Muneko Nishijo

High-Density Lipoprotein Cholesterol and Risk of Stroke in Japanese Men and Women The Oyabe Study

Background and Purpose— Evidence of an inverse relationship between serum high-density lipoprotein cholesterol (HDL-C) and the risk of stroke is sparse in Asians and in women. The purpose of this investigation was to examine the relationship in a long-term cohort study of Japanese men and women among whom stroke occurrence is higher than in Western countries. Methods— A prospective cohort study was performed involving 4989 participants (1523 men, 3466 women) 35 to 79 years of age at baseline with ≈10 years of follow-up in a rural area of Japan. End points included all stroke incidence and ischemic stroke incidence. Results— During follow-up, 132 participants developed stroke, including 81 ischemic stroke cases. Age-adjusted incidence rates per 10 000 person-years for all stroke in subjects with low HDL-C (<30 mg/dL [0.78 mmol/L]) were 103.4 in men and 49.3 in women, which were remarkably higher than in subjects with high HDL-C (≥60 mg/dL [1.56 mmol/L]) (26.4 in men and 15.5 in women). A similar relationship was observed for ischemic stroke. Multivariate-adjusted relative risks for all stroke incidence and ischemic stroke incidence were 2.89 (95% CI, 1.35 to 6.20) and 2.92 (95% CI, 1.17 to 7.32), respectively, for low versus high HDL-C participants. The relationships were independent of sex, age, body mass index, blood pressure, serum total cholesterol, alcohol consumption, and smoking. Conclusions— This 10-year follow-up study of Japanese men and women demonstrated that lower HDL-C levels were related significantly and independently to increased risk of all stroke incidence and ischemic stroke incidence.

Effects of maternal exposure to cadmium on pregnancy outcome and breast milk

Objective: The effects of cadmium (Cd) on birth weight have been discussed in the scientific literature. However, investigations on the effects of maternal body burden of Cd on the next generation during pregnancy and lactation have been limited. The relation between maternal exposure to Cd and pregnancy outcome or Cd in breast milk in Japanese mothers was investigated. Methods: Cd concentrations in urine and colostrum milk samples of 57 mothers were measured by atomic absorption spectrophotometery. The relations between maternal urinary Cd and infant growth, gestational age at birth, and Cd in breast milk were investigated. Results: The rate of perterm deliveries of mothers with higher urinary Cd (≥2 nmol/mmol creatinine (Cr)) was higher than that of mothers with lower urinary Cd (<2 nmol/mmol Cr). The gestational age was significantly correlated with urinary Cd even after adjustment for maternal age. The height and weight of newborn infants of mothers with higher urinary Cd were significantly lower than those of the newborn infants of mothers with lower urinary Cd, but these decreases were ascribed to early delivery induced by Cd. The Cd in breast milk of mothers with higher urinary Cd was significantly higher than that of mothers with lower urinary Cd. A significant positive correlation was found between maternal urinary Cd and Cd in breast milk. Conclusion: Maternal exposure to Cd seems to increase early delivery, which leads to a lower birth weight. Also, the Cd is transferred in part to the next generation through breast milk after birth.

Trends in stroke incidence and acute case fatality in a japanese rural area: The oyabe study

BACKGROUND AND PURPOSE Stroke mortality in Japan has significantly declined during recent decades. To determine the cause of this decrease, we studied the trends in stroke incidence and case fatality within 28 days after stroke in a rural area in Japan. METHODS We used a population-based registry during 1977-1991 in Oyabe, a rural area in the central part of Japan. The average population aged 25 years and older numbered 32 859 persons. Changes in age-standardized stroke incidence rate were calculated and compared between the 3 periods 1977-1981, 1982-1986, and 1987-1991. The 28-day case fatality rate was evaluated and also compared between the 3 periods by onset year. RESULTS The total number of strokes was 2068. The age-standardized incidence rate of all strokes decreased during the 15-year period, from 605 to 417 per 100 000 in men and from 476 to 329 per 100 000 in women. A marked decline was found during 1977-1986 but was not apparent during 1987-1991. Moreover, there was an increase in the group aged 75 years and older. The 28-day case fatality rates for all strokes improved from 18.0% to 14.2% in men and from 26.8% to 19.1% in women during the observation period. CONCLUSIONS These data indicate that declines in the stroke incidence and the 28- day case fatality have been associated with a marked decrease in stroke-related mortality in Japan.

