The mutations of Th1 cell-specific T-box transcription factor may be associated with a predominant Th2 phenotype in gastric cancers.

Gastric cancer is a serious public health cancer and causes nearly 1 million deaths a year worldwide. Th1 cells play critical roles in orchestrating the adaptive immune responses against gastric cancer. T-bet, a member of the T-box family of transcription factors, is the Th1 master regulator and up-regulated during Th1 differentiation. Polymorphisms have also been shown to exist in T-bet. Some reports indicated that some tumours were associated with the drift of Th1 and Th2. In the present work, we investigated the drift of Th1/Th2 by detecting the expression levels of T-bet, IFN-gamma, IL-4, and GATA-3 in peripheral blood mononuclear cell of gastric cancer patients by real-time PCR, explored the relationship between the polymorphism of T-bet gene and drift of Th1/Th2 by gene sequence, western blot, and gene transfection. Our results indicated that a predominant Th2 phenotype was existence. T-bet gene mutations may be associated with Th2-dominated condition in gastric cancers.

Levels of calcium, magnesium and zinc in urine among adult women in relation to age with special reference to menopause.

OBJECTIVES: This study was initiated to examine, on a basis of large-scale epidemiology, if urinary calcium (Ca), magnesium (Mg) and zinc (Zn) levels change as a function of age and menopause. METHODS: Spot urine samples were collected from adult women, and analyzed for the minerals. Additional information e.g. on smoking habits was obtained by questionnaires, so that cases were classified into 10,464 never-smokers, 1,351 current smokers and 343 past smokers. The mineral concentrations were evaluated as observed (e.g. Ca-U(ob)), and after correction for creatinine (CR) concentration (e.g. Ca-U(cr)) or specific gravity (SG) (e.g. Ca-U(sg)). RESULTS: Analyses with never-smokers showed that age-dependent changes in Ca-U(ob), Mg-U(ob) and Zn-U(ob) were minute. Menopause induced a small increase in Ca-U(ob) and a small decrease in Zn-U(ob). Values after CR or SG correction were increased in accordance with both age and menopause, possibly due to age- and menopause-associated decreases in urine density. CONCLUSIONS: Ca-U(ob), Mg-U(ob) and Zn-U(ob) did not vary substantially throughout life. Ca-U(ob) and Zn-U(ob) were slightly higher and lower, respectively, in post-menopausal women than in pre-menopausal women, but such changes were too small to affect life-long stabilities. Thus, the urinalyses did not suggest need of additional supply of Ca, Mg or Zn at advanced ages. Correction for CR or SG may induce a bias in evaluation of age-dependent changes in mineral concentrations, because CR and SG decrease in accordance with age.

No meaningful increase in urinary tubular dysfunction markers in a population with 3 microg cadmium/g creatinine in urine.

The critical Cd exposure level to induce tubular dysfunctions is a focus of public concern among general populations in Japan. To answer this question, one group each (about 1000 adult women/area) in nonpolluted areas with high (Area H) and low Cd exposure (Area L) was obtained, and 742 strictly age-matched pairs of never-smoking adult women were selected for comparison. Cd, alpha1-MG (microglobulin) and beta2- MG in urine were taken as markers of exposure and tubular dysfunction, respectively. Geometric mean Cd levels as corrected for creatinine (Cdcr) was greater than three times higher in Area H (2.8 microg/g cr) than in Area L (0.8 microg/g cr). Nevertheless, beta2-MGcr did not differ between the two areas (125 microg/g cr for Area H vs 118 microg/g cr for Area L). alpha1-MGcr was only marginally higher in Area H (2.8 mg/g cr) than in Area L (2.1 mg/g cr), with no biomedical significance. Results were essentially the same when analyses were conducted with noncorrected observed values or values corrected for a specific gravity. Thus, the effects of Cd exposure in Area H on renal tubular function should be essentially nil.

Low-level cadmium exposure in Toyama City and its surroundings in Toyama prefecture, Japan, with references to possible contribution of shellfish intake to increase urinary cadmium levels.

