Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.

AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Population-based distribution of plasminogen activity and estimated prevalence and relevance to thrombotic diseases of plasminogen deficiency in the Japanese: the Suita Study.

Reduced plasminogen activity with a normal level of antigen is commonly observed in Japanese individuals. The first reported patient with plasminogen deficiency was accompanied with deep vein thrombosis. The present study examines whether heterozygous or homozygous deficiency of plasminogen is a risk factor for thrombotic disease. This study measures the plasminogen activity of 4517 individuals in the general population, determines the cut-off to define plasminogen deficiency, and identifies plasminogen deficiencies in the control groups and thrombotic disease groups. In another study, we examined the phenotypes of consecutive patients with homozygous plasminogen deficiency detected in our hospital. We found 173 and two of 4517 individuals to have heterozygous and homozygous deficiency with normal plasminogen antigen level, respectively, and 19 to have heterozygous deficiency with reduced antigen levels. The incidence of plasminogen deficiency in an age- and sex-matched control group (13/324, 4.01% for deep vein thrombosis or 13/330, 3.94% for stroke) selected from the 4517 individuals was not significantly different from those in patients with deep vein thrombosis (3/108, 2.78%) or cardioembolic stroke (6/110, 5.55%). Among 19 patients with homozygous plasminogen deficiency showing about 10% plasminogen activity, none had deep vein thrombosis. These findings indicate that neither heterozygous nor homozygous plasminogen deficiency constitutes a significant risk factor for thrombotic disease.

Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study.

OBJECTIVES: Endothelium-derived nitric oxide plays a key role in the regulation of vascular tone. Recently, endothelial nitric oxide synthase (eNOS) gene polymorphisms were reported to be associated with hypertension or coronary spasm. We investigated the association between the eNOS gene polymorphisms and hypertension in a large population-based sample of 4055 Japanese. DESIGN AND METHODS: We investigated two polymorphisms of the eNOS gene, Glu298Asp polymorphism of exon 7 and T(-786)C polymorphism of the promoter region. The genotype distribution in hypertensive subjects was compared to that in the other subjects. The influence of the genotype on blood pressure values was analyzed in the subjects not taking hypertensive medication. The promoter activities of the eNOS gene with the (-786)T or (-786)C allele were measured by a luciferase reporter gene assay. RESULTS: There was significant linkage disequilibrium between the two polymorphisms (P < 0.0001). The genotype distribution of the Glu298Asp or T(-786)C polymorphism did not differ between the hypertensive and the other subjects. No significant differences in the blood pressure of subjects not taking hypertensive medication were observed among the three genotypes of Glu298Asp or T(-786)C polymorphisms. No significant differences in the promoter activity were observed between bovine endothelial cells transfected with the (-786)T and (-786)C alleles. CONCLUSIONS: Our data suggested that these polymorphisms of the eNOS gene are unlikely to be major factors in the susceptibility to hypertension in the Japanese population studied.

The aldehyde dehydrogenase 2 gene is a risk factor for hypertension in Japanese but does not alter the sensitivity to pressor effects of alcohol: the Suita study.

Excessive alcohol consumption is a potent risk factor for high blood pressure. About half of Japanese show an extremely high sensitivity to alcohol, which is due to a genetic deficiency in an isoenzyme of aldehydede-hydrogenase with a low Km (ALDH2). It is possible that the effects of alcohol consumption on blood pressure differ according to the ALDH2 genotype. The purpose of the present study was to assess the influence of the ALDH2 genotype on the pressor effects of alcohol. The influence of the ALDH2 genotype on blood pressure was investigated in a large cohort (4,000 subjects) representing the general population in Japan. The genotype was determined by the TaqMan method. The genotype was significantly associated with alcohol consumption, gamma-GTP level, and HDL cholesterol level in both males and females. The odds ratio for the presence of hypertension for the Glu/Glu genotype in comparison to other genotypes was 1.67 (p< 0.0001, odds ratio=1.37-2.08, 95% confidence interval) among males. In contrast, the ALDH2 genotype had no significant effects on blood pressure among females. To investigate whether the ALDH2 genotype affected the sensitivity to the pressor effects of alcohol, we analyzed the effects of the ALDH2 genotype (Lys/Lys+Lys/Glu=0, Glu/Glu=1) and the level of alcohol consumption on blood pressure values after adjusting for age and BMI (residuals after adjusting for age and BMI). Among males, while the level of alcohol consumption significantly affected systolic, diastolic and pulse pressure, no significant interaction was observed between the ALDH2 genotype and the level of alcohol consumption in determining blood pressure levels. These results suggest that the Glu/Glu genotype is a potent risk factor for hypertension among males mainly through its association with the level of alcohol consumption, and that the ALDH2 genotype does not affect the sensitivity to the pressor effects of alcohol.

