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Reviews December 2010 | Volume 118 | Issue 12
Blood and Urine Cadmium, Blood Pressure, and Hypertension: A Systematic Review and Meta-analysis
Carolyn M. Gallagher1,2, Jaymie R. Meliker2,3
1Doctoral Program in Population Health and Clinical Outcomes Research, and 2Department of Preventive Medicine, Stony Brook University Medical Center, Stony Brook, New York, USA; 3Graduate Program in Public Health, State University of New York at Stony Brook, Stony Brook, New York, USA
Environ Health Perspect 118:1676-1684 (2010). http://dx.doi.org/10.1289/ehp.1002077 [online 17 August 2010]
Background: Cadmium exposure has been inconsistently related to blood pressure.
Objectives: We updated and reevaluated the evidence regarding the relationships of blood cadmium (BCd) and urine cadmium (UCd) with blood pressure (BP) and hypertension (HTN) in nonoccupationally exposed populations.
Data sources and extraction: We searched PubMed and Web of Science for articles on BCd or UCd and BP or HTN in nonoccupationally exposed populations and extracted information from studies that provided sufficient data on population, smoking status, exposure, outcomes, and design.
Data synthesis: Twelve articles met inclusion criteria: eight provided data adequate for comparison, and five reported enough data for meta-analysis. Individual studies reported significant positive associations between BCd and systolic BP (SBP) among nonsmoking women [® = 3.14 mmHg per 1 μg/L untransformed BCd; 95% confidence interval (CI), 0.14–6.14] and among premenopausal women (® = 4.83 mmHg per 1 nmol/L log-transformed BCd; 95% CI, 0.17–9.49), and between BCd and diastolic BP (DBP) among women (® = 1.78 mmHg comparing BCd in the 90th and 10th percentiles; 95% CI, 0.64–2.92) and among premenopausal women (® = 3.84 mmHg per 1 nmol/L log-transformed BCd; 95% CI, 0.86–6.82). Three meta-analyses, each of three studies, showed positive associations between BCd and SBP (p = 0.006) and DBP (p < 0.001) among women, with minimal heterogeneity (I2 = 3%), and a significant inverse association between UCd and HTN among men and women, with substantial heterogeneity (I2 = 80%).
Conclusion: Our results suggest a positive association between BCd and BP among women; the results, however, are inconclusive because of the limited number of representative population-based studies of never-smokers. Associations between UCd and HTN suggest inverse relationships, but inconsistent outcome definitions limit interpretation. We believe a longitudinal study is merited.
Key words: blood, blood pressure, cadmium, hypertension, meta-analysis, smoking, systematic review, urine
Address correspondence to C.M. Gallagher, Stony Brook University, School of Medicine, Health Sciences Center Level 3, Room 071, Stony Brook, NY 11794 USA. Telephone: (631) 444-1145. Fax: (631) 444-3480. E-mail: email@example.com
C.M.G. gratefully acknowledges the educational guidance of A.L.W. Shroyer. We also thank J.S. Kovach for comments on earlier versions of the manuscript.
The authors declare they have no actual or potential competing financial interests.
Received 19 February 2010; accepted 17 August 2010; online 17 August 2010.
Hypertension (HTN) and smoking are established risk factors for cardiovascular disease (U.S. Department of Health and Human Services 2000), the leading cause of death worldwide (World Health Organization 2009). The etiology of essential HTN, however, is unknown (Carretero and Oparil 2000), but cadmium exposure has been inconsistently associated with blood pressure (BP). For example, Järup and Akesson (2009) recently reviewed the literature on cadmium and health effects and identified single-study–reported associations between cadmium and cardiovascular effects other than HTN. More than 10 years earlier, Nakagawa and Nishijo (1996) conducted a review of cadmium exposure and HTN and found that, although general population studies had reported positive associations of blood cadmium (BCd) and urinary cadmium (UCd) with BP, inverse associations had been reported in studies of residents or workers with known environmental or occupational exposures. Nakagawa and Nishijo (1996) interpreted these differences as an effect of low versus high exposures to cadmium, identified exposure misclassification as a limitation of studies conducted before the 1970s when cadmium measurements were semiquantitative, and also noted failure to account for the influence of smoking as a concern. Smoking is associated with increased cadmium levels because cigarettes contain cadmium taken up by the tobacco plant [Agency for Toxic Substances and Disease Registry (ATSDR) 2008]. Smokers have approximately twice the cadmium body burden of nonsmokers (ATSDR 2008). In nonsmokers, however, food is the primary source of exposure (ATSDR 2008). Nakagawa and Nishijo (1996) concluded that additional studies that control for smoking are needed, and several new studies that separated smokers from nonsmokers have been published since their review.
Since 1989, advancements in the technology to analyze BCd and UCd have improved the reliability of human exposure measures (Tsalev 1995); however, the use of these biomarkers has been inconsistent across epidemiological studies of HTN and BP. UCd is a biomarker for lifetime cadmium exposure among people with lower, nonoccupational exposures because, in the absence of episodes of high-level exposure, cadmium-binding sites, primarily in the kidney and liver, are not saturated, and UCd increases in proportion to the amount of cadmium stored in the body (Dillon and Ho 1991). UCd, however, can also reflect recent exposure (ATSDR 2008). BCd is a biomarker of recent exposure, with a half-life of 3–4 months, and is considered a biomarker for longer term exposure that reflects accumulation in the blood from body stores over a 10-year period (Järup et al. 1998). A greater percentage of inhaled rather than ingested cadmium is absorbed into the bloodstream (Järup et al. 1983, 1998). Thus, UCd and BCd levels may provide different information regarding the timing and source of exposure among smokers and nonsmokers.
The objectives of our systematic review and meta-analysis were to update and reevaluate the evidence regarding the relationships of BCd and UCd and BP and HTN and to discern the extent to which previously reported correlations may be associated with nonsmoking-related exposures, as indicated by BCd and UCd estimated effects in never-smokers.
Materials and Methods
We conducted an electronic search using PubMed (National Library of Medicine; http://www.ncbi.nlm.nih.gov/sites/entrez) to locate all relevant articles that address BCd and/or UCd and BP in humans and smoking status. We used the following a priori inclusion criteria: UCd and BCd levels and systolic BP (SBP), diastolic BP (DBP), or HTN; the study population was not restricted to a specific disease, condition, or otherwise unique subset. We adjusted the statistical evaluation for smoking status, age, and sex; the difference in mean cadmium values between HTN cases and normotensive controls and/or associations between cadmium levels and BP and/or HTN were evaluated for statistical significance. We used cross-sectional, case–control, or cohort study design and conducted original analyses. To assess general population exposures, we excluded studies that specifically assessed occupationally exposed populations. We used the following medical subject heading (MeSH) terms—population, intervention and exposure, comparison, outcome, study design (Liberati et al. 2009): a) population: human AND adult AND NOT occupational exposure; b) biomarker of exposure: cadmium and administration and dosage, cadmiumand adverse effects or cadmium and blood or cadmium and urine or cadmium and toxicity; c) comparisons: smoking status and sex (no MeSH terms specified); d) outcomes: BP or BP monitoring, ambulatory, or HTN; e) study designs: cross-sectional, case–control, cohort. We excluded studies that were limited to occupationally exposed populations (no MeSH terms specified).
Additionally, we conducted an electronic "bottom-up" search in the Web of Science (Thomson Reuters, New York, NY) to find articles that cite results of the PubMed literature search. Studies were limited to those published from 1989 to 2009 based on evidence of reliability of the technology to measure and analyze BCd and UCd (Tsalev 1995).