OBJECTIVES: This study was initiated to examine if exposure to cadmium (Cd) was high also outside of the previously identified Itai-itai disease endemic region in the Jinzu River basin in Toyama prefecture in Japan. METHODS: Morning spot urine samples were collected in June-August 2004 from 651 adult women (including 535 never-smokers) in various regions in Toyama prefecture, and subjected to urinalyses for cadmium (Cd), alpha1-microglobulin (alpha1-MG), beta2-microglobulin (beta2-MG), N-acetyl-beta-D-glucosaminidase (NAG), specific gravity (SG or sg) and creatinine (CR or cr). Three months later, the second urine samples were collected from those with elevated Cd in urine (e.g., > or =4 microg/g cr), together with answers to questionnaires on shellfish consumption. RESULTS: The geometric mean (GM) Cd, alpha1-MG, beta2-MG and NAG (after correction for CR) for the total participants were 2.0 microg/g cr, 2.4 mg/g cr, 104 microg/g cr and 2.8 units/g cr, respectively; further analysis with never-smoking cases only did not induce significant changes in these parameters. Analyses of the second urine samples from the high Cd subjects showed that there was substantial decrease (to about a half) in Cd in the 3-month period, and that the decrease was accompanied by reduction in alpha1-MG and NAG (beta2-MG did not show elevation even in the first samples). The urinalysis results in combination with the results of the questionnaire survey suggest that the high urinary Cd was temporary and might be induced by intake of shellfish that is edible whole. CONCLUSIONS: The overall findings appear to suggest that Cd exposure in Toyama populations (outside of the Itai-itai disease endemic region) was at the levels commonly observed on the coast of the Sea of Japan, and that the Cd level in urine might be modified by the intake of some types of seafood. Further studies are necessary to elucidate the relation of urinary Cd with seafood intake.

Smoking-induced increase in urinary cadmium levels among Japanese women.

OBJECTIVE: To examine if cigarette smoking will induce elevation in cadmium (Cd) in urine. METHODS: Information on smoking habits, and urinary levels of cadmium (Cd-U), alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG), creatinine (CR or cr), and urine specific gravity (SG or sg) was cited from a combination of three previously established databases on adult Japanese women. After exclusion of those with unclear answers on smoking habits (412 cases), the combination (12,846 cases) gave 11,092, 1420 and 334 cases of never, current and former smokers, respectively, for present statistical analyses. RESULTS: Multiple regression analyses taking Cd-U as a dependent variable and 11 regions of urine collection, age and smoking habits as independent variables showed that age and regions were powerful confounders in the analysis for the effects of smoking on Cd-U. To exclude the confounding effects, current and former smokers were paired with age- and region-matched never smoking controls in subsequent analyses. In addition, former smokers were paired with age- and region-matched current smokers. The comparison of the paired cases showed that Cd-U for current smokers was significantly higher than that for never smokers. The levels for former smokers were however not higher than the levels for never smokers. When classified by the number of cigarettes consumed per day, Cd-U for current smokers increased dependently to the number of cigarettes (about 0.09 microg/cigarette/day) with leveling off at 15 or more cigarettes. There was a subtle cigarette dose-dependent increase in alpha(1)-MG, but the increase was insignificant in case of beta(2)-MG. Estimation of the amount of Cd absorbed due to cigarette smoking followed by comparison with the increase in Cd-U suggested that almost all Cd absorbed will be excreted into urine. CONCLUSIONS: Among currently smoking Japanese women, cadmium in urine increased in a manner dependent to the number of cigarettes consumed daily. Thus, smoking is a confounder of Cd-U evaluation even among the population with relatively high dietary Cd burden.

Decreases in urine specific gravity and urinary creatinine in elderly women.