Causes of death and renal tubular dysfunction in residents exposed to cadmium in the environment

Objectives: To clarify the causes of death of residents with renal tubular dysfunction induced by cadmium (Cd) in the environment. Methods: A 15 year follow up study was performed with the inhabitants living in the Cd polluted Kakehashi River basin in Japan. Standardised mortality ratios (SMRs) for causes of death, classified by ICD-9, were computed using the person-years method to investigate the excess mortality of subjects with urinary β2-MG (microglobulin) ⩾1000 μg/gCr. Mortality risk analysis was performed using Cox’s proportional model to compare mortality between subjects with urinary β2-MG ⩾1000 and <1000 μg/gCr, and to investigate the relationship between the degree of urinary β2-MG and mortality. Results: Excess mortality due to heart failure and cerebral infarction in both sexes, and nephritis and nephrosis in men, was observed among subjects with urinary β2-MG ⩾1000 μg/gCr. Significant increases in mortality risk for cerebral infarction in men and for malignant neoplasms in women with urinary β2-MG ⩾1000 μg/gCr were observed during the first five year observation period. For nephritis and nephrosis, the mortality risks for men and women with urinary β2-MG ⩾1000 μg/gCr significantly increased over the 15 year observation period. The mortality risks for heart failure and cerebral infarction increased in proportion to the increased urinary β2-MG in both sexes. Increased mortality risks for nephritis and nephrosis were identified in the subjects with urinary β2-MG ⩾10000 μg/gCr in both sexes. Conclusion: Renal tubular dysfunction induced by Cd affected the causes of death, and mortality for heart failure, cerebral infarction, and nephritis and nephrosis was increased among inhabitants living in a Cd polluted area in Japan. In women, cancer mortality may have been increased while Cd pollution was ongoing.

The gender differences in health effects of environmental cadmium exposure and potential mechanisms

On a viewpoint of gender differences in Cd body burden and its health effects, we reviewed the population-based research including our own which conducted in Japan, Thailand, Australia, Poland, Belgium and Sweden to assess health effects of human exposure to environmental cadmium and their potential mechanisms. As a result, six risk factors in Cd health effects in women have been identified; (1) more serious type of renal tubular dysfunction, (2) difference in calcium metabolism and its regulatory hormones, (3) kidney sensitivity; difference in P450 phenotype, (4) pregnancy, (5) body iron store status, and (6) genetic factors. Further studies of Cd toxicity targeted to women would now appear necessary.

Cadmium exposure and trace elements in human breast milk.

The interrelations of the seven elements, calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), phosphorus (P), copper (Cu), zinc (Zn), and cadmium (Cd) in human breast milk were examined in Japanese mothers to clarify the effects of Cd exposure on these important elements for infant growth. Breast milk and urine samples were obtained from 68 mothers, aged 19-38 years, at 5-8 days postpartum. The concentrations were determined by inductively-coupled plasma atomic emission spectrometry for Ca, Mg, Na, K, P, by flame atomic absorption spectrophotometry for Cu and Zn, and by flameless atomic absorption spectrophotometry for Cd. Geometrical mean Cd concentrations were 0.28 (geometrical standard deviation=1.82) microg/l in breast milk and 1.00 (1.93) microg/g creatinine in urine. Among the above elements only Cd concentration in breast milk was significantly correlated with urinary Cd concentration (r=0.451, P<0.001). Significant positive correlations were found between Cu and Ca (r=0.500, P<0.001), Cu and Mg (r=0.378, P<0.01), and Zn and Mg (r=0.355, P<0.01) in breast milk. Cd concentration in breast milk showed an inverse relationship with Ca concentration in breast milk (r=-0.248, P<0.05). These results indicate that the Cd concentration in breast milk closely reflects Cd body burden, with increased Cd in breast milk possibly affecting Ca secretion in breast milk.

Cadmium induced renal dysfunction among residents of rice farming area downstream from a zinc-mineralized belt in Thailand

High levels of cadmium (Cd) in paddy soil and rice, and a concurrent increase in urinary Cd of inhabitants in the Mae Sot District, Tak Province, Thailand first emerged in 2003. Risk factors such as occupation, sources of staple food and drinking water as well as biomarkers of adverse renal effects of the increased body burden of Cd were investigated in 795 residents, 30 years or older, whose urinary Cd levels were between 0.02 and 106mug/g creatinine. Farmers who consumed their own rice and residents who sourced drinking water from wells and/or the river demonstrated increased urinary Cd. Age-adjusted mean urinary cadmium for male and female subjects who consumed well water was 5.7mug/g vs. 6.1mug/g creatinine while the corresponding value for male and female subjects who did not consume well water was 3.7mug/g vs. 4.8mug/g creatinine, respectively. Increased urinary levels of beta(2)-microglobulin and N-acetyl-beta-d-glucosaminidase were observed with the increase in urinary Cd, indicating tubular dysfunction and renal damage associated with increase in Cd body burden. Consumption of well water and rice grown in the contaminated area increase the body burden of Cd. Cessation of exposure is essential to prevent and possibly recover from Cd toxicity, especially among the residents whose kidney damage and malfunction may be reversible.

