) cells were elevated with clustered features of the metabolic syndrome in middle-aged men, which suggest the involvement of altered cellular immune status in the pathogenesis of atherosclerosis.

Adult↗
PubMed2004

Relationships of craniofacial morphology and body mass index with sleep-disordered breathing in Japanese men.

OBJECTIVE/HYPOTHESIS: Obesity is an established risk factor for sleep-disordered breathing, but the impact of craniofacial morphology is uncertain. The aim of this study was to assess the impact of craniofacial morphology and body weight on sleep-disordered breathing in Japanese men. STUDY DESIGN: A cross-sectional study. METHODS: We measured body mass index, seven cephalometric variables, and 3% oxygen desaturation index recorded by a pulse oximeter in 313 Japanese men aged 20 to 65 years who attended a sleep clinic. We defined craniofacial score as the sums of quartile points (0-3) for distance from sella to nasion and that from hyoid bone to mandibular plane. RESULTS: The mean value of 3% oxygen desaturation index and odds ratios of 3% oxygen desaturation index 15 or greater progressively increased with craniofacial score as well as body mass index. Multivariate odds ratios associated with craniofacial score were higher in men with body mass index 25.0 kg/m or greater (odds ratio = 4.2, 95% confidence interval [CI] = 2.1-8.6) than in men with lower body mass index (odds ratio = 1.6, 95% CI = 0.7-3.6). CONCLUSIONS: Our results imply the importance of cephalometric assessment in overweight patients.

Adult↗
PubMed2004

Relationship between sleep-disordered breathing and blood pressure levels in community-based samples of Japanese men.

To examine the relationship between sleep-disordered breathing (SDB) and blood pressure levels among Japanese men, we conducted a population-based cross-sectional study of 1,424 men aged 40-69 years in rural and urban communities. The 3% oxygen desaturation index (ODI) was selected as the indicator of SDB, representing the number of desaturation events per hour of recording time in which blood oxygen fell by > or = 3% according to overnight pulse oximetry. To estimate the associations of 3% ODI levels with blood pressure levels and hypertension, multiple linear regression and logistic regression analyses were performed. The 3% ODI level was positively associated with systolic and diastolic blood pressure levels (SBP/DBP); a 5 event per hour increment of the 3% ODI level was associated with 0.8 mmHg (95% confidence interval [CI], 0.0-1.6) greater SBP and 0.7 mmHg (95% CI, 0.3-1.1) greater DBP after adjustment for age, body mass index, ethanol intake, smoking category and community. The multivariate odds ratio of hypertension for the low vs. high category of 3% ODI level was 1.63 (95% CI, 1.1-2.5). These associations were more evident among overweight than non-overweight individuals. The significant association of nocturnal oxygen desaturation with high blood pressure levels suggests that SDB plays a role in the development of hypertension among Japanese men.

Adult↗
PubMed2004

High sodium intake strengthens the association between angiotensinogen T174M polymorphism and blood pressure levels among lean men and women: a community-based study.

Evidence on the effect of salt intake on the interaction between angiotensinogen (AGT) T174M polymorphism and high blood pressure is sparse. We therefore conducted a large population-based cross-sectional study of 2,823 men and women aged 30-74 in a Japanese farming community to examine associations between AGT polymorphism and blood pressure levels stratified by age (30-64 and 65-74), body mass index (BMI; median), and salt intake (median) estimated by 24-h urine collection and dietary questionnaire. Our a priori hypothesis is that individuals, particularly younger and non-overweight individuals, with the 174M allele have elevated blood pressure levels in response to higher sodium intake, and thus the association between T174M polymorphism and blood pressure is more evident among individuals with higher sodium intake than those with lower sodium intake. There were no differences in systolic or diastolic blood pressure levels (SBP or DBP) between the TT and TM+MM genotype groups overall. However, the mean difference in DBP between the TM+MM and TT groups was +1.0 mmHg in subjects of younger age (p=0.06), +1.7 mmHg in non-overweight subjects (BMI<23.5 kg/m2, p=0.01), and +2.3 mmHg in younger and non-overweight subjects (p = 0.002). Furthermore, among younger and non-overweight subjects, blood pressure differences were larger for those with higher urinary sodium excretion (+3.1 mmHg, p = 0.03), those with a higher sodium/potassium excretion ratio (+4.1 mmHg, p=0.007), those with higher present sodium intake score (+3.0 mmHg, p=0.003), and those with higher past sodium intake score (+3.4 mmHg, p<0.001). In conclusion, AGT T174M polymorphism was associated with higher DBP levels in younger and non-overweight Japanese. This association was more evident among subjects with higher sodium intake.