OBJECTIVE: To examine the effects of aging on urinary levels of creatinine (CR) and urine specific gravity (SG) among women in a large-scale epidemiology survey. METHODS: Data on CR and SG in urine, together with smoking habits and menopausal status, were selected from previously established databases and combined with the results of supplemental sample collection. In total, CR and SG data were available for 11,090 never-smoking women (total group; 29-80 years of age); a subgroup of 1,851 women who lived in Kyoto was also selected from the total group. Data from the two groups were subjected to statistical analyses. In statistical evaluation, SG was converted to factor G, which was defined as (SG-1.000)x1,000. RESULTS: Classification by decade of years of age showed that both CR and SG decreased steadily as a function of advancement in age over 30 years, both in the total group and in the Kyoto subgroup, showing high reproducibility of the observation on a whole-country basis and on a local basis. When the levels at 80 years of age were compared with those at 30 years, there was an approximately 60% and 30% decrease in CR and factor G, respectively. Thus, the effects of aging were more marked on CR than on factor G (and therefore on SG). Menopause appeared to be an influential factor in the reduction of CR and SG, separately from aging itself. CONCLUSIONS: Urinary levels of creatinine and, to a lesser extent, urine specific gravity, steadily decreased as a function of ages of over 30 years in women.

Effects of aging on cadmium and tubular dysfunction markers in urine from adult women in non-polluted areas.

OBJECTIVES: The objectives of the present analyses were to examine if Cd and tubular dysfunction marker levels in urine show age-dependent changes among women who lived in areas with no known cadmium (Cd) pollution in Japan, and if the trends would be further modified by correction of analyte concentration in terms of urinary creatinine (CR or cr) or urine specific gravity (SG or sg). METHODS: The results of urinalysis for Cd, alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG), and N-acetyl-beta-D: -glucosaminidase (NAG) concentrations together with CR and SG were cited from previously established databases. A majority of urine samples were collected in 2000-2002 from adult women (mostly at 40-60 years of age) in various areas in Japan, and the collection was supplemented by cases of > or =60-year-old women in 2003. In total, 11,090 never-smoking cases were subjected to statistical analysis. The values as observed (e.g., Cd(ob)), together with after correction for CR (e.g., Cd(cr)) or SG (e.g., Cd(sg)), were examined by linear regression analysis after logarithmic conversion. RESULTS: The geometric mean (GM) values for Cd were 1.10 microg/l (as observed) or 1.32 microg/g cr (after correction for creatinine concentration). No increases were found in the levels of alpha(1)-MG, beta(2)-MG or NAG on a group basis, in agreement with the conditions that there was no known environmental pollution with Cd in the sampling areas. There were almost linear increases in logarithm of Cd, alpha(1)-MG, beta(2)-MG and NAG concentrations as age advanced. As CR, and to a lesser extent SG, also decreases steadily throughout life, the correction of the analyte concentrations for urine density induced substantial increases in the analyte values; i.e., the correction by CR and SG induced amplification of the increases by two- and 1.4-times, respectively, compared with the increase in non-corrected observed values. CONCLUSIONS: There were age-related increases in Cd and tubular dysfunction markers in urine among women in areas with no known Cd pollution. The increase was amplified two- or 1.4-times when CR or SG correction was applied, respectively. The observation suggests that care should be practiced in applying CR or SG correction, especially when evaluation of Cd exposure and resulting health effects is made among elderly populations.

Reproducibility of urinary cadmium, alpha1-microglobulin, and beta2-microglobulin levels in health screening of the general population.

The present study examined whether levels of cadmium, and alphal- and beta2-microglobulin in urine (Cd-U, ac-MG-U, and beta2-MG-U, respectively) were reproducible in urine samples collected from the same subjects on multiple occasions. For this purpose, two databases on background exposure to cadmium in Japan-one from study I between 2000 and 2001 and the other from study II in 2002-were revisited to find 231 apparently healthy, nonpregnant, nonlactating adult women who participated in both studies and thus had provided two urine samples. The databases contained information on Cd-U, alphal,-MG-U, and beta2-MG-U, creatinine (CR), and specific gravity (SG) as well as smoking and other lifestyle factors. Of the 231 women, 195 who had never smoked were selected for the present analysis. Cd-U as well as alpha1-MG-U were reproducible (e.g., with correlation coefficients [r] between study I and II results of 0.4 to 0.6) when measured on two occasions 9 to 10 months apart. The r values were lower for beta2-MG-U (r0.3). Exclusion of urine samples with inadequate urine density(i.e., CR <0.5 or >3.0 g/L or SG <1.010 or >1.030) resulted in substantial improvement of the agreements between the two measures (e.g., r = 0.6 to 0.7 for Cd-U and alpha1-MG-U). CR and SG correlated closely with each other, especially in low-density urine samples (r >0.9), and therefore the effects of CR and SG could not be evaluated separately. In the overall evaluation,single determination (i.e., without repeated urine sampling) of Cd-U and alpha1-MG-U should be acceptable, and it may also be acceptable for beta2-MG-U. Use of samples with adequate urine density rather than application of density correction to low-density urine samples in recommended.