We developed a combined approach to weight the evidence of individual studies [see Supplemental Material, Table 1 (doi:10.1289/ehp.1002077)]. Study characteristics that merited higher weight-of-evidence (WOE) grades included separation by smoking status (i.e., either results were presented separately for smokers and never-smokers, or the population was restricted to never-smokers or nonsmokers), control for anti-HTN medication use, ambulatory or multiple BP measurements, analysis of both BCd and UCd biomarkers, or samples that represent general populations. In Table 1, the footnote gives the WOE codes that were used to qualitatively guide interpretation of the findings of the systematic review.
Study characteristics, key findings, and WOE codes.
Findings of studies that reported multivariate-adjusted measures of association and 95% confidence intervals (CIs), and/or standard errors (SEs) or t-values, are presented in Figures 1–5. In the absence of reported CIs (Pizent et al. 2001; Satarug et al. 2005; Staessen et al. 2000; Whittemore et al. 1991), we calculated 95% CIs as 1.96 × SE and thus represent approximate intervals. Unreported SEs (Satarug et al. 2005) were calculated by dividing the reported coefficient by the reported t-value (Rosner 2006). For results presented in the original article in graph format only (i.e., findings for never-smokers reported by Whittemore et al. 1991), values for estimates and 95% CIs were visually approximated. Mean BCd and UCd values originally reported in nanomoles per liter were converted to micrograms per liter by dividing by 8.897, and creatinine-adjusted UCd values originally reported as nanomoles per millimole creatinine were converted to micrograms per gram creatinine by dividing by 1.006 (Tellez-Plaza 2008). Interpretations of statistical significance are based on an alpha level ≤ 0.05.
BCd dose–response comparisons: HTN ORs and 95% CIs. Tellez-Plaza et al. (2008): HTN = mean SBP ≥ 140, mean DBP ≥ 90 mmHg, self-report of a physician diagnosis or anti-HTN drug use; BCd (μg/L) quartiles: Q1 (ref), ≤ 0.20; Q2, 0.20–0.40; Q3, 0.40–0.70; Q4, ≥ 0.70. Eum et al. (2008): HTN = SBP ≥ 140, DBP ≥ 90 mmHg, or self-report of HTN; BCd (μg/L) tertiles: T1 (reference), 0.18–1.28; T2, 1.29–1.86; T3, 1.87–5.52. All data are for men and women combined. Sizes of different point estimate symbols for quartiles and tertiles reflect increasing BCd levels.
Because two studies are a suggested minimum requirement for a systematic review to include a meta-analysis (Littell et al. 2008), we required at least three studies with comparable exposure and outcome measures. Meta-analysis was conducted using random effects models and inverse variance methods to weight effect estimates. Random effects models were used to account for variation among the studies (Littell et al. 2008). Inverse variance methods were used to give greater weight to studies characterized by greater precision, that is, relatively narrow CIs (Littell et al. 2008). Meta-analysis was performed using Review Manager 5.0 (RevMan; Cochrane Collaboration, Copenhagen, Denmark, http://ims.cochrane.org/revman).
Literature search. Electronic search results yielded a total of 33 citations; of these only 12 met the inclusion criteria [see Supplemental Material, Table 2 (doi:10.1289/ehp.1002077) for citations of excluded articles and the reasons for exclusion].
Large representative population-based samples, stratified by smoking status. Tellez-Plaza et al. (2008) analyzed data from the 1999–2004 National Health and Nutrition Examination Survey (NHANES; n = 10,991), and Whittemore et al. (1991) analyzed data from the 1976–1988 NHANES II (n = 960); both were cross-sectional studies (Table 1). Tellez-Plaza et al. (2008) defined HTN as mean SBP ≥ 140 mmHg, a mean DBP ≥ 90 mmHg, a self-reported physician diagnosis, or the use of medication for HTN; Whittemore et al. (1991) defined HTN by anti-HTN drug use only. Exposure measures included spot urine samples for both studies; however, Tellez-Plaza et al. (2008) used multivariate adjustment for creatinine to adjust for urine dilution effects, whereas Whittemore et al. (1991) directly adjusted UCd measurements for specific gravity. Tellez-Plaza et al. (2008) also estimated associations with BCd. Whittemore et al. (1991) estimated associations with continuous, untransformed UCd measures, and Tellez-Plaza et al. (2008) estimated associations for cadmium quartiles (relative to the lowest quartile) and for cadmium levels at or above the 90th percentile compared with cadmium at or below the 10th percentile, in addition to estimating associations with log-transformed continuous biomarker measures. The NHANES II database used by Whittemore et al. (1991) lacked appropriate sample weights for the subsample with cadmium measurements. Thus, p-values and CIs were calculated based on the assumption that this subsample is a simple random sample of the U.S. population. Tellez-Plaza et al. (2008) adjusted for HTN medication use in multivariate analyses but did not exclude treated HTN subjects from the analysis of never-smokers; in contrast, Whittemore et al. (1991) conducted two sets of analyses: One included all subjects and statistically adjusted for current hypertensive medication use, and the second set excluded subjects who had been treated for HTN.
Small studies, limited to nonsmokers. These four studies ranged in sample size from 53–267 subjects. Outcome measures included continuous SBP and DBP (Pizent et al. 2001; Satarug et al. 2005); dichotomous SBP and/or DBP, that is, SBP > 140 mmHg and/or DBP > 90 mmHg (Vivoli et al. 1989); mean SBP (Satarug et al. 2005); and mean arterial pressure (Lin et al. 1995). Exposure measures included 3-hr log-transformed UCd (Satarug et al. 2005), mean creatinine-adjusted spot UCd (Vivoli et al. 1989), and untransformed BCd (Lin et al. 1995; Pizent et al. 2001). The three cross-sectional studies were limited to nonsmokers (Lin et al. 1995; Pizent et al. 2001; Satarug et al. 2005), and the one case–control study matched cases and controls for smoking status (Vivoli et al. 1989). Treated HTN subjects were excluded from all four studies. Study populations were urban (Satarug et al. 2005) and rural (Pizent et al. 2001), clinic recruited (Lin et al. 1995), and occupation specific (Vivoli et al. 1989). Findings from Lin et al. (1995) are not depicted in graph format because the outcome measure (i.e., mean arterial BP) was not comparable with those of the other studies. Additionally, findings from Vivoli et al. (1989) are not plotted because this study analyzed the difference in mean cadmium between cases and controls and did not report comparable measures of association.
Large studies, not limited to nonsmokers. These three cross-sectional studies used the following number of subjects: 2,853 (Kurihara et al. 2004), 1,902 (Eum et al. 2008), and 1,223 (Menditto et al. 1998). Outcome measures included categorical measures of HTN, that is, SBP ≥ 140 mmHg and/or DBP > 90 mmHg or taking anti-HTN drugs (Kurihara et al. 2004) or SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or self-reported HTN in medical examination (Eum et al. 2008); continuous SBP and DBP (Eum et al. 2008; Menditto et al. 1998); and mean BP, that is, DBP + pulse pressure ÷ 3 (Eum et al. 2008) and DBP + 1/3 × (SBP – DBP) (Menditto et al. 1998). Exposure measures included BCd tertiles (0.18–1.28 μg/L, 1.29–1.86 μg/L, 1.87–5.52 μg/L (Eum et al. 2008); 84% upper cutoff dichotomized BCd and UCd, that is, geometric means × geometric SDs: UCd, men, 1.8 × 2.5 = 4.5 μg/g; UCd, women, 2.4 × 2.8 = 6.72 μg/g; BCd, men, 2.2 × 1.9 = 4.18 μg/L; BCd, women, 2.3 × 1.8 = 4.14 μg/L (Kurihara et al. 2004); and continuous log-transformed BCd (Menditto et al. 1998). Kurihara et al. (2004) used multivariable analysis to control for smoking status but did not separate former smokers from nonsmokers. Eum et al. (2008) controlled for former, current, and never-smokers, and Menditto et al. (1998) controlled for number of cigarettes smoked per day. Each of these studies statistically adjusted for smokers and nonsmokers but did not present the results separately for these two groups. Eum et al. (2008) ran separate regression models for low (< 0.95 mg/dL), medium (≥ 0.95 and < 1.05 mg/dL), and high (≥ 1.05 mg/dL) serum creatinine to adjust for renal dysfunction, and Kurihara et al. (2004) adjusted for β-2-microglobulin, which is a measure of tubular renal dysfunction. The study conducted by Menditto et al. (1998) was unique among this group of studies because they excluded treated hypertensive subjects; however, they did not report measures of association.