Adult↗
PubMed2004

[Trends for stroke incidence, severity, and prognosis in a rural community with a long-term stroke prevention program].

OBJECTIVE: To examine the benefit of a long-term community-based stroke prevention program, we explored 35 years of surveillance data of stroke incidence for residents in a rural area in Japan. METHOD: The surveyed community was Ikawa town (population in 2000 was 6,116) in Akita prefecture, where a community-based stroke prevention program has been conducted since 1963. Incidence rates and numbers of stroke episodes, proportions for loss of consciousness and motor paralysis at onset, proportions for each seriousness category (A: death within one day after onset, B: death during 2-7 days after onset, C: survival more than 8 days after onset with complete hemiparesis, D: survival more than 8 days after onset with incomplete or no hemiparesis), and one-year survival rates and activity of daily living were investigated for 1964-69, 1970-79, 1980-89 and 1990-98. RESULTS: Stroke incidence declined 66% and 64% among the 30-69 years age group and 70 years over age group, respectively between 1964-69 and 1990-98. Incident numbers of stroke episodes declined 41% among those aged 30-69 years and, while it increased 100% in the 70 years over age group, this was much less than the increase rate of 271% rated for the corresponding aged population growth over time. In the 30-69 years age group, the proportion of patients with no loss of consciousness at onset increased from 53-64% during the former three periods to 79% in 1990-98. The proportion of patients with no motor paralysis also increased progressively over the study periods and the proportions for A or B categories in the seriousness classification decreased between 1964-69 and 1990-98 while the proportion in the D category increased between 1980-89 and 1990-98. One-year survival rates increased from 71% and 36% in 1964 to 86% and 61% in 1990-98 among the 30-69 years age group and 70 years over age group, respectively. With both, the numbers of totally dependent patients at one-year after onset, did not change significantly over time, despite the marked increase in the population of risk. CONCLUSION: The present study showed that a long-term community-based stroke prevention program can not only decrease stroke incidence and number of episodes, but also reduce the likelihood of severe stroke attack and improve prognosis, thereby suppressing the increase of totally dependent patients expected from growth of the old population in the community.

Adult↗
PubMed2004

Hypermethylation of E-cadherin gene is frequent and independent of p16INK4A methylation in non-small cell lung cancer: potential prognostic implication.

E-cadherin gene is often termed a 'metastasis suppressor' gene and inactivation of this gene through promoter methylation occurs in various epithelial cancer. This study assessed the methylation status of p16INK4a and E-cadherin genes, correlated with clinical characteristics in lung cancer patients. Forty-five patients with non-small cell lung cancer (NSCLC) were evaluated for methylation status of p16INK4a and E-cadherin genes by using the methylation-specific PCR. E-cadherin expression in tumor samples was examined by immunohistochemistry. Overall duration of survival in different subsets of NSCLC with or without p16INK4a or E-cad methylation at diagnosis was compared by using the Kaplan-Meier method and log-rank test. We found the hypermethylation of p16INK4a gene in 38% (17/45) of our subjects. While the E-cadherin gene was hypermethylated in 62% (28/45) related with reduced E-cadherin expression, and methylation status of both p16INK4a and E-cadherin genes seemed to be independent. Seventy-six percent (34/45) of NSCLC patients had an abnormal methylation pattern in at least one gene. Although there was no difference in overall survival of patients between methylated p16INK4a and unmethylated p16INK4a, NSCLS patients with hypermethylation of both genes (concordant pattern) had a significantly good prognosis. In contrast, NSCLC patients with hypermethylated p16INK4a but un-methylated E-cadherin gene (discordant pattern) had a significantly poor prognosis. E-cadherin and p16INK4a are commonly methylated in NSCLC and the methylation pattern of p16INK4a and E-cadherin genes may have prognostic value for the outcome of NSCLC patients.