Correlation of ABO blood group with clinicopathologic characteristics of patients with esophageal squamous cell carcinoma.

The aim of the current study was to determine the nvolvement of ABO blood group in clinicopathologic features in squamous cell carcinoma (SCC) of the esophagus, that has not previously been studied fully. Two hundred and eighty four consecutive patients with esophageal SCC were enrolled for the study. The relationship between patients' ABO blood group and the clinicopathologic features was analyzed. The proportion of poorly differentiated SCC among patients with blood group O was significantly lower than in those patients with other blood types (P = 0.001). The mean size of the tumors in patients with blood group AB was significantly larger than those in patients with other blood groups. The proportion of tumors associated with venous invasion was significantly higher in patients with blood type A than those of tumors in other blood types (P = 0.007). The TNM stages of tumors in blood group AB were found to be significantly more advanced (P = 0.036) than other groups. The functional significance of ABO blood group distribution might be associated with biological behavior of SCCs. However, it was found not to be a clinical predictor for the prognosis of the patients with esophageal SCC.

No effects of hematuria and proteinuria in school days, and probably current pregnancy and current lactation also, as risk factors of cadmium-induced renal tubular dysfunction among adult women in general populations in Japan.

This study was initiated to examine if hematuria and proteinuria in school days, current pregnancy, or current lactation are risk factors of cadmium-induced tubular dysfunction for adult women among general populations in Japan. For this purpose, a database of 9,967 never-smoking adult women were reviewed for urinary levels of cadmium (Cd) and three other elements, calcium (Ca), magnesium (Mg), and zinc (Zn), and two tubular dysfunction markers of alpha1-microglobulin (alpha1-MG) and beta2-microglobulin (beta2-MG); the analyte concentrations were corrected for creatinine (cr) and expressed as, e.g., Cd-Ucr. From the total, 160 cases were selected as those who were informed of urinary abnormality (i.e., proteinuria, hematuria, or both) in their school days (the abnormality being found to be transient, later), and each case was matched by age and prefecture of residence. Separately, seven women with persistent urinary abnormality, seven pregnant women, and six lactating women were identified, and the case was matched with three cases each of the same age and living in the same prefecture. Statistical analyses showed that Cd-Ucr and other markers were not elevated in the transient urinary abnormality group as compared with the matched controls. This was also observed in the subjects with persistent abnormality. In the pregnant women, alpha1-MG-Ucr and possibly beta2-MG-Ucr were elevated, but Cd-Ucr did not increase, suggesting that the observed elevation in alpha1-MG and beta2-MG was not due to the effects of Cd but a part of the physiology of pregnancy itself. There was no change in marker levels in lactating women except for an increase in alpha1-MG. In overall evaluation, it was considered prudent to conclude that urinary abnormality in school days does not increase the risk of Cd-induced nephrotoxicity in adult women, whereas the negative findings with pregnancy and lactation should be taken as preliminary because the numbers of cases studied were limited.

Clinicopathologic significance of cyclin A expression in colorectal carcinoma.

The clinical significance of cyclin A expression, which has been known to act in the mitotic phase of the cell cycle, as an indicator of malignant potential in human tumors, has been suggested. The aim of this study was to elucidate the significance of immunohistochemical expression of cyclin A in colorectal carcinomas based on a larger study population. Immunohistochemical staining for cyclin A was performed for 167 colorectal carcinomas and the correlation between cyclin A expression and the clinicopathological characteristics was analyzed. One hundred and two carcinomas (61.1%) had cyclin A expression and the other 65 (38.9%) did not. The mean size of the tumors with cyclin A expression was significantly larger than that of tumors without cyclin A expression (p = 0.012). Survival in patients with cyclin A-expressing carcinomas was significantly worse than that in patients with carcinomas without cyclin A expression (p = 0.004). Cyclin A expression (p = 0.030), as well as lymph node metastasis (p = 0.007) and Dukes' stage of the tumors (p < 0.0001) were found to be factors independently associated with unfavorable prognosis in patients with colorectal carcinoma. Our results demonstrated that immunohistochemical expression of cyclin A is an independent prognostic indicator in patients with colorectal carcinoma.