Small studies, not limited to nonsmokers. These studies ranged in sample size from 154 to 692 subjects. Outcome measures included SBP and DBP (Schutte et al. 2008; Staessen et al. 2000; Telisman et al. 2001) and 24-hr ambulatory SBP and DBP (Staessen et al. 2000). Exposure measures included 24-hr log-transformed UCd (Schutte et al. 2008; Staessen et al. 2000) and log-transformed BCd (Schutte et al. 2008; Staessen et al. 2000; Telisman et al. 2001). Staessen et al. (2000) conducted a combined cross-sectional and prospective study of 692 residents of two rural areas in Belgium, one with known environmental exposures to cadmium from zinc smelters. The study period included the years 1985–1989 and 1991–1995 for the same participants (less those lost to follow-up) after interventions to reduce cadmium exposure. The Schutte et al. (2008) analysis evaluated cross-sectional data from a sample of 557 subjects from this same study restricted to the years 1991–1994 and included 26 occupationally exposed men. A case–control study (Telisman et al. 2001) restricted participants to 154 nonoccupationally exposed men; however, measures of association were not presented.
Comparison of multivariate adjusted estimated effects. Results from eight studies provided adequate data to compare estimated effects. Results from five studies provided sufficient data for meta-analysis, using three studies for each analysis, with one study used in two meta-analyses of different exposures.
BCd and HTN. Figure 1 presents the estimated dose–response effects of BCd on HTN. In multivariable analysis that adjusted for smoking status and use of anti-HTN medications, Tellez-Plaza et al. (2008) estimated associations between HTN and BCd levels categorized by quartiles, with the first quartile used as the reference group (BCd ≤ 0.20 μg/L); quartile 2 = 0.20–0.40 μg/L; quartile 3 = 0.40–0.70 μg/L; and quartile 4 = > 0.70 μg/L. Relative to the first quartile (819 cases and 1,689 noncases), subjects in the third quartile (1,452 cases and 1,369 noncases) were 25% more likely to be hypertensive [odds ratio (OR) = 1.25; 95% CI, 0.87–1.81], but HTN was not associated with exposures in the second and fourth quartiles. Additionally, the authors compared the 90th and 10th percentiles in never-smokers (n = 5,486); the nonsignificant effect estimate (OR = 1.14; 95% CI, 0.89–1.45) was equivalent to that of the third quartile. Eum et al. (2008) categorized BCd levels into tertiles, with tertile 1 (reference group) ranging from 0.18 to 1.28 μg/L, tertile 2 from 1.29 to 1.86 μg/L, and tertile 3 from 1.87 to 5.52 μg/L. Subjects in the highest tertile were 52% more likely to have HTN than were those in the lowest tertile of BCd (OR = 1.52; 95% CI, 1.13–2.05).
BCd, and SBP and DBP. Figure 2 shows the relationships between BCd and SBP and DBP in men and women separately. Tellez-Plaza et al. (2008) reported that, in men, BCd (nmol/L) in the 90th relative to the 10th percentile was significantly associated with DBP (β = 1.81 mmHg; 95% CI, 0.40–3.22); this relationship, however, was not significant for SBP. In contrast, Staessen et al. (2000) reported inverse associations of log-transformed BCd (nmol/L) with SBP and DBP among men never on anti-HTN medications; however, this inverse relationship was only significant for DBP (β = –3.10 mmHg; 95% CI, –5.86 to –0.34). Because results from a third study were not available, meta-analysis was not performed using these findings for men.
BCd: SBP and DBP, women and men separately (partial regression coefficients and 95% CIs). Staessen et al. (2000): BCd (nmol/L) = continuous log-transformed; 95% CI, coefficient ± 1.96 × SE. Pizent et al. (2001): BCd (μg/L) = continuous untransformed; 95% CI, coefficient ± 1.96 × SE. Tellez-Plaza et al. 2008: BCd (nmol/L), 90th to 10th percentile. Size of point estimate symbols varies to identify different studies without quantitative or qualitative ranking.
Results were available from three studies that evaluated the relation between BCd and SBP among women, so we conducted a meta-analysis. Statistically significant positive associations were reported by Pizent et al. (2001) for a one-unit increase in untransformed BCd (micrograms per liter) among nonsmoking women (β = 3.14 mmHg; 95% CI, 0.14–6.14) and by Staessen et al. (2000) for a one-unit increase in log transformed BCd (nanomoles per liter) among premenopausal women (β = 4.83 mmHg; 95% CI, 0.17– 9.49). Tellez-Plaza et al. (2008) also reported positive, although insignificant, associations between BCd (nanomoles per liter), comparing 90th and 10th percentiles and SBP among women (β = 1.40 mmHg; 95% CI, –0.81 to 3.61). Overall estimated effects were significantly positive (β = 2.39 mmHg; 95% CI, 0.69–4.09; p = 0.006), with minimal heterogeneity (I2 = 3%).
All three studies showed positive relationships between BCd and DBP, with similar effect estimates, among women; however, only the findings of Staessen et al. (2000) and Tellez-Plaza et al. (2008) showed statistical significance (respectively: β = 3.84 mmHg; 95% CI, 0.86–6.82; β = 1.78; 95% CI, 0.64–2.92). The effect estimate for nonsmoking women found by Pizent et al. (2001) was similar to that found by Tellez-Plaza et al. (2008) for all women (β = 1.40 mmHg; 95% CI, –0.15 to 2.95). As in the meta-analysis for BCd and SBP, overall associations for BCd and DBP were significantly positive (β = 1.84 mmHg; 95% CI, 0.95–2.74; p < 0.0001), with minimal heterogeneity (I2 = 3%).
BCd dose response. In Figure 3, we compared BCd associations with SBP and DBP by levels of exposure. Among never-smokers, BCd levels in the 90th percentile were significantly associated with elevated SBP (β = 2.35 mmHg; 95% CI, 0.64–4.05) and DBP (β = 3.25 mmHg; 95% CI, 1.69–4.84) relative to the 10th percentile (Tellez-Plaza et al. 2008). In the smoking-adjusted analysis, the third quartile of BCd exposure relative to the lowest level showed a larger estimated effect (SBP: β = 1.85 mmHg; 95% CI, 0.52–3.19; DBP: β = 2.01 mmHg; 95% CI, 0.86–3.15) than did the second quartile; however, for both SBP and DBP, the effect estimate for the fourth quartile was attenuated relative to that of the third (Tellez-Plaza et al. 2008). For SBP, Eum et al. (2008) reported a positive association with the second tertile of BCd compared with the reference group (β = 1.651 mmHg; 95% CI, 0.099–3.203) and a slightly stronger association with BCd exposures in the third tertile (β = 2.204 mmHg; 95% CI, 0.649–3.760) relative to the first quartile. For DBP, only the third tertile reached statistical significance (β = 1.671 mmHg; 95% CI, 0.626–2.716). Comparisons of second and third levels across these two studies of lower population mean BCd (0.42 μg/L; Tellez-Plaza et al. 2008) and higher population mean BCd (1.67 μg/L; Eum et al. 2008) suggest a positive dose response.