Association of sodium channel gamma-subunit promoter variant with blood pressure.

The SCNN1G gene, located on human chromosome 16p12, encodes the gamma subunit of the amiloride-sensitive epithelial sodium channel, and mutations in SCNN1G can result in Liddle's syndrome or pseudohypoaldosteronism type I. We identified sequence variations in the promoter region of SCNN1G and examined the association between this polymorphism and blood pressure in a large cohort (n=4075) representing the general population in Japan. We found T(-1290)C, T(-501)G, G(-173)A, and G(-104)T polymorphisms in the promoter region of SCNN1G and confirmed the existence of T387C and T474C polymorphisms in exon 3 and the C1947G polymorphism in exon 13. Because the genotypes of the T(-1290)C, T(-501)G, G(-104)T, and T474C polymorphisms were in tight linkage disequilibrium, we selected the T474C and G(-173)A polymorphisms for an association study. The G(-173)A polymorphism of SCNN1G had a significant effect on systolic pressure (P=0.0050) and pulse pressure (P=0.0050). The AA genotype was associated with an 11 mm Hg drop in systolic pressure and an 8 mm Hg drop in pulse pressure and with a higher prevalence of hypotension (P=0.0195). A transient transfection assay using MDCK cells and human renal epithelial cells indicated that the promoter activity of the G(-173) allele was higher than that of the A(-173) allele. Although the effects of the A(-173) allele were recessive and although the AA genotype was found in just 0.7% of our study population, we observed that this variation of human SCNN1G had significant effects on blood pressure.

Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: characterization of malt lymphoma and reactive lymphoid hyperplasia.

Malignant lymphomas and reactive lymphoid hyperplasia (RLH) in the ocular adnexa are sometimes difficult to differentiate morphologically and have often been categorized together as a lymphoproliferative disorder. Immunogenotypic characters of these diseases have not yet been well clarified. This study included 76 cases of ocular adnexal lymphoproliferative disorders. These consisted of 52 cases of malignant lymphoma (43 primary and 9 secondary), 22 of RLH, and 2 borderline cases. There were slightly more male than female subjects. Diagnoses were based on morphology and immunophenotypic characteristics. Clonalities were detected by means of polymerase chain reaction (PCR), and immunoglobulin heavy-chain variable region (VH) genes were sequenced in 10 cases of mucosa-associated lymphoid tissue (MALT) lymphoma. MALT lymphoma constituted 86% (37 cases) of the primary lymphomas. MALT lymphomas were more indolent, more rarely disseminated, and had a lower death rate than the other primary lymphomas. Two patients exhibited coexistence of MALT and diffuse large B-cell lymphoma. The average age of patients with RLH was 5.5 years younger than that of those with MALT lymphoma. One of the cases of RLH later progressed to malignant lymphoma. B-cell clonality was detected by PCR in 57%, 55%, and 0% of primary lymphomas, MALT lymphomas and RLHs, respectively. Sequencing of VH genes revealed that the VH3 family was the most commonly expressed germline VH family (70%) and that DP-63, DP-54 and DP-47 genes were frequently found in the MALT lymphomas examined. PCR analysis was useful for differentiation between MALT lymphoma and RLH. Sequence analysis of VH genes showed that an autoimmune mechanism may be involved in the lymphomagenesis of ocular adnexal MALT lymphoma.