Neurilemmoma of the diaphragm mimicking a liver tumor: case report.

A 47-year-old male with a solid, previously cystic tumor in the subphrenic part of the liver consulted for surgery. Laparotomy showed a well-circumscribed tumor originating from the diaphragm, which made a significant depression in the liver. Complete removal of the tumor was achieved. Pathologic examination led to a diagnosis of neurilemmoma originating from the diaphragm.

alpha1-Microglobulin as a promising marker of cadmium-induced tubular dysfunction, possibly better than beta2-microglobulin.

The purpose of the present study was to evaluate the validity of alpha1-microglobulin (alpha1-MG) in comparison with popularly used beta2-microglobulin (beta2-MG). A database on 8975 cases of never-smoking adult women was revisited; the data were based on spot urine samples from the women in 10 prefectures all over Japan. The validity of alpha1-MG was examined following essentially the same protocol as beta2-MG was examined in a previous study. Comparisons were made for alpha1-MG as observed (e.g. alpha1-MG(ob)), as corrected for creatinine (CR or cr) (e.g. alpha1-MGcr) and as corrected for a specific gravity (SG or sg) of 1.016 (e.g. alpha1-MGsg). A cut-off value of 5.0 mg alpha1-MG/g cr or l was deduced from 400 microg beta2-MG/g cr taking advantage of the regression equation between alpha1-MG and beta2-MG. The prevalence of alph1-microglobulinuria as corrected for a specific gravity of 1.016 (or alpha1-MGsg-uria in short) was essentially unchanged irrespective of SG, except for in very dense or very thin urine samples. alpha1-MGcr-uria prevalence decreased at higher CR. Comparison of the present observation with previous findings on beta2-MG-uria prevalence showed that the variation in prevalence of MG-uria as a function of urine density was smaller for alpha1-MGsg whereas it was substantially larger for beta2-MGcr, and thus it appeared prudent to consider alpha1-MGsg rather than beta2-MGcr as a marker of tubular dysfunction.

Significance of immunohistochemical over-expression of CD44v6 as an indicator of malignant potential in esophageal squamous cell carcinoma.

PURPOSE: The aim of the current study was to find out a clinicopathologic significance of CD44v6 over-expression in esophageal squamous cell carcinoma (ESCC), which has not been elucidated fully. METHODS: Immunohistochemical expression of CD44v6 was examined for 81 ESCCs. Correlation of CD44 over-expression with the clinicopathologic features were investigated. RESULTS: Thirty-eight ESCCs (46.9%) had over-expression of CD44v6. The proportions of the incidence of lymph node metastasis (P=0.039), lymphatic permeation (P=0.003), and blood vessel invasion (P=0.037) in ESCCs with over-expression of CD44v6 were significantly higher than those in ESCCs without over-expression of CD44v6. The stage of the tumor in ESCCs with over-expression of CD44v6 was significantly more advanced (P=0.045). Survival rates of patients with ESCC with over-expression of CD44v6 were significantly worse (P=0.0005). Moreover, CD44v6 over-expression (P=0.048) as well as blood vessel invasion (P=0.014) and stage of the tumor ( P=0.010) were factors independently associated with the unfavorable prognosis of the patients with ESCC. CONCLUSIONS: Over-expression of CD44v6 can be an indicator of the malignant potential of ESCC.

Critical evaluation of alpha1- and beta2-microglobulins in urine as markers of cadmium-induced tubular dysfunction.