BCd dose–response comparisons: SBP and DBP (partial regression coefficients and 95% CIs) Tellez-Plaza et al. (2008): BCd (μg/L) quartiles: Q1 (reference), ≤ 0.20; Q2, 0.20–0.40; Q3, 0.40–0.70; Q4, ≥ 0.70. Eum et al. (2008): BCd (μg/L) tertiles: T1 (reference), 0.18–1.28; T2, 1.29–1.86; T3, 1.87–5.52. All data are for men and women combined. Sizes of different point estimate symbols for quartiles and tertiles reflect increasing BCd levels.
UCd and HTN. Figure 4 presents study findings regarding the association between UCd and HTN. Tellez-Plaza et al. (2008) used a dichotomous measure of UCd obtained from spot urine samples, compared the 90th and 10th percentiles, and used multivariate adjustment to statistically adjust for urine creatinine; in contrast, Kurihara et al. (2004) used an 84% cutoff (4.5 μg/g for men and 6.72 μg/g for women) and directly adjusted UCd for urine creatinine. Whittemore et al. (1991) also measured cadmium from spot urine samples but adjusted for specific gravity. They used anti-HTN drug use to define HTN, whereas Kurihara et al. (2004) used standard BP cutoff measures, and Tellez-Plaza et al. (2008) incorporated both definitions, as well as self-report of a physician diagnosis of HTN. Despite these methodological differences, inverse relationships were found between UCd and HTN (HTN) among men and among women. ORs varied considerably across studies, with ORs of 0.62 for men and 0.67 for women in the Kurihara et al. (2004) study, and ORs of 0.34 and 0.94 for never-smoking men and women in the Tellez-Plaza et al. (2008) and Whittemore et al. (1991) studies, respectively. Meta-analysis of results from these three studies showed UCd to be significantly negatively associated with HTN (OR = 0.65; 95% CI, 0.45–0.94; p = 0.02); however, heterogeneity was substantial (I2 = 83%).
UCd and HTN (ORs and 95% CIs). Kurihara et al. (2004): HTN = SBP ≥ 140 or DBP > 90 mmHg, UCd (μg/g) = 84% upper cut-off level is 4.47 μg/g creatinine for men and 6.67 μg/g for women; spot urine sample, creatinine adjusted. Tellez-Plaza et al. (2008): HTN = mean SBP ≥ 140, mean DBP ≥ 90 mmHg, self-report of a physician diagnosis, or anti-HTN drug use; UCd (nmol/L) = 90th:10th percentile; spot urine sample, statistical model adjusted for creatinine. Whittemore et al. (1991): HTN = anti-HTN drug use, UCd (μg/L) = continuous untransformed; spot urine sample, specific gravity adjusted. Size of different point estimate symbols varies to identify different studies without quantitative or qualitative ranking.
UCd, and SBP and DBP. Figure 5 presents partial regression coefficients (adjusted for covariates in multivariable analysis) and 95% CIs for the relationship of UCd with SBP and DBP, evaluated separately for women and men. Statistically significant inverse relationships for a one-unit increase in log-transformed 24-hr UCd (nanomoles/liter) with SBP (β = –5.55 mmHg; 95% CI, –11.04 to –0.06) and DBP (β = –4.80 mmHg; 95% CI, –8.19 to –1.41) were reported for men who were never on anti-HTN drugs (Staessen et al. 2000). Although Whittemore et al. (1991) reported positive relationships of untransformed UCd (μg/L) with SBP and DBP among both never-smoking men and women, associations were not statistically significant. Satarug et al. (2005) observed a statistically significant positive relationship of log-transformed 3-hr UCd (nanomolar) with SBP (β = 0.31 mmHg; 95% CI, 0.05–0.57) among nonsmoking men who were not on anti-HTN medications; however, the estimated effect size was small, and findings were null for women. Overall, these results are inconsistent, which may be attributable, in part, to different units of exposure measures, variations in sample sizes, and differences in smoking status and anti-HTN drug use.
UCd: SBP and DBP, women and men separately (partial regression coefficients and 95% CIs). Whittemore et al. (1991): spot UCd (μg/L) adjusted for specific gravity, untransformed; 95% CI visually estimated from published graphs. Staessen et al. (2000): 24-hr UCd (nmol) log transformed; 95% CIs calculated as 1.96*SE. Satarug et al. (2005): 3-hr UCd (nanograms) log transformed; 95% CIs estimated from coefficient and t-value. Size of different point estimates varies to identify different studies without quantitative or qualitative ranking.
Synthesis of findings using a causal inference framework. Causal inference criteria provide a framework useful to interpret the strength and limitations of the evidence regarding an association between BCd and/or UCd with BP. Hill (1965) and contemporaries (Kundi 2006; Rothman and Poole 2007) caution against using epidemiological causal inference criteria as a checklist. Noting these cautionary concerns, it is informative to qualitatively group these criteria as follows: strength of association, consistency among studies, and temporality; and dose response, epidemiological coherence, and biological plausibility.
Strength of association, consistency, and temporality. Positive associations between BCd with elevated SBP and DBP were found among nonsmokers (Pizent et al. 2001) and never-smokers (Tellez-Plaza et al. 2008). Statistically significant relationships between BCd, SBP and DBP among nonsmokers and never-smokers are interpreted as providing stronger evidence than associations from smoking-adjusted studies because the effects of current and ever-smoking, respectively, are removed rather than statistically adjusted for. Meta-analysis supported strength of association, and the relationship between BCd and BP was evident across three studies of women (Pizent et al. 2001; Staessen et al. 2000; Tellez-Plaza et al. 2008), regardless of smoking adjustment or stratification methods. In the only prospective study, Staessen et al. (2000) found that BCd was positively related to SBP and DBP in premenopausal women. Moreover, a longitudinal decrease in BCd was documented after environmental remediation, and decreased BCd was associated with decreased DBP in women (Staessen et al. 2000). Because BCd is more influenced by recent exposure, and SBP and DBP are concurrent measures, the evidence suggests a temporal relationship between BCd and recent effects. BCd may also reflect accumulation of cadmium with age; however, all studies adjusted for or matched on age.
BCd was less consistently associated with HTN. This may be due to the disparate definitions of HTN. Studies similar in terms of adjustment for measures of renal dysfunction and populations with relatively high BCd levels reported discrepant findings; specifically, Eum et al. (2008) reported positive associations between BCd, and BP and HTN in a sample with a geometric mean > 2.0 μg/L, whereas Kurihara et al. (2004) reported no association between BCd and HTN in a sample with similarly high BCd (1.67 μg/L). BCd means for both of these samples were greater than that of the NHANES sample (0.42 μg/L) (Tellez-Plaza et al. 2008), and BCd was positively associated with BP in this low-exposure population, as well as in the Eum et al. (2008) study of a high-exposure population. Thus, the results of the present review do not support Nakagawa and Nishijo's (1996) conclusions that general populations with low exposures show positive associations between cadmium and BP, whereas populations with kidney dysfunction and high exposures show inverse associations. Of note, the only study reviewed in both the present and original review was the Staessen et al. (2000) study; however, Nakagawa and Nishijo (1996) referenced earlier versions (Staessen et al. 1984, 1991) and thus did not include the more recent findings of a positive association between BCd and BP in women (Staessen et al. 2000).
Several studies showed an inverse association between UCd, a biomarker of long-term exposure, and HTN. This inverse relationship was evident in both high- and low-exposure populations, so again, this does not support the earlier systematic review's interpretation that inverse associations between cadmium and BP are characteristic of populations with higher exposures and associated renal dysfunction (Nakagawa and Nishijo 1996). Specifically, both the Tellez-Plaza et al. (2008) study of a low-exposure population (mean BCd = 0.42 μg/L; mean UCd = 0.28 μg/L) and the Kurihara et al. (2004) study of a high-exposure population (BCd geometric mean, 2.2–2.3 μg/L; UCd geometric mean 1.8–2.4 μg/g creatinine) found statistically significant inverse relationships between UCd and HTN. Staessen et al. (2000) evaluated SBP and DBP averaged over 15 readings taken during the period 1985–1995; this time-integrated analysis also showed an inverse relationship between UCd and long-term DBP in men.
