Cigarette smoking and risk of disabling dementia in a Japanese rural community: a nested case-control study.

BACKGROUND: Previous prospective cohort studies have examined the association between smoking and the risk of dementia, but the results were inconsistent. METHODS: A prospective, nested, case-control study was conducted to examine the association between cigarette smoking and risk of disabling dementia within the cohort of 6,343 men and women aged 35-85 years. Incident dementia was documented in 208 men and women (95 cases with and 113 cases without a history of stroke). Two control subjects per case were selected by matching for sex, age and year of examination. RESULTS: The multivariable odds ratios (95% CI) for current versus never smokers were 2.3 (1.1-4.7) for total dementia, 2.6 (0.8-8.2) for dementia with a history of stroke and 2.2 (0.8-5.7) for dementia without it, yielding no effect of stroke history on the smoking-dementia association. A dose-response relationship was noted between the years of cigarette smoking and the risk of total dementia, and a significant excess risk was found for smoking duration of >or=45 years. CONCLUSIONS: The present prospective study suggests that long-term cigarette smoking may raise the risk of disabling dementia.

Aldosterone synthase gene T-344C polymorphism, sodium and blood pressure in a free-living population: a community-based study.

There have been few epidemiological studies on the gene-environmental interaction between the aldosterone synthase gene (CYP11B2) T-344C polymorphism and sodium in relation to blood pressure in a free-living general population. We hypothesized a priori that persons with the T allele of CYP11B2 would have elevated blood pressure levels in response to a higher sodium intake, and thus the association between the T-344C polymorphism and blood pressure would be more evident among persons with a high sodium intake than among those with a low sodium intake. Study subjects were 2,823 men and women aged 30-74 in a Japanese community. We examined the associations between the T-344C polymorphism and blood pressure levels, stratified by sodium variables estimated by 24-h urinary sodium excretion and a dietary questionnaire. There was no significant difference in blood pressure levels among the CC, TC and TT groups for either or both sexes. However, among persons with higher sodium excretion, mean systolic blood pressure levels tended to be higher in those with the TC (+3.0 mmHg, p=0.06) and TT (+2.9 mmHg, p=0.07) genotypes than in those with the CC genotype, but this tendency was not seen among those with lower sodium excretion (-4.0 mmHg, p=0.03 for TC vs. CC; -3.0 mmHg, p=0.11 for TT vs. CC; p for interaction =0.006). In conclusion, we found no association between CYP11B2 and blood pressure for total subjects or for persons with a higher sodium intake. However, a possible gene-blood pressure association among persons with higher sodium intake needs to be explored further.

High sodium intake strengthens the association of ACE I/D polymorphism with blood pressure in a community.

BACKGROUND: Limited evidence is available on a gene-environment interaction of angiotensin-converting enzyme (ACE) gene I/D polymorphism and high blood pressure (BP) with salt intake among general populations. We hypothesized that persons with the I allele of the ACE gene have elevated BP levels in response to a higher sodium intake, and thus the association of ACE I/D polymorphism with BP levels was stronger among persons with a higher sodium intake than those with a 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 ACE I/D polymorphism with BP levels stratified by salt intake, as estimated by 24-h urine collection and dietary questionnaire. Polymorphism of the ACE I/D was detected by an allele-specific polymerase chain reaction. RESULTS: There was no significant difference in BP levels among DD, ID, and II groups for either sex or total samples. However, mean difference in diastolic BP levels for II versus DD groups was +3.0 mm Hg (P = .003) among persons with higher sodium excretion, +1.8 mm Hg (P = .04) among those with higher present sodium intake score, and +1.7 mm Hg (P = .06) among those with higher past sodium intake score. CONCLUSIONS: A high sodium intake strengthens the association of ACE I/D polymorphism with BP levels in community-based samples.

Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia.

Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes.

[Evaluation of a community-based health education program for salt reduction through media campaigns].

PURPOSE: To provide the strategies, achievement and evaluation of a community health education program for salt reduction with media campaigns. METHODS: The intervention community was Kyowa town (A district of Chikusei city, census population in 1985 = 16,792) where we have systematically conducted a community-based blood pressure control program since 1981, and health education on reduction of salt intake since 1983 for primary prevention of hypertension. The education program was performed through media campaigns including use of banners, signboards, posters, and calendars with health catchphrases. We also used catchphrase-labeled envelopes when sending documents from the municipal health center to individuals. Health festivals were held annually to enhance health consciousnesses and to improve health behavior. Some of the posters and calligraphy were painted or drawn by elementary schoolchildren as part of their education. The program was evaluated by repeated questionnaires and examination of salt concentrations of miso soup and dietary salt intake. RESULTS: Between 1983 and 1988, the prevalence of persons who were aware that health consultation including blood pressure measurements were available at the town office increased from 65% to 84%. The prevalence of those who knew the salt intake goal (10 g or less/day) increased from 47% to 63% and that of those who reported to reduce salt intake also increased from 38% to 58%. As for salt concentrations of miso soup, the proportion with less than 1.1% increased from 47% to 66% between 1985 and 2004. Age-adjusted mean salt intake for persons aged 40-69 years declined from 14 g to 11 g in men and from 12 g to 10 g in women between 1982-1986 and 2000-2004. CONCLUSION: A long-term systemic education program through media campaigns proved feasible with the cooperation of community leaders, schools and food associations.