The purpose of the study was to examine the validity of alpha1-microglobulin (alpha1-MG) in comparison with popularly used beta2-microglobulin (beta2-MG). A database was revisited to select ca. 7,500 spot urine samples (of adequate urine density) from non-pregnant, non-lactating and never-smoking adult women. The validity of the MGs was examined in terms of stability of the MG-uria prevalence in urine samples of various creatinine (CR or cr) concentration or specific gravity (SG or sg). Comparisons were made for MGs as observed (e.g., alpha1-MGob), as corrected for CR (e.g., alpha1-MGcr) and as corrected for SG of 1.016 (e.g., alpha1-MGsg). A cut-off value of 5.7 mg/g cr (or mg/l) for alpha1-MG was deduced from a cut-off value of 400 microg/g cr (or mcirog/l) for beta2-MG, because the correlation between alpha1-MGcr and beta2-MGcr was statistically significant. The prevalence of a 1-MGsg-uria was essentially unchanged (i.e., from a low of 13.6% to a high of 17.0%, or 1.2 times) except for in very dense or very thin urine samples, in contrast, beta2-MGcr-uria showed a substantial increase (from 0.0% to 2.8% with an infinite rate) as a reverse function of a decrease in CR in urine. The prevalence of uncorrected markers, i.e., alpha1-MGob-uria and beta2-MGob-uria, showed even greater CR- or SG-dependent changes. Thus, it appeared prudent to consider a alpha-MGsg rather than beta2-MGcr as a marker of tubular dysfunction among a general population with various urine density.

Bias induced by the use of creatinine-corrected values in evaluation of beta2-microgloblin levels.

The present study was initiated to examine if the correction for creatinine (CR or cr) is the best approach among the three methods of correction for CR, correction for a specific gravity (SG or sg) and the use of observed values in managing difference in urine density. For this purpose, a database previously developed on 10,753 adult women in 10 non-polluted areas in Japan was re-visited for information on age, urinary levels of Cd, Mg, Ca, Zn, beta(2)-MG, and creatinine, and urine specific gravity as well as smoking habits. Never-smoking women with various urine density counted 8975 cases (the various urine density group). From these cases, 7081 cases with adequate urine density (i.e. 0.5 g/l < or = CR < or = 3.0 g/l and 1.010 < or = SG < or = 1.030) were selected (the adequate urine density group). When a beta(2)-MG level of 400 microg/g CR or 400 microg/l was taken as a cut-off value for beta(2)-MG-uria, both the prevalence of beta(2)-MG(cr)-uria [i.e. cases with beta(2)-MG (as corrected for CR) in excess of 400 microg/g cr] and that of beta(2)-MG(sg)-uria increased as a function of the decrease in Cd(cr) or Cd(sg). The prevalence of beta(2)-MG(ob)-uria also varied as a function of CR and SG, especially of CR, but its range of variation was smaller than the corresponding changes in beta(2)-MG(cr)-uria prevalence. A noteworthy advantage for the use of observed values over that of SG-corrected values was the minimum effect of age. In over-all evaluation, therefore, the recommended approach appeared to be the use of non-corrected observed values (after selection of urine samples for adequate urine density if desired) or correction for SG, rather than correction for CR.

Comparative evaluation of four urinary tubular dysfunction markers, with special references to the effects of aging and correction for creatinine concentration.

Comparative evaluation was made on alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG), retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG), as a marker of renal tubular dysfunction after environmental exposure to cadmium (Cd), with special references to the effects of aging and correction for creatinine concentration. For this purpose, a previously established database of 817 never-smoking Japanese women (at the ages of 20 to 74 years) on hematological [hemoglobin, serum ferritin (FE), etc.] and urinary parameters [alpha(1)-MG, beta(2)-MG, creatinine (cr), and a specific gravity] was revisited. For the present analysis, the database was supplemented by the data on RBP and NAG in urine. The exposure of the women to Cd was such that the geometric mean Cd in urine was 1.3 microg/g cr. Among the four tubular dysfunction markers, NAG showed the closest correlation with Cd, followed by alpha(1)-MG and then beta(2)-MG, and RBP was least so although the correlations were all statistically significant. The observed values of the markers gave the best results, whereas correction for a urine specific gravity gave poorer correlation, and it was the worst when correction for creatinine concentration was applied. Age was the most influential confounding factor. The effect of age appeared to be attributable at least in part to the fact that both creatinine and, to a lesser extent, the specific gravity decreased as a function of age. Iron deficiency anemia of sub-clinical degree as observed among the women did not affect any of the four tubular dysfunction markers. In conclusion, NAG and alpha(1)-MG, rather beta(2)-MG or RBP, are more sensitive to detect Cd-induced tubular dysfunction in mass screening. The use of uncorrected observed values of the markers rather than traditional creatinine-corrected values is recommended when comparison covers people of a wide range of ages.