A limitation common to all studies, and thus to the meta-analysis of the relation between UCd and HTN, is that the outcome of HTN was not consistently defined across studies. Although meta-analysis findings support an inverse relationship, the finding of substantial heterogeneity might reflect outcome misclassification. Thus, although causal inference criteria support the interpretation of a positive association between BCd and higher SBP and DBP, the relationship between UCd, and BP and HTN remains uncertain.
Dose response, epidemiologic coherence, and biologic plausibility. Dose–response analyses of BCd tertiles and quartiles were not restricted to never-smokers, so interpretations regarding cadmium's exposure–response effects independent of smoking are limited. It is notable in the Tellez-Plaza et al. (2008) study, however, that for the outcomes of SBP and DBP, never-smokers show the largest effect estimates when comparing the 90th and 10th percentiles of BCd exposures and that, in the smoking-adjusted analysis of dose response in this same study, the fourth quartile of cadmium exposure shows a smaller effect estimate compared with the third quartile. Some studies show that smokers have lower BP than do nonsmokers (Green et al. 1986; Primatesta et al. 2001; Stolarz et al. 2003), and Lee (2008) found that smoking was a risk factor for masked HTN, that is, normal clinic BP but elevated ambulatory BP, suggesting that effect estimates in the upper range of cadmium exposure may be confounded by cigarette smoking. This hypothesis warrants investigation.
Based upon animal and in vitro studies, cadmium may increase BP through vascular effects. A hypothesized mechanism of action (MOA) for cadmium in humans is inhibition of endothelial nitric oxide synthase protein in blood vessels, which suppresses acetylcholine-induced vascular relaxation to induce HTN (Yoopan et al. 2008). On the other hand, serum cotinine, a metabolite of nicotine, has been inversely related to BP in smokers (Benowitz and Sharp 1989), and Ghasemi et al. (2010) reported a significantly positive correlation between serum nitric oxide and the number of cigarettes smoked per day, suggesting a possible MOA for how smoking might confound the relationship between cadmium and BP.
The inverse relationships observed between UCd and BP raise the question of whether cadmium might have depressor effects. Experimental findings suggest that cadmium binds to calcium-binding sites on the regulatory protein calmodulin, and like calcium, cadmium can increase dopamine synthesis in the brain that lowers BP (Sutoo and Akiyama 2000). Further research is merited to investigate this hypothesized MOA in humans.
HTN is a disease of differential physiological characterization. Approximately one-fourth of HTN subjects, particularly those with renovascular HTN, show high levels of angiotensin II, a vasoconstrictor (Malpas 2010). Angiotensin II receptor binding sites are located in the brain at sites involved with sympathetic nerve activity via baroreflex regulation (Malpas 2010). Puri and Saha (2003) found that in rats cadmium inhibited angiotensin-converting enzyme (ACE) at low, medium, and high doses without a dose–response effect yet paradoxically induced HTN; they postulated that cadmium's vascular effects predominated over its central effects in HTN rats. Although cadmium's central versus vascular effects in humans are unknown, it has been shown that the ACE inhibitor valsartan is more effective in preventing cardiac failure in HTN men than in HTN women (Zanchetti et al. 2006). In light of meta-analysis findings of an association between BCd and elevated BP in women, perhaps future research into cadmium's mechanisms of action may lead to improved gender-specific therapeutic interventions.
Staessen et al. (2000) found an inverse association between BCd and BP in men never on anti-HTN drugs. This finding and the meta-analysis finding of UCd's inverse association with HTN, yet UCd's positive associations with heart failure (Peters et al. 2010), seem counterintuitive, because HTN is an established risk factor for cardiovascular disease. In as many as 33% of HTN heart disease patients, however, heart failure is unrecognized because as this condition develops, the left ventricle becomes too weak to raise DBP (Riaz 2010). Further, masked HTN is prevalent in 10–20% of the adult population (O'Brien 2008). The extent to which undiagnosed and untreated HTN disease is associated with cadmium exposure has not been evaluated.
Methodological critique of individual studies. Cross-sectional analysis and inadequate specification of the duration of HTN limit temporal interpretations. Misclassification bias may result from the inconsistent measurement of HTN across studies. Even the measurement of BP may be biased by the phenomenon of masked HTN, which has been associated with cardiac and arterial target organ damage comparable with that of sustained HTN (Kotsis et al. 2008). Hypertensive heart failure is of even greater prevalence (Riaz 2010), and thus, nonmeasurement may be an additional source of outcome misclassification.
Sample selection considerations and exposure measurement error are additional limitations in these studies. Staessen et al. (2000) included men with known occupational exposures, as did Schutte et al. (2008), thus limiting interpretations of findings in men. Further, industrial exposures to cadmium emissions may have uniquely influenced dietary cadmium intake for subjects who consumed food grown in cadmium-contaminated soil. Of the six studies that separated smokers from nonsmokers, the four smaller studies used specific samples that limited generalizability of findings, and the Whittemore et al. (1991) study was not a probability sample. Treated HTN subjects were either analyzed separately or excluded in all smoking-stratified studies except the Tellez-Plaza et al. (2008) study. Further, the use of spot urine samples in the Tellez-Plaza et al. (2008), Whittemore et al. (1991), Vivoli et al. (1989), and Kurihara et al. (2004) studies may limit the accuracy of exposure assessment due to variable urinary dilution effects throughout the day (Barr et al. 2005). Urine specific gravity and creatinine correction were used to address this limitation, however, and Berlin et al. (1985) reported a correlation between cadmium levels measured in spot and 24-hr samples from occupationally exposed subjects.
Limitations of meta-analysis. The small number of studies precluded quantitative bias assessment, as well as meta-analysis of the relation between BCd with SBP and DBP among men. Further, Menditto et al. (1998) and Kurihara et al. (2004) did not report statistics for null findings regarding the relation between BCd and BP, so meta-analysis may be subject to positive reporting bias. On the other hand, Lin et al. (1995) and Vivoli et al. (1989) found positive relationships between BCd and BP but did not report comparable measures of association, which may have subjected the meta-analysis to negative reporting bias. Meta-analysis of SBP and DBP used both continuous (Pizent et al. 2001; Staessen et al. 2000) and 90:10th percentile exposure measures (Tellez-Plaza et al. 2008). Similarly, meta-analysis of HTN used both continuous (Whittemore et al. 1991) and high:low UCd exposure measures (Kurihara et al. 2004; Tellez-Plaza et al. 2008). Further, units of measure varied across studies. Thus, there were substantial differences in exposure measures that limited interstudy comparisons of effect estimates.
Conclusion and Recommendations
The body of evidence relating BCd to BP suggests a positive relationship, especially in females, but in the absence of dose–response gradients in never-smokers is inconclusive. The inverse relationships between UCd and BP reported in the meta-analysis lack strong mechanistic support. Our findings offer new insights, however, because these paradoxical relationships were evident in both high- and low-exposure populations, as indicated by mean population cadmium exposure levels, and thus contradict earlier assumptions that this inverse association only reflected higher cadmium exposures. In light of this review's evidence of an association between BCd and higher BP, an established risk factor for cardiovascular disease, and recent evidence of a prospective association between long-term cadmium exposure and cardiovascular mortality (Menke et al. 2009), cadmium merits further epidemiologic inquiry. The European Food Safety Authority (2009) recognized that cadmium has been associated with myocardial infarction (Everett and Frithsen 2008) and alterations in cardiovascular function (Schutte et al. 2008). More rigorous investigation of both short- and longer-term effects of nonsmoking cadmium exposures may shed insights regarding susceptibility to HTN and cardiovascular disease by identifying cadmium dose–response relationships over time.