Low potentiality of angiotensin-converting enzyme gene insertion/deletion polymorphism as a useful predictive marker for carotid atherogenesis in a large general population of a Japanese city: the Suita study.

BACKGROUND AND PURPOSE: Some previous studies, almost all western, have investigated whether there is a relationship between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and carotid atherosclerosis. The results, however, have not been consistently positive. Further, there have been few investigations based on a large, general population. Therefore, the present study aimed to clarify whether ACE gene deletion polymorphism was associated with carotid atherosclerosis in a large Japanese general population with a more homogeneous genetic background than Caucasian populations. METHODS: Subjects aged 30 to 86 years were randomly selected from Suita City, located in Osaka, the second largest urban area of Japan, and included 1894 men and 2137 women. With the aid of high-resolution ultrasonography, carotid atherosclerosis was evaluated using our atherosclerotic indexes of intimal-medial thickness (IMT), plaque number (PN), plaque score (PS), and percentage of stenosis of the carotid artery assessed using high-resolution B-mode ultrasonography. ACE gene I/D polymorphism was detected by polymerase chain reaction. RESULTS: There were no significant differences among the ACE genotypes for age and conventional cardiovascular risk factors, except for systolic blood pressure (SBP) and the percentage of hypertension in men. The values of IMT, PN, and PS as carotid atherosclerotic indexes were not significantly different among genotypes for either sex. After adjusting for age, body mass index, smoking habit, high-density lipoprotein cholesterol, triglycerides, presence of hypertension, presence of diabetes mellitus, and presence of hyperlipidemia, the estimated ORs for the presence of IMT >/=1.10 mm (defined as thickened IMT), according to ACE genotype (DD versus II, DD+ID versus II, and DD versus ID+II), for men were 0.80 (95% CI 0.60 to 1.23), 0.89 (0.62 to 1.29), and 0.89 (0.70 to 1.28), respectively. On the other hand, the ORs for women after the same adjustment were 0.92 (95% CI 0.58 to 1.35), 0.93 (0.59 to 1.45), and 0.91 (0.59 to 1.27), respectively. CONCLUSIONS: Our present data suggest that ACE I/D polymorphism is not potentially a useful predictive marker for carotid atherogenesis when investigated in a large and homogeneous general Japanese population of 4031 subjects, a finding similar to that in a Caucasian population study, the Perth Carotid Ultrasound Disease Assessment Study, an Australian study based on a general population using 1111 subjects.

Lack of association between genetic polymorphism of CYP11B2 and hypertension in Japanese: the Suita Study.

Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a polymorphism in the 5'-flanking region of the CYP11B2 gene [T(-344)C] has been reported to be associated with blood pressure and plasma aldosterone levels. We investigated the association between this polymorphism and hypertension in a large population-based sample of 4,000 Japanese. The genotype distribution in hypertensive subjects (n=1,535) was compared to that in normotensive subjects (n=2,514). In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. All analyses were performed separately for men and women. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of C allele: 30.3% vs. 31.4%, p=0.48) or women (31.5% vs. 31.7%, p=0.93). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the T(-344)C polymorphism of CYP11B2 is unlikely to influence blood pressure status in the Japanese population.

T+31C polymorphism of angiotensinogen gene and essential hypertension.