Adult↗
PubMed2004

[Relapse of diffuse large B cell lymphoma to CD20-negative multiple cutaneous tumors immediately after anti-CD20 monoclonal antibody (rituximab) therapy].

A 60-year-old male was referred to our hospital because of cervical lymphadenopathy and a left hilar abnormal shadow seen on chest X-ray in May 1999. The pathological findings of the cervical lymph nodes revealed that the patient had a malignant lymphoma, of the diffuse large B cell type, at clinical stage IIIB. Immunohistochemistry demonstrated that the lymphoma cells were positive for CD11a, CD19, CD20, CD23, CD25, CD45, IgM, IgD and lambda, but negative for CD5. Although a complete remission was obtained after 8 courses of CHOP therapy, the patient relapsed 32 months later. Two courses of a half dose of CHASE therapy consisting of CPM, ara-C, VP-16 and dexamethasone, followed by rituximab (600 mg/week x4) resulted in a transient re-induction of complete remission. However, multiple cutaneous tumors became apparent just 10 days after the last rituximab therapy. Immunohistochemistry of the cutaneous tumors revealed infiltration of CD20-negative lymphoma cells. A series of chemotherapy including high-dose MTX was ineffective, and the patient died in August 2003. Autopsy findings revealed the systemic intra-capillary infiltration of CD20 negative-lymphoma cells into multiple organs, including the lungs, liver, and kidneys. A CD20 negative-clone selected by rituximab therapy appeared to have expanded in this case.

Antibodies, Monoclonal↗
PubMed2003

Prospective study of major and minor ST-T abnormalities and risk of stroke among Japanese.

BACKGROUND AND PURPOSE: The association between minor ST-T abnormalities and stroke incidence has not been well elucidated. We sought to examine the relationship between nonspecific minor or major ST-T abnormalities and the incidence of stroke among Japanese men and women. METHODS: A 15.4-year prospective study was conducted with 10 741 men and women aged 40 to 69 years in 4 Japanese communities. Electrocardiograms were taken at baseline and were read according to the Minnesota Code. The incidence of stroke was ascertained using systematic surveillance. RESULTS: During the 15.4-year follow-up, 602 strokes (339 ischemic strokes, 129 intracerebral hemorrhages, 80 subarachnoid hemorrhages, and 54 unclassified strokes) occurred. Both men and women with major ST-T abnormalities had approximately 3-fold higher age-adjusted relative risk and 2-fold higher multivariate-adjusted relative risk of total stroke than did those without such abnormalities. Men with minor ST-T abnormalities had a 2.3-fold higher age-adjusted relative risk of total stroke, both ischemic and hemorrhagic, than did those without such abnormalities. After we adjusted further for hypertension category, the relative risk for minor ST-T abnormalities was reduced substantially but remained statistically significant: 1.8 (95% CI, 1.3 to 2.4) for total stroke, 1.9 (95%CI, 1.3 to 2.8) for ischemic stroke, and 1.7 (95% CI, 1.0 to 3.0) for hemorrhagic stroke. For women, however, there was no relation between minor ST-T abnormalities and stroke incidence. CONCLUSIONS: Minor ST-T abnormalities have predictive value for the risk of total stroke, both ischemic and hemorrhagic, among middle-aged Japanese men, as do major ST-T abnormalities for both sexes.

Adult↗
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↗