This line of research would benefit from both physiological studies of cadmium's MOA, and longitudinal epidemiological studies of never-smoking, general populations (i.e., non-occupationally and nonindustrially exposed) to evaluate the relationships among BCd and UCd, and SBP, DBP, and sustained HTN. Sufficient power would be needed to examine effects in the never-smoking general population, with subset analyses by gender,
A longitudinal study would help tease out temporally relevant influences, such as menopausal status and hormonal effects. Cadmium has been shown to suppress progesterone production (Paksy et al. 1997) and has also been associated with increased serum levels of follicle-stimulating hormone (Gallagher et al. 2010). Insights regarding gender differences in cadmium toxicokinetics may be gained by measuring iron levels, because iron competes with cadmium for binding sites on the metal transporter divalent metal transporter 1 (DMT1) (Nishijo et al. 2004). Because cadmium has been associated with peripheral arterial disease (PAD) (Navas-Acien et al. 2004), and zinc and UCd were inversely associated in patients with PAD (Tsai et al. 2004), zinc intake also merits consideration. Further, Guallar et al. (2006) found that BCd partially explained the relationship between elevated homocysteine levels and PAD. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine metabolism, and MTHFR gene polymorphisms were associated with essential HTN (Ilhan et al. 2008).
An increasing body of evidence suggests that cadmium is a risk factor for cardiovascular morbidity and mortality, as well as a contaminant of concern in our food supply (European Food Safety Authority 2009; Reuben 2010). Findings from this meta-analysis indicate a positive association between BCd and increased BP, particularly in women, and identify gaps in research regarding the association of cadmium exposure with HTN. Longitudinal studies are merited to evaluate the relationships of cadmium exposures with more rigorous measures of HTN; physiological indicators of cadmium's central, cardiac, and vascular effects; hormonal nutritional factors; genetic susceptibilities; and cardiovascular disease among never-smokers.
Attached Files
- ATSDR (Agency for Toxic Substances and Disease Registry) 2008. Public Health Statement for Cadmium. Available: http://www.atsdr.cdc.gov/phs/phs.asp?id=46&tid=15 [accessed 6 September 2009]
- Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkel JL. 2005. Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect 113:192–200.
- Benowitz NL, Sharp DS. 1989. Inverse relation between serum cotinine concentration and blood pressure in cigarette smokers. Circulation 80(5):1309–1312.
- Berlin A, Alessio L, Sesana G, Dell'Orto A, Ghezzi I.. 1985. Problems concerning the usefulness of adjustment of urinary cadmium for creatinine and specific gravity. Int Arch Occup Environ Health 55(2):107–111.
- Carretero OA, Oparil S. 2000. Essential hypertension. Part I: definition and etiology. Circulation 101(3):329–335.
- Dillon HK, Ho MH, eds. 1991. Biological Monitoring of Exposure to Chemicals: Metals. New York:John Wiley and Sons.
- European Food Safety Authority 2009. Scientific opinion, cadmium in food. EFSA J 980:1–139.
- Eum K, Lee M, Paek D.. 2008. Cadmium in blood and hypertension. Sci Total Environ 407(1):147–153.
- Everett CJ, Frithsen IL. 2008. Association of urinary cadmium and myocardial infarction. Environ Res 106(2):284–286.
- Gallagher CM, Moonga BS, Kovach JS. 2010. Cadmium, follicle-stimulating hormone, and effects on bone in women age 42–60 years, NHANES III. Environ Res 110(1):105–111.
- Ghasemi A, Syedmoradi L, Momenan AA, Zahediasl S, Azizi F. 2010. The influence of cigarette and qalyan (hookah) smoking on serum nitric oxide metabolite concentrations. Scand J Clin Lab Invest 70(2):116–121.
- Green MS, Jucha E, Luz Y. 1986. Blood pressure in smokers and nonsmokers: epidemiologic findings. Am Heart J 111(5):932–940.
- Guallar E, Silbergeld EK, Navas-Acien A, Malhotra S, Astor BC, Sharrett AR, et al. 2006. Confounding of the relation between homocysteine and peripheral arterial disease by lead, cadmium, and renal function. Am J Epidemiol 163(8):700–708.
- Hill AB. 1965. The environment and disease: association or causation? Proc R Soc Med 58(5):295–300.
- Ilhan N, Kucuksu M, Kaman D, Ilhan N, Ozbay Y.. 2008. The 677 C/T MTHFR polymorphism is associated with essential hypertension, coronary artery disease, and higher homocysteine levels. Arch Med Res 39(1):125–130.
- Järup L, Akesson A.. 2009. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238(3):201–208.
- Järup L, Berglund M, Elinder CG, Nordberg G, Vahter M. 1998. Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand J Work Environ Health 24: suppl 11–51.
- Järup L, Rogenfelt A, Elinder CG, Nogawa K, Kjellström T. 1983. Biological half-time of cadmium in the blood of workers after cessation of exposure. Scand J Work Environ Health 9(4):327–331.
- Kotsis V, Stabouli S, Toumanidis S, Papamichael C, Lekakis J, Germanidis G, et al. 2008. Target organ damage in "white coat hypertension" and "masked hypertension." Am J Hypertens 21(4):393–399.
- Kundi M.. 2006. Causality and the interpretation of epidemiologic evidence. Environ Health Perspect 114:969–974.
- Kurihara I, Kobayashi E, Suwazono Y, Uetani M, Inaba T, Oishiz M.. 2004. Association between exposure to cadmium and blood pressure in Japanese peoples. Arch Environ Health 59(12):711–716.
- Lee HY. 2008. Prevalence and risk factors of masked hypertension identified by multiple self-blood pressure measurement. Hypertension 52:1–2.
- Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis PA, et al. 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6(7).)doi:10.1371/journal.pmed.1000100
- Lin JL, Lu FH, Yeh KH. 1995. Increased body cadmium burden in Chinese women without smoking and occupational exposure. J Toxicol Clin Toxicol 33(6):639–644.
- Littell JH, Corcoran J, Pillai V. 2008. Systematic Reviews and Meta-Analysis. New York:Oxford University Press.
- Malpas SC. 2010. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 90(2):513–557.
- Menditto A, Chiodo F, Patriarca M, Morisi G, Menotti A, Spagnolo A, NRF Project Research Group. 1998. Blood cadmium levels in nonexposed male subjects living in the Rome area: relationship to selected cardiovascular risk factors. Microchem J 59(1):173–179.
- Menke A, Muntner P, Silbergeld EK, Platz EA, Guallar E. 2009. Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect 117:190–196.
- Nakagawa H, Nishijo M.. 1996. Environmental cadmium exposure, hypertension and cardiovascular risk. J Cardiovasc Risk 3(1):11–17.
- Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E. 2004. Lead, cadmium, smoking, and increased risk of peripheral arterial disease. Circulation 109(25):3196–3201.
- Nishijo M, Satarug S, Honda R, Tsuritani I, Aoshima K.. 2004. The gender differences in health effects of environmental cadmium exposure and potential mechanisms. Mol Cell Biochem 255(1–2):87–92.
- O'Brien E.. 2008. Ambulatory blood pressure measurement: the case for implementation in primary care. Hypertension 51(6):1435–1441.
- Paksy K, Rajczy K, Forgács Z, Lázár P, Bernard A, Gáti I, et al. 1997. Effect of cadmium on morphology and steroidogenesis of cultured human ovarian granulose cells. J Appl Toxicol 17(5):), 321–327.
- Peters JL, Perlstein TS, Perry MJ, McNeely E, Weuve J. 2010. Cadmium exposure in association with history of stroke and heart failure. Environ Res 110(2):199–206.
- Pizent A, Jurasovie J, Telisman S.. 2001. Blood pressure in relation to dietary calcium intake, alcohol consumption, blood lead, and blood cadmium in female nonsmokers. J Trace Elem Med Biol 15(2–3):123–130.