Mortality of inhabitants in an area polluted by cadmium: 15 year follow up.

OBJECTIVE--To assess the influence of environmental exposure to cadmium (Cd) on long term outcome of inhabitants living in an area polluted by Cd. METHODS--A follow up study for 15 years (from 1974-5 to 1991) was carried out on 2408 inhabitants (amounting to 95% of the target population, 1079 men and 1329 women) of the Kakehashi River basin in Ishikawa Prefecture, Japan. These inhabitants had been the subjects of the health impact survey in 1974-5 to evaluate (by measurement of urinary retinol binding protein (RBP)) renal dysfunction induced by Cd. Analysis of mortality was performed by dividing subjects into a urinary RBP positive (> or = 4 mg/l) group and RBP negative (< 4 mg/l) group. RESULTS--After adjustment for age with Coxs proportional hazard model, RBP > or = 4 mg/l showed a significant relation to mortality in both sexes. At this time, the mortality risk ratio of the RBP positive to negative group was 1.71 in the men and 1.42 in the women. When the SMRs according to causes of deaths in the RBP positive group were compared with those of the RBP negative group or the overall Japanese population increases of SMR for cardiovascular diseases, especially heart failure, and renal diseases were found in both sexes. CONCLUSION--These results suggest that the prognosis of the exposed inhabitants with renal tubular dysfunction is unfavourable, and these increases of mortality are due to heart failure and renal diseases.

Comparison of Four Blood Pressure Indexes for the Prediction of 10-Year Stroke Risk in Middle-Aged and Older Asians

Information has been sparse on the comparison of 4 blood pressure (BP) indexes (systolic BP [SBP], diastolic BP [DBP], pulse pressure [PP], and mean BP [MBP]) in relation to long-term stroke incidence, especially in middle-aged and older Asian people. A prospective cohort study was performed in 4989 Japanese (1523 men and 3466 women) aged 35 to 79 at baseline with 10 years of follow-up. End points included stroke incidence (total, ischemic, and hemorrhagic). Multivariate-adjusted hazard ratios with a 1-SD higher value for each BP index were determined by Cox proportional hazard analyses; Wald &khgr;2 tests were used to compare the strength of relationships. Analyses were also done for each of 4 age-gender groups consisting of men and women aged 35 to 64 and 65 to 79 years. During follow-up, 132 participants developed stroke. Adjusted hazard ratios for all strokes were 1.68 for SBP, 1.72 for DBP, and 1.80 for MBP, which were higher than that for PP (1.34). SBP and DBP were related positively to stroke risk after adjustment of each other. PP was not the strongest predictor in any age-gender groups among 4 BP indexes. In men aged 65 to 79 years, SBP showed the strongest relationship to all stoke risk (hazard ratio 1.62) among 4 BP indexes. In women aged 65 to 79 years, hazard ratios for all strokes were 2.48 for MBP, 2.46 for DBP, 2.25 for SBP, and 1.57 for PP. The long-term incident stroke risk of high BP in Asians should be assessed by SBP and DBP together, or by MBP, not by PP.

Urinary β2-microglobulin Concentration and Mortality in a Cadmium-polluted Area

A 9-y follow-up study of 3,178 persons who lived in a cadmium-polluted area was conducted to assess the influence of environmental cadmium exposure on long-term outcome. The standardized mortality ratios of the urinary beta 2-microglobulin-positive subjects (> 1,000 micrograms/g creatinine) of both sexes were higher than those of the general Japanese population, whereas the cumulative survival curves were lower than those of the urinary beta 2-microglobulin-negative group. A significant association was also found between urinary beta 2-microglobulin and mortality, using a Coxs proportional hazards model. Moreover, mortality rates increased in proportion to increases in the amount of urinary beta 2-microglobulin excreted. These results suggest that the prognosis for cadmium-exposed subjects with proximal tubular dysfunction is unfavorable. The mortality rate tended to become higher as the severity of renal dysfunction progressed.