Analysis for threshold levels of cadmium in urine that induce tubular dysfunction among women in non-polluted areas in Japan.

OBJECTIVE: To examine if there is a threshold in urinary cadmium concentration that induces elevation in urinary microglobulins. METHODS: The database developed in a previous field survey (Ezaki et al. 2002) was employed. In the survey conducted in 2000 and 2001, more than 10,000 middle-aged women (with no occupational exposure to Cd) in ten prefectures all over Japan gave morning spot urine samples, which were analyzed for cadmium (Cd-U), calcium (Ca-U), magnesium (Mg-U), zinc (Zn-U), alpha(1)- and beta(2)-microglobulins (alpha(1)- and beta(2)-MG-U), and creatinine (cr). The urinary analyte concentrations were corrected for cr concentration (to be expressed as, e.g., Cd-Ucr), and the data thus obtained were subjected to statistical evaluation. The largest geometric mean (GM) for Cd-Ucr among the ten prefecture was 3.2 microg Cd/g cr, and the maximum Cd-Ucr observed among the women studied was 20.9 microg Cd/g cr. RESULTS: Both alpha(1)-MG-Ucr and beta(2)-MG-Ucr increased as a function of the increase in Cd-Ucr among all the women and also in sub-populations of narrow age ranges (i.e., 41-50 and 51-60 years), with no apparent threshold Cd-Ucr. Comparison of the cases exceeding cut-off alpha(1)-MG-Ucr and beta(2)-MG-Ucr levels also indicated a Cd dose-dependent increase in the prevalence, similarly without a threshold Cd-Ucr. In addition, such findings were essentially reproducible when elevation in alpha(1)-MG-Ucr and beta(2)-MG-Ucr levels was examined with the three essential elements, especially with Ca-Ucr and Mg-Ucr, although less clearly with Zn-Ucr. The observations as a whole suggest a possibility that the dose-dependent increases in alpha(1)-MG-Ucr and beta(2)-MG-Ucr with no apparent threshold for element concentration is not specific to Cd-Ucr but common to other elements. CONCLUSIONS: No threshold Cd-Ucr was detected in relation to the increases in alpha(1)-MG-Ucr and beta(2)-MG-Ucr. The element dose-dependent increases in the two MGs with no threshold in the element concentration might be not limited to Cd, but common to other elements. Further studies are apparently necessary.

No clear-cut evidence for cadmium-induced renal tubular dysfunction among over 10,000 women in the Japanese general population: a nationwide large-scale survey.