- Primatesta P, Falaschette E, Gupta S, Marmot MG, Poulter NR. 2001. Association between smoking and blood pressure: evidence from the health survey for England. Hypertension 37(2):187–193.
- Puri VN, Saha S. 2003. Comparison of acute cardiovascular effects of cadmium and captopril in relation to oxidant and angiotensin converting enzyme activity in rats. Drug Chem Toxicol 26(3):213–218.
- Reuben SH. 2010. Reducing Environmental Cancer Risk: What We Can Do Now. 2008–2009 Annual Report, President's Cancer Panel. Bethesda, MD:National Institutes of Health, National Cancer Institute.
- Riaz K, Ahmed A. 2010. Hypertensive Heart Disease. Available: http://emedicine.medscape.com/article/162449-print [accessed 16 May 2010]
- Rosner B. 2006. Fundamentals of Biostatistics. 6th ed. Belmont, CA:Thomson-Brooks/Cole.
- Rothman KJ, Poole C. 2007. Some guidelines on guidelines; they should come with expiration dates. Epidemiology 18(6):794–796.
- Satarug S, Nishijo M, Ujjin P, Vanavanitkum Y, Moore MR. 2005. Cadmium-induced nephropathy in the development of high blood pressure. Toxicol Lett 157(1):57–68.
- Schutte R, Nawrot T, Richart T, Thijs L, Roels HA, Van Bortel LM, et al. 2008. Arterial structure and function and environmental exposure to cadmium. Occup Environ Med 65(6):412–419.
- Staessen J, Amery A, Bernard A, Bruaux P, Buhet JP, Bulpitt CJ, et al. 1991. Blood pressure, the prevalence of cardiovascular diseases, and exposure to cadmium: a population study. Am J Epidemiol 134(3):257–267.
- Staessen J, Bulpitt CJ, Roels H, Bernard A, Fagard R, Joossens JV, et al. 1984. Urinary cadmium and lead concentrations and their relation to blood pressure in a population with low exposure. Br J Ind Med 41(2):241–248.
- Staessen JA, Kuznetsova T, Roels HA, Emelianov D, Fagard R. 2000. Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Am J Hypertens 13(2):146–156.
- Stolarz K, Staessen JA, Kuznetasova T, Tikhonoff V, State D, Babenu S, et al. 2003. Host and environmental determinants of heart rate and heart rate variability in four European populations. J Hypertens 21(3):525–535.
- Sutoo D, Akiyama K.. 2000. Effect of cadmium or magnesium on calcium-dependent central function that reduces blood pressure. Arch Toxicol 74(1):1–4.
- Telisman S, Jurasovic J, Pizent A, Cuitkovic P.. 2001. Blood pressure in relation to biomarkers of lead, cadmium, copper, zinc, and selenium in men without occupational exposure to metals. Environ Res 87(2):57–68.
- Tellez-Plaza M, Navas-Acien A, Craincanu CM, Guallar E. 2008. Cadmium exposure and hypertension in the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Environ Health Perspect 116:51–56.
- Tsai JL, Horng PH, Hwang TJ, Hsu JW, Horng CJ. 2004. Determination of urinary trace elements (arsenic, copper, manganese, zinc, selenium) in patients with blackfoot disease. Arch Environ Health 59(12):686–692.
- Tsalev DL. 1995. Atomic Absorption Spectrometry in Occupational and Environmental Health Practice. Vol 3. Progress in Analytical Methodology. Boca Raton, FL:CRC Press.
- U.S. Department of Health and Human Services 2000. Healthy People 2010: Understanding and Improving Health. 2nd ed. Washington, DC:U.S. Government Printing Office.
- Vivoli G, Bergomi M, Borella P, Fantuzzi G, Caselgrandi E.. 1989. Cadmium in blood, urine, and hair related to human hypertension. J Trace Elem Electrolytes Health Dis 3(3):139–145.
- Whittemore AS, DiCiccio Y, Provenzano G. 1991. Urinary cadmium and blood pressure: Results from the NHANES II Survey. Environm Health Perspect 91:133–140.
- World Health Organization 2009. Cardiovascular diseases. Fact Sheet No. 317. Available: http://www.who.int/mediacentre/factsheets/fs317/en/index.html [accessed 21 September 2009]
- Yoopan N, Watcharasit P, Wongsawatkul O, Piyachaturawat P, Satayavivad J.. 2008. Attenuation of eNOS expression in cadmium-induced hypertensive rats. Toxicol Lett 176(2):157–161.
- Zanchetti A, Julius S, Kjeldsen S, McInnes GT, Hua T, Weber M, et al. 2006. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: an analysis of findings from the VALUE trial. J Hypertens 24(11):2163–2168.
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United States District Court, S.D. Illinois
July 21, 2014
METROPOLITAN CASUALTY INSRUANCE COMPANY, Plaintiff/Counterclaim-Defendant,v.GEORGIA GORIOLA, Defendant/Counterclaim-Plaintiff.
DAVID R. HERNDON, Chief District Judge.
Before the Court is plaintiff and counterclaim-defendant Metropolitan Casualty Insurance's ("Metropolitan") motion for reasonable attorneys' fees and expenses (Doc. 55). Defendant and counterclaim-plaintiff Georgia Goriola ("Goriola") subsequently filed a request for adversary submissions on Metropolitan's motion for reasonable attorneys' fees and expenses (Doc. 60). The Court GRANTS the motion and will therefore consider Goriola's response (Doc. 61). Metropolitan thereafter replied (Doc. 63). For the following reasons, the Court GRANTS in part and DENIES in part Metropolitan's motion for reasonable attorneys' fees and expenses.
I. Background
Metropolitan brought this declaratory judgment action pursuant to 28 U.S.C. §§ 2201 and 2202, against Goriola seeking declaration by this Court that it does not owe a duty to indemnify Goriola pursuant to a homeowner's insurance policy issued to Goriola by Metropolitan. Metropolitan further sought recovery of any advance payments, the amount paid to the mortgage holder, if any, and the amount of expenses incurred in investigation, adjustment, and evaluation of the claim including attorney's fees. On December 11, 2013, the Court granted Metropolitan's motion for summary judgment and closed the case.
Metropolitan seeks recovery of its attorney's fees and expenses incurred in the investigation, adjustment, evaluation and litigation of this claim, including amounts advanced to Goriola. Metropolitan indicates that it provided Goriola with advance payments totaling $9, 000 ($5, 000 on September 27, 2010, $2, 000 on November 1, 2010, and $2, 000 on November 15, 2010). Metropolitan also states that it advanced expenses to Goriola totaling $12, 213.58 to fund her extended stay at the Comfort Inn in Cahokia, Illinois, an additional $19, 328.45 for cleaning and storing various content items belonging to Goriola, and $5, 537.28 to board-up Goriola's dwelling and to make emergency repairs to the same. Metropolitan additionally requests reasonable attorneys' fees totaling $58, 501. In support of these totals, Metropolitan provides the affidavit of Debra-Lynn Benvenuto, Senior Claim Adjuster for Metropolitan (Doc. 55-1 at 1-4), relevant invoices (Doc. 55-1 at 5-50), and the affidavit of Robert W. Cockerham, counsel of record for Metropolitan. Metropolitan then moved for leave to file under seal its billing records as Exhibit C (Doc. 56).
In her response, Goriola asserts that Metropolitan's motion should be denied because it is untimely, provides no authority for the imposition of attorneys' fees against Goriola, and because it requests additional relief without providing Goriola with reasonable notice of the claim and an opportunity to be heard.
Metropolitan subsequently replied (Doc. 63). Metropolitan asserts that the motion was in fact timely as it was filed to resolve Metropolitan's remaining claim and therefore Federal Rule of Civil Procedure 54 does not apply. Metropolitan also argues that its motion contains authority supporting the recovery of attorneys' fees and specifically notes its citations regarding Illinois precedent on rescission. Finally, Metropolitan asserts that its motion seeks the precise relief it sought when this suit was filed.
