Ken Okubo

Trends in the Incidence, Mortality, and Survival Rate of Cardiovascular Disease in a Japanese Community The Hisayama Study

Background and Purpose— The slowdown of a steeply declining trend in cardiovascular mortality has been reported in Japan, but precise reasons for this trend are uncertain. Methods— We established 3 study cohorts of Hisayama residents aged ≥40 years without a history of stroke or myocardial infarction in 1961 (1618 subjects, first cohort), 1974 (2038 subjects, second cohort), and 1988 (2637 subjects, third cohort). We followed up with each cohort for 12 years, comparing the incidence, mortality, and survival rate of cardiovascular disease. Results— The age-adjusted incidence of cerebral infarction significantly declined by 37% for men and by 32% for women from the first to the second cohort. It continued to decline by 29% for men, but the decline decelerated for women in the third cohort. The incidence of cerebral hemorrhage steeply declined by 61% from the first to the second cohort in men only, while it was sustained for both sexes in the third cohort. Stroke mortality continuously declined as a result of these incidence changes and significant improvement of survival. In contrast, the incidence and mortality rate of coronary heart disease were unchanged except for the increasing incidence in the elderly. The prevalence of severe hypertension and current smoking significantly decreased, while that of glucose intolerance, hypercholesterolemia, and obesity greatly increased among the cohorts. Conclusions— Our data suggest that the decline in stroke incidence is slowing down and that the incidence of coronary heart disease has been increasing in the elderly in recent years. Insufficient control of hypertension and the increase in metabolic disorders may contribute to these trends.

Ten-Year Prognosis of Stroke and Risk Factors for Death in a Japanese Community The Hisayama Study

Background and Purpose— There have been very few population-based cohort studies of long-term prognosis and risk factors for death after stroke. We examined the 10-year prognosis, causes, and risk factors of death after stroke in a Japanese cohort. Methods— During a 26-year follow-up of a cohort of 1621 subjects ≥40 years of age, 333 subjects developed first-ever stroke and were prospectively followed up for 10 years after onset. During these 10-year follow-up periods, 268 of the 333 stroke patients died. Of those, 239 (89.2%) underwent autopsy. Results— The risk of death was greatest in the first year after first-stroke onset in both sexes (men, 40.3%; women, 43.7%). Thereafter, the survival curves decreased gradually, and risk of death reached 80.7% for men and 80.2% for women by the end of the 10-year follow-up. The 30-day case fatality rate was substantially greater in patients with cerebral hemorrhage (63.3%) or subarachnoid hemorrhage (58.6%) than in patients with cerebral infarction (9.0%). The risk of dying after the first stroke was twice the risk for stroke-free subjects. The most common cause of death was the index stroke in the first year. Thereafter, the impact of the first stroke gradually decreased, while that of recurrent stroke increased. Multivariate analysis revealed that age, lower body mass index, and hemorrhagic stroke were significant risk factors for death after stroke. Conclusions— Our findings suggest that the risk of death after first-ever stroke is high, in part because of the larger proportion of hemorrhagic stroke in Japanese relative to stroke victims in Western countries.

C-Reactive Protein and Risk of First-Ever Ischemic and Hemorrhagic Stroke in a General Japanese Population. The Hisayama Study

Background and Purpose— The role of high-sensitivity C-reactive protein (hsCRP) in the development of stroke is not clearly understood. We investigated the relationship between serum hsCRP levels and stroke occurrence in a general Japanese population. Methods— We followed 2692 subjects ≥40 years of age for 12 years. The relative risks and 95% CIs for ischemic and hemorrhagic stroke occurrence were calculated according to the hsCRP quintiles. Results— During the follow-up, 129 first-ever ischemic and 59 hemorrhagic strokes occurred. In men, the age-adjusted incidence of ischemic stroke significantly increased with elevated serum hsCRP levels; the difference between the first and fifth quintiles was statistically significant (1.4 versus 6.6 per 1000 person-years; P=0.02). This association remained significant even after adjustment for other confounding factors, such as age, systolic blood pressure, ECG abnormalities, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol, smoking habits, alcohol intake, and regular exercise (adjusted relative risks, 3.11; 95% CI, 1.04 to 9.32; P=0.04). However, such associations were not observed for ischemic stroke in women or in hemorrhagic stroke in either sex. Among male subjects who were both in the fifth hsCRP level and had hypertension, diabetes, obesity, hypercholesterolemia, or a smoking habit, the risk of ischemic stroke was extremely increased, even after adjustment for other risk factors. Conclusions— Our findings suggest that elevated serum hsCRP levels are an independent risk factor for future ischemic stroke in Japanese men and that the coexistence of a high hsCRP level with another risk factor extremely increases the risk of ischemic stroke.

Cyclodepsipeptides produced by actinomycetes inhibit cyclic-peptide-mediated quorum sensing in Gram-positive bacteria.