Plasma fibrinogen concentrations and risk of stroke and its subtypes among Japanese men and women.

BACKGROUND AND PURPOSE: We aimed to examine the impact of fibrinogen concentrations on the incidence of stroke. METHODS: We examined the association between fibrinogen and risk of total stroke and stroke subtypes in an 11-year prospective study of 4608 men and 7589 women aged 40 to 79 years with no history of stroke and/or coronary heart disease. The analysis was repeated, stratified by smoking status, to examine whether the association between fibrinogen and stroke was modified by smoking. RESULTS: There were 317 incident total strokes comprising 103 hemorrhagic strokes (70 intraparenchymal hemorrhages [22.1% of strokes], 33 subarachnoid hemorrhages [10.4%]), 206 ischemic strokes (65.0%), and 8 strokes of undetermined type (2.5%). The multivariable hazard ratio (95% CI) for the highest versus lowest fibrinogen quartiles after adjustment for age, sex, area, and known cardiovascular risk factors was 2.5 (1.3 to 5.0), P<0.01, for hemorrhagic stroke and 3.2 (1.4 to 7.4), P<0.01, for intraparenchymal hemorrhage. There was no positive association of fibrinogen with risk of ischemic stroke or subarachnoid hemorrhage. Among never-smokers, the multivariable hazard ratio (95% CI) for the highest versus lowest fibrinogen quartiles was 3.5 (1.3 to 9.3), P=0.01, for hemorrhagic stroke and 4.4 (1.3 to 15.2), P=0.02, for intraparenchymal hemorrhage. CONCLUSIONS: High plasma fibrinogen concentration can be a predictor for risk of intraparenchymal hemorrhage.

The relationship between sleep-disordered breathing and high-sensitivity C-reactive protein in Japanese men.

STUDY OBJECTIVES: Elevated C-reactive protein (CRP), an inflammatory marker and emerging risk factor for atherosclerosis and coronary heart disease, has been reported in overweight patients with sleep-disordered breathing (SDB). However, the contribution of C-reactive protein to this disease among non-overweight individuals is uncertain. We thus examined the relationship between serum C-reactive protein levels and nocturnal arterial oxygen desaturation, stratified by category of body mass index (BMI). DESIGN: Cross-sectional study. PARTICIPANTS: Subjects were 316 men with a mean BMI of 25.4 kg/m2, aged 20-79 years, who attended a sleep clinic at Osaka, Japan. MEASUREMENTS AND RESULTS: SDB was assessed by oxygen desaturation index (ODI) measured by pulse oximetry during sleep. We used 3% oxygen desaturations per hour (3% ODI), as the indicator of SDB. We also measured serum levels of C-reactive protein (CRP). After adjustment for age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking status, alcohol consumption, and daily sleep duration, mean high-sensitivity CRP levels were 0.63, 0.65, and 0.96 mg/L for SDB severity levels of 3%ODI<5, 5 to 19.9, and >=20, respectively (p for trend=0.015). This association with SDB tended to be stronger in non-overweight men (BMI<25 kg/m2) (0.47, 0.48 and 1.02 mg/L, p for trend=0.017) than in overweight men (BMI > or = 25 kg/m2) (0.92, 0.87 and 1.21 mg/L, p for trend=0.11). CONCLUSION: SDB is associated with increased levels of CRP, especially in non-overweight men. Our results suggest the importance of follow-up and control of SDB in the prevention of cardiovascular disease even in non-overweight SDB patients.

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.