A common variant at codon 235 of the angiotensinogen gene with methionine to threonine amino acid substitution (AGT M235T) has been reported as a genetic risk for essential hypertension. However, the frequency of AGT T235 was heterogeneous among races, and a positive association between AGT M235T and hypertension was not settled. To examine the association in a general population of Japanese (n=4013), we introduced the TaqMan polymerase chain reaction method and examined the relation between hypertension and T+31C polymorphism, which was in absolute linkage disequilibrium with AGT M235T. The C+31 allele of AGT was significantly associated with the positive family history of hypertension (FH) but not with the presence of hypertension or blood pressure. The subjects with CC tended to have hypertensive relatives, especially a hypertensive father or siblings, and its statistical significance was stronger in men. Adjustment of confounding factor did not alter the results of simple association study, suggesting that this positive association with FH is independent and significant. Our findings revealed that the TaqMan polymerase chain reaction method is a powerful tool for genetic association study with a large number of subjects and that AGT T+31C is significantly associated with paternal FH.

Second nation-wide study of atherosclerosis in infants, children and young adults in Japan.

This paper reports the results of the second nation-wide cooperative study of atherosclerosis in young Japanese, aged from 1 month to 39 years, who were autopsied between 1991 and 1995. Atherosclerotic lesions in 1066 aortas and 974 coronary arteries were classified into fatty streaks, fibrous plaques and complicated lesions and quantificated with the point-counting method. The results of this study were compared with those of the former study, which was conducted 13 years earlier in almost the same fashion as this study. Atherosclerosis of aorta, which was determined by surface involvement (SI) of atherosclerotic lesions and atherosclerotic index (AI), increased with age in both sexes of the former and the present studies and their tendency for the progression of the extent of atherosclerotic lesions appeared to be similar. In the coronary arteries, the mean values of SI and AI in the males of the present study were greater significantly than those in the male of the former studies and in the female of the both studies in the third and fourth decades. This difference suggests that atherosclerotic lesions are increasing in young Japanese males. It also suggests that these subjects may be increasingly susceptible to atherosclerotic cardiovascular disease with increasing age.

Multiple organ mucosa-associated lymphoid tissue lymphomas often involve the intestine.

BACKGROUND: Low grade mucosa-associated lymphoid tissue (MALT) lymphomas usually are confined to single extranodal organs. Although some case reports have been published, clinicopathologic characteristics of multiorgan MALT lymphomas remain unclear. METHODS: The authors evaluated 7 MALT lymphoma cases involving multiorgans in the past 7 years. In this period, they experienced 304 cases of MALT lymphomas. They analyzed the clinicopathologic features of these cases, including examination of clonal comparison among the lesions. RESULTS: The patients, 4 females and 3 males, were aged 55-68 years old (average, 60.1 years). Four cases showed multiple organ involvement at the initial diagnosis or after a short period. In the other three cases, primary foci were the stomach, thyroid gland, and ocular adnexa; after a rather long period (3 years or more), distant metastases were found. Although intestinal primary lymphomas are rather rare, six of the seven cases showed large intestinal involvement. Lymph node involvement was proven in only three cases. The patients were rather resistant to the various therapeutic approaches. Although six patients are alive, five are with disease. DNA analyses revealed that in five of the cases evaluated, identical clones were detected among the different affected organs. CONCLUSIONS: Multiorgan MALT lymphomas are rather rare. Most cases probably derived from a single clone, and lymphoma cells may selectively move among MALTs via a homing system with preferential involvement of the colon. Because multiorgan MALT lymphomas rarely achieve complete remission by treatment with combination chemotherapy or irradiation, MALT lymphomatous lesions should be checked carefully, especially in the large intestine.

Anthropometric measures, blood pressure and major laboratory examination results in the health check-up examination among the JPHC study participants at baseline survey. Japan Public Health Center-based Prospective Study on Cancer and Cardiovascular Diseases.

Health check-up data were compared in all 11 populations included in the cohort. The collected sample size was 23,313 in Cohort I and 24,654 in Cohort II. Height was greater in two urban populations, and body mass index (BMI) was largest in the two populations in Okinawa prefecture. Blood pressure was higher in the populations in northeast part of Japan and Okinawa prefecture, and lower in Suita. Serum total cholesterol level was higher in Okinawa and two urban populations, and lower in the populations in northeast part of Japan, and in Arikawa and Saku.

Two cases of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto's disease) following diffuse large B-cell lymphoma.