Cyclic peptides are commonly used as quorum-sensing autoinducers in Gram-positive Firmicutes bacteria. Well-studied examples of such molecules are thiolactone and lactone, used to regulate the expression of a series of virulence genes in the agr system of Staphylococcus aureus and the fsr system of Enterococcus faecalis, respectively. Three cyclodepsipeptides WS9326A, WS9326B and cochinmicin II/III were identified as a result of screening actinomycetes culture extracts for activity against the agr/fsr system. These molecules are already known as receptor antagonists, the first two for tachykinin and the last one for endothelin. WS9326A also inhibited the transcription of pfoA regulated by the VirSR two-component system in Clostridium perfringens. Receptor-binding assays using a fluorescence-labeled autoinducer (FITC-GBAP) showed that WS9326A and WS9326B act as receptor antagonists in this system. In addition, an ex vivo assay showed that WS9326B substantially attenuated the toxicity of S. aureus for human corneal epithelial cells. These results suggest that these three natural cyclodepsipeptides have therapeutic potential for targeting the cyclic peptide-mediated quorum sensing of Gram-positive pathogens.

Secular trends in the incidence, mortality, and survival rate of gastric cancer in a general Japanese population: the Hisayama study

To examine secular trends in the incidence and mortality of gastric cancer in a Japanese community, Hisayama, we established three study-cohorts of Hisayama residents aged ≥40 years in 1961 (1637 subjects), 1974 (2054), and 1988 (2602). Each cohort was followed up for ten years. The age-standardized mortality from gastric cancer significantly decreased from 2.4 per 1000 person-years in the first cohort to 0.8 in the third cohort for men, and from 1.0 to 0.2, respectively, for women (p < 0.01 for trend in both sexes). The five-year survival rate after gastric cancer significantly improved from the first (32.6%) to the third cohort (73.0%, p < 0.01) for men and from 43.2% to 72.3% (p < 0.05), respectively, for women. The age-standardized incidence of cancer in men was not different among the cohorts (4.3 per 1000 person-years in the first, 5.0 in the second, and 4.9 in the third cohort), while it decreased significantly in women (2.0, 1.8, and 1.2, respectively, p < 0.01 for trend). In conclusion, our findings suggest that in a Japanese population, the mortality from gastric cancer declined during the past 40 years, due mainly to the improvement of survival in both sexes and a decrease in the incidence for women.

Incidence and prognosis of gastric cancer in a population-based cohort survey: The Hisayama study

Background: No population‐based cohort studies have been undertaken to evaluate the incidence and prognosis of gastric cancer. The purpose of this investigation was to clarify the incidence and fatal prognosis of gastric cancer and to determine the factors that contribute to the prognosis in a general Japanese population in Hisayama using a prospective study design. Methods: From 1988 to 1998 a total of 2605 subjects aged 40 years or older with no history of gastrectomy or gastric cancer were followed‐up prospectively after a health examination. The diagnosis of gastric cancer was based on clinical records or autopsy findings. Results: During the follow‐up period, 76 subjects developed gastric cancer. The age‐adjusted incidence of gastric cancer for men (4.9 per 1000 person‐years) was 4‐fold higher than that for women (1.2, P < 0.05). In men, the incidence of gastric cancer increased with advancing age, but this trend was not observed in women. The age‐ and sex‐adjusted 5‐year survival rate was significantly higher in cancers of the middle third of the stomach than in those of the upper third of the stomach. The survival rate was higher in cancers of well‐differentiated adenocarcinoma than in those of the other histological types. There were no cases of cancer‐related death among the early gastric cancers during the follow‐up period. Conclusions: Our data suggest that men are at higher risk of gastric cancer than women in the general Japanese population. Clinical stage, histological type, and site of cancer in the stomach contribute to a fatal prognosis.

Rationale design of quorum-quenching peptides that target the VirSR system of Clostridium perfringens

In Clostridium perfringens, a 5-membered thiolactone peptide acts as an autoinducing peptide (AIPCp) to activate the VirSR two-component signal transduction system, which in turn controls the expression of genes encoding multiple toxins, including α, θ and κ. To develop anti-pathogenic agents against virulent C. perfringens, quorum-quenching peptides were rationally designed based on the structure-activity relationship (SAR) data on AIPCp. Alanine scanning study of AIPCp suggested that Trp(3) and Phe(4) are involved in receptor binding and activation, respectively. On the basis of the SAR, we designed two quorum-quenching peptides with different modes of action: Z-AIPCp-L2A/T5A (partial agonist) and Z-AIPCp-F4A/T5S (partial antagonist). Both peptides significantly attenuated transcription of θ toxin gene (pfoA) in a virulent strain of C. perfringens with IC50 = 0.32 and 0.72 μM, respectively.