OBJECTIVE: To examine whether environmental exposure to cadmium has been inducing kidney dysfunction among middle-aged women in the general population in Japan. METHODS: This study was conducted in 2000 and 2001. Morning spot urine samples were collected from 10,753 women (mostly aged 35 to 60 years) in ten prefectures all over Japan (thus about 1,000 women per site). Urine samples were analyzed for cadmium (Cd-U), calcium (Ca-U), magnesium (Mg-U), zinc (Zn-U), alpha(1)- and beta(2)-microglobulins (alpha(1)- and beta(2)-MG-U). The urinary analyte concentrations were corrected for creatinine (cr) concentration (i.e., Ucr). The data thus obtained were subjected to statistical evaluation by chi-square test, ANOVA, multiple comparison test, and simple regression analysis (SRA) as well as multiple regression analysis (MRA) including logistic regression analysis (LRA). Log-normal distribution was assumed for Cd-Ucr, alpha(1)-MG-Ucr and beta(2)-MG-Ucr, whereas normal distribution was considered for age, Ca-Ucr, Mg-Ucr and Zn-Ucr. RESULTS: Geometric mean values (GM) of Cd-Ucr were distributed unevenly, depending on the sampling areas, with a grand GM of 1.3 microg/g cr, the highest (3.2 microg/g cr) and lowest GM values(0.8 microg/g cr) being significantly different from GMs of other areas. Correlation matrix analysis with subjects of all ages showed that log alpha(1)-MG-Ucr and log beta(2)-MG-Ucr correlated significantly (r=0.272 and 0.202, respectively) with log Cd-Ucr, but they correlated also with age (r=0.280 and 0.213, respectively). The same analysis with the two selected age groups (41-50 and 51-60 years), however, failed to show close correlation of alpha(1)-MG-Ucr and log beta(2)-MG-Ucr with Cd-Ucr. Both MRA and LRA indicated that age was a confounding factor in the evaluation of the effect of Cd-U on the two MG levels. Whereas the LRA with the all-age group showed a positive influence of log Cd-Ucr on log alpha(1)-MG-Ucr and log beta(2)-MG-Ucr, such effect disappeared in parallel with the disappearance of age effects when LRA was conducted with the two selected age groups. An exceptional observation was the influence of log Cd-Ucr on log alpha(1)-MG-Ucr (but not on log beta(2)-MG-Ucr) in LRA when a cut-off value of 5.00 mg for alpha(1)-MG-U/g cr was applied. Comparison between the low and high Cd-U groups showed that both alpha(1)-MG-Ucr and beta(2)-MG-Ucr were higher in the high Cd-U groups, but prevalence of cases with alpha(1)-MG-Ucr and beta(2)-MG-Ucr in excess of the cut-off values did not differ between the two groups except when a cut-off value of 5.00 mg/g cr was employed for alpha(1)-MG-U. CONCLUSIONS: In over-all evaluation, no clear-cut evidence was obtained in the present study to show that environmental exposure to Cd has induced tubule dysfunction among middle-aged women in the general population in Japan. It might be the case, however, that an increase in alpha(1)-MG-U was associated with Cd exposure. In this sense, it is apparently desirable from public health viewpoints to make further efforts to reduce the intensity of the general population's exposure to environmental Cd.

No significant effect of iron deficiency on cadmium body burden or kidney dysfunction among women in the general population in Japan.

OBJECTIVE: To examine if iron-deficient conditions modify body burden or health effects of cadmium among women in the general population in Japan. METHODS: In 2002, 1,482 women aged 20 to 74 years in six prefectures in Japan provided informed consent to participate in this study. They offered peripheral blood and spot urine samples, and answered questionnaires on their social habits and health conditions. Never-smoking, non-pregnant and non-lactating healthy women (1,190 subjects) were selected from the volunteers. Blood samples were analyzed for serum iron, ferritin and total iron-binding capacity (TIBC) in addition to red blood cell (RBC) counts and hemoglobin (Hb) concentration as markers of anemia and iron deficiency. Urine samples were analyzed for cadmium (Cd), alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG) as markers of Cd burden and Cd-induced tubular dysfunction; the measures were expressed after being corrected for creatinine (cr) as, e.g., Cd-Ucr. RESULTS: The subjects were classified into anemic (37 women) and iron-deficient (388 women) groups separately from healthy controls (765 women), taking ferritin (<20 ng/ml) and Hb (<10 g/100 ml) as classification indicators. Strictly matched pairs (with regard to age and prefecture) were established for 36 anemic and 280 iron-deficient cases. Comparison between the cases and the matched controls showed that serum iron was lower and TIBC was higher in accordance with lower levels of ferritin and Hb in the anemic and iron-deficient groups, although the RBC count was only slightly reduced (the anemic group) or stayed essentially unchanged (the iron-deficient group). In contrast, no significant increase in Cd-Ucr, alpha(1)-MG, or beta(2)-MG was observed in either the anemic group or the iron-deficient group compared with the matched controls. Cd-Ucr in one case of clinical anemia, however, tended to be higher than the levels among women of the same age range and from the same prefecture. Her alpha(1)-MG-Ucr and beta(2)-MG-Ucr, however, remained un-elevated. CONCLUSIONS: The current level of iron deficiency among women in the general population in Japan may not induce significant increase in Cd body burden or Cd-induced tubular dysfunction.