Methylation of promoter region in p27 gene plays a role in the development of lymphoid malignancies.

p27 belong to the cyclin-dependent kinase inhibitor family and plays an important role in regulation of cell cycle progression. Expression of these genes is epigenetically suppressed by methylation of their promoter regions. In this study, we examined protein expression and methylation status of the promoter region of p27 in 70 cases with non-Hodgkin's lymphoma and their relationship with proliferative activity of the tumor cells as revealed by Ki-67 index. There were 35 cases of B-cell, 11 of T-cell, 23 of NK/T-cell lymphoma, and 1 undetermined type. Immunohistochemically the loss of p27 protein expression was observed in 24 (69%) of 35 cases. Significant inverse correlation between p27 protein expression and Ki-67 index was found. Single strand conformation polymorphism (SSCP) followed by sequencing could not detect point mutations in any of the 68 cases. Bisulfite sequencing analysis showed that methylation of the promoter region of p27 were observed in 17 (25%) of 68 cases, in that several specific CpG sites around the start codon of p27 gene were preferentially methylated. Eight of 22 cases with loss of p27 protein expression showed methylation in CpG island of 5' region of p27 gene. These findings suggested that gene methylation plays a role in loss of expression of p27, which gives the cells proliferative advantages.

Pyothorax-associated lymphoma: a review of 106 cases.

PURPOSE: Pyothorax-associated lymphoma (PAL) is a non-Hodgkin's lymphoma developing in the pleural cavity after a long-standing history of pyothorax. Full details of PAL are provided here. PATIENTS AND METHODS: Clinical and pathologic findings were reviewed in 106 patients with PAL collected through a nationwide survey in Japan. RESULTS: Age of the patients with PAL was 46 to 82 years (median, 64 years), with a male/female ratio of 12.3:1. All patients had a 20- to 64-year (median, 37-year) history of pyothorax resulting from artificial pneumothorax for treatment of pulmonary tuberculosis (80%) or tuberculous pleuritis (17%). The most common symptoms on admission were chest and/or back pain (57%) and fever (43%). Laboratory data showed that the serum neuron-specific enolase level was occasionally elevated (3.55 to 168.7 ng/mL; median, 18.65 ng/mL), suggesting a possible diagnosis of small-cell lung cancer. Histologically, PAL usually showed a diffuse proliferation of large cells of B-cell type (88%). In situ hybridization study showed that PAL in 70% of the patients was Epstein-Barr virus (EBV)-positive. PAL was responsive to chemotherapy, but the overall prognosis was poor, with a 5-year survival of 21.6%. CONCLUSION: This study established the distinct nature of PAL as a disease entity. PAL is a non-Hodgkin's lymphoma of exclusively B-cell phenotype in the pleural cavity of patients with long-standing history of pyothorax, and is strongly associated with EBV infection. Development of PAL is closely related to antecedent chronic inflammatory condition; therefore, PAL should be defined as malignant lymphoma developing in chronic inflammation.

Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers.

Expression of the Wilms' tumor gene WT1 in de novo lung cancer was examined using quantitative real-time RT-PCR and immunohistochemistry. Overexpression of the WT1 gene was detected by RT-PCR in 54/56 (96%) de novo non-small cell lung cancers examined and confirmed by detection of WT1 protein with an anti-WT1 antibody. Overexpression of the WT1 gene was also demonstrated in 5/6 (83%) de novo small cell lung cancers by immunohistochemistry. Furthermore, when the WT1 gene was examined for mutations by direct sequencing of genomic DNA in 7 lung cancers, no mutations were found. These results suggest that the nonmutated, wild-type WT1 gene plays an important role in tumorigenesis of de novo lung cancers and may provide us with the rationale for new therapeutic strategies for lung cancer targeting the WT1 gene and its products.

Microarray analysis of gene-expression profiles in diffuse large B-cell lymphoma: identification of genes related to disease progression.

To identify genes that are associated with progression of malignant lymphoma, the expression profiles of 18,432 genes were analyzed in diffuse large B-cell lymphomas at early (stages I and II, 6 cases) and advanced stages (stages III and IV, 9 cases) by means of cDNA microarrays. By comparing expression profiles between localized and advanced lymphomas, a number of genes that were differentially expressed were identified: 48 genes with increased expression and 30 genes with reduced expression in advanced-stage diffuse large B-cell lymphomas. Increased expression of MPHOSPH1, RUVBL1, CHN2, PSA and CDC10 genes, and reduced expression of COL1A2, COL4A1, FBLN5, CLECSF6, MIC2, CAV1 and S100A10 genes in the advanced lymphoma group were confirmed by semi-quantitative reverse transcription-PCR. RUVBL1 and PSA expression was further confirmed by real-time quantitative PCR, whose results paralleled the microarray data. The highly expressed genes encode proteins that promote cell proliferation and the genes with reduced expression encode adhesion proteins and target protein for cytotoxic T-lymphocytes. These findings suggested that analysis with cDNA microarrays is a useful approach for identifying genes related to tumor progression and their products could be potential tumor markers or disease-specific targets for anti-tumor therapy.