Histiocytic necrotizing lymphadenitis (HNL) is often mistaken for malignant lymphoma clinically and is also sometimes difficult to differentiate from lymphoma even histopathologically. In this report, we describe the first 2 reported cases of HNL following non-Hodgkin's lymphomas. The patients were 27- and 30-year-old women who developed cervical and axillary lymph node swellings, respectively, in the course of remission of diffuse large B-cell lymphoma. The affected lymph nodes showed the typical histology of HNL: irregular-shaped "necrotic" foci with histiocytes engulfing apoptotic bodies intermingled with large-sized blastic lymphocytes. These findings mimicked the partial involvement of large-cell lymphoma. However, the blastic cells were almost exclusively T cells, and numerous apoptotic bodies were present, which excluded the possibility of recurrence of diffuse large B-cell lymphoma.

Histologic transformation of follicular lymphoma after allogeneic bone marrow transplantation.

A 38-year-old man with refractory follicular lymphoma underwent allogeneic BMT from an HLA-identical sibling donor. He had generalized lymphadenopathy, hepatosplenomegaly and lymphoma infiltration of the marrow, all of which disappeared within 3 months following transplantation. Six months post-transplant, progressive hepatomegaly developed in the absence of splenomegaly and lymphadenopathy, and he died from hepatic failure. Autopsy disclosed diffuse large B cell lymphoma of the liver, into which the follicular lymphoma had transformed. Future issues to be investigated should include the optimal timing of allogeneic BMT for low-grade lymphomas.

Strong and significant relationships between aggregation of major coronary risk factors and the acceleration of carotid atherosclerosis in the general population of a Japanese city: the Suita Study.

BACKGROUND: Carotid arterial intimal-medial thickness (IMT) measured by high-resolution B-mode ultrasonography has come to be used as a noninvasive surrogate end point to measure progression of atherosclerosis. However, there are no detailed data on the relationship between aggregation of coronary risk factors and carotid atherogenesis. METHODS: Cross-sectional assessment of the relationship between carotid atherosclerosis detected by high-resolution ultrasonography and integration of major coronary risk factors by age and sex. Subjects aged 30 to 86 years were randomly selected from Suita, located in Osaka, the second largest urban area of Japan, including 1896 men and 2102 women. Carotid atherosclerosis was evaluated by using our atherosclerotic indexes of IMT, plaque number, plaque score, and percentage of stenosis of the carotid artery assessed using ultrasonography by sex and age group classified by number of major coronary risk factors (ie, hypertension [diastolic blood pressure > or =90 mm Hg and/or systolic blood pressure > or 140 mm Hg or receiving medication], smoking [current smoker], and hypercholesterolemia [serum total cholesterol level > or =5.68 mmol/L [220 mg/dL] or receiving medication]). RESULTS: The mean carotid atherosclerotic index value, especially the mean IMT value, of the subjects with 1 major coronary risk factor was on average 0.028 mm (3.2%) higher for men and 0.025 mm (2.9%) higher for women than that of the subjects without major coronary risk factors; for subjects with 2 risk factors, 0.054 mm (6.3%) higher for men and 0.053 mm (6.2%) higher for women; and for high-risk subjects with 3 major risk factors, 0.135 mm (15.8%) higher for men and 0.137 mm (15.4%) higher for women. The percentage of the subjects with severe stenosis of at least 50% increased stepwise with increases in the number of coronary risk factors and showed a significant difference (P<.05) between men and women, ie, 2.4% vs 0. 6% (P =.01) among the subjects with no risk factors; 6.7% vs 1.5% (P<.001), subjects with 1 risk factor; 10.7% vs 2.7% (P<.001), subjects with 2 risk factors; and 18.6% vs 5.0% (P =.01), high-risk subjects. CONCLUSIONS: Aggregation of established major coronary risk factors strongly influenced carotid atherogenesis in both sexes. There were significant differences between sexes in the acceleration or progression of carotid atherosclerosis.