II. Analysis
A. Advances
Metropolitan requests recoupment of the advance payments it made to Goriola. Under Illinois law, "[t]he remedy of rescission generally requires each party to return to the other the value of the benefits received under the rescinded contract." Newton v. Aitken, 633 N.E.2d 213, 216 (2nd Dist. 1994). On December 11, 2013, this Court concluded that the insurance policy at issue would be rescinded due to Goriola's material misrepresentations. Accordingly, Metropolitan is entitled to the advances and Goriola to her insurance premiums. However, Goriola fails to address the premiums in her response, instead relying on 28 U.S.C. § 2202's notice and hearing requirement. Further, she states, "[a]t a minimum, if Metropolitan wishes to recover its advances on the basis of rescission, Ms. Goriola must be provided with an opportunity to determine premiums paid to Metropolitan for the policy, and the fourteen (14) days Ms. Goriola has to respond to Metropolitan's Motion is insufficient to explore that issue" (Doc. 61 at 3). The Court disagrees - this was Goriola's opportunity to address the issue. If Goriola needed more time to review her premiums, then she should have requested an extension of time. Furthermore, while the parties did not address this issue at the Summary Judgment stage of the litigation, Metropolitan's complaint clearly indicates a request for these advance payments (Doc. 2 at 7). Therefore, the Court finds that Goriola has waived the argument. Goriola also does not object to Metropolitan's statements regarding the amount of the advances. As such, the Court finds that Metropolitan is entitled to recoup its advances to Goriola totaling $46, 079.31.
B. Attorneys' Fees
Metropolitan also seeks to recover its attorneys' fees. Pursuant to Federal Rule of Civil Procedure 54(d)(2)(B)(i), a motion for attorneys' fees must "be filed no later than 14 days after the entry of judgment." Judgment in this case was entered on December 16, 2013 (Doc. 54). However, Metropolitan's motion for attorney fees and expenses was not filed until January 8, 2014, outside the 14-day window. The Court finds unpersuasive Metropolitan's argument that its request for attorneys' fees is a separate claim. While Metropolitan did indicate the request in the complaint, the procedures of Rule 54 still apply. Therefore, the Court DENIES Metropolitan's request for attorneys' fees. Further, the Court need not review Metropolitan's billing statements, therefore the Court also DENIES Metropolitan's motion to seal document (Doc. 56).
III. Conclusion
Accordingly, the Court GRANTS in part and DENIES in part Metropolitan's motion for attorney fees and expenses (Doc. 55). The Court GRANTS Goriola's request for adversary submissions (Doc. 60) and DENIES Metropolitan's motion to seal document (Doc. 56).
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text:
La Bete Broadway Show
Discount Tickets to La Bete on Broadway
La Bete on Broadway
This revival of playwright David Hirson's Moliere-inspired comedy, directed by Matthew Warchus (God of Carnage), is coming to Broadway following a limited engagement in London. The 1991 play, set in 17th century France, is about theater troupe performer Elomire, who goes head-to-head with street entertainer Valere. The production stars Tony Award winner David Hyde Pierce (Broadway's Spamalot and Curtains, TV's Frasier), Mark Rylance (Boeing-Boeing), and Joanna Lumley (Absolutely Fabulous).
La Bete Discount Tickets
Please check today's discount Broadway ticket listings to see what discount ticket offers we have for this Broadway show. CLICK HERE
La Bete Regular Price Tickets
Regular Price Tickets are available for this show . Please CLICK HERE for current prices and availability of regular price tickets for this Broadway Show.
Broadway Theatre
La Bete is currently playing at the following Broadway Theatre:
Music Box Theatre
239 West 45th Street
New York, NY 10019
Click Here For More Info On The Theatre
Music Box Theatre
239 West 45th Street
New York, NY 10019
Click Here For More Info On The Theatre
Show Synopsis:
La Bete tells the story of a princess who decides to hire a common street performer to join her royal theater company. When that loud-mouthed clown meets the troupe's classically-trained leader, the two men square off to defend their pride in a rollicking, hilarious showdown.
Cast List:
David Hyde Pierce
Mark Rylance
Joanna Lumley
Stephen Ouimette
Lisa Joyce
Greta Lee
Robert Lonsdale
Michael Milligan
Liza Sadovy
Sally Wingert
Deanne Lorette
Steve Routman
Production Credits:
Matthew Warchus (Direction)
Other Credits:
David Hirson (Playwright)
Summary A princess (Joanna Lumley) hires a common street performer (Mark Rylance) to be a player in her royal theater company, but the loud-mouthed clown soon clashes with the troupe's classically-trained leader (David Hyde Pierce).
Age May be inappropriate for 12 and under. Children under the age of 4 are not permitted in the theatre.
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Copyright © 2009 New York TV Show Tickets Inc. - nytix.com


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Highly-skilled specialists, above-average pay, long-term placement
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Knowledge transfer from experts for experts
Over 35 years ago top itservices AG began specialising in recruiting IT experts and engineers. The company is still one of only a few personnel specialists and service providers that focuses on placing highly-specialised experts. For this reason we pay above average.
We bring together what belongs together: people and solutions, teams and projects, developers and software, engineers and technologies. We offer contract work in the following sectors:
As at January 2015, there were 791,000 people contracting in Germany.
(Source: iGZ)
We are your recruitment partner for highly skilled experts for temporary roles!


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Social Media Volunteer - Facebook
Cause Areas
WhenIt's flexible! We'll work with your schedule.
WhereThis is a Virtual Opportunity, with no fixed address.
Cercle Social Members
Do you use Facebook every day?
You may like this!
We are looking for a volunteer admin for our Facebook page.
- Implement a social media strategy on Facebook
- Share custom posts on the Facebook page
- Share videos
- Invite the audience to like and share the page and more.
This is an excellent opportunity to get your volunteer hours.
Join our team of volunteers for a great cause.
Approved 501c3 non-profit organization
- Social Media / Blogging
- Advertising
- Interactive/Social Media/SEO
- Public Relations
- Brand Development & Messaging
Good Match For
Requirements & Commitment
- Must be at least 21
- Minimum of 2 hours/week


text: Home > Bookshop > Australian Subjects > Australian Aboriginals > Australian Aboriginals - General « Back Nanberry: Black Brother White French, Jackie Our Price Retail Price AUD$16.99 Your Price AUD$14.44 Minimum Order: 1 In Stock (1) Dispatch: 1 day Nanberry: Black Brother White/French, Jackie/Paper/0732290228/S008-B AUD$14.44 QTY Gift Wrapping Add Gift Wrapping (click checkbox) If you would like a gift wrapping message, please add it in the Notes section on the checkout page, thank you. AUD$2.95 Publisher: HarperCollins ISBN-13: 9780732290221 Series: . Binding: Paperback Year Published: 2011 It's 1789, and as the new colony in Sydney Cove is established, Surgeon John White defies convention and adopts Nanberry, an Aboriginal boy, to raise as his son. Nanberry is clever and uses his unique gifts as an interpreter to bridge the two worlds he lives in. With his white brother, Andrew, he witnesses the struggles of the colonists to keep their precarious grip on a hostile wilderness. And yet he is haunted by the memories of the Cadigal warriors who will one day come to claim him as one of their own. This true story follows the brothers as they make their way in the world - one as a sailor, serving in the Royal Navy, the other a hero of the Battle of Waterloo. No less incredible is the enduring love between the gentleman surgeon and the convict girl, saved from the death penalty, to become a great lady in her own right. ID: 226153 Code: HC001519


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Having a blog could be dangerous because, for many of us, the entire process of administering and maintaining can turn into an addictive task, one not being happy until a new post is published; moreover, the addiction may be acute and one will wait for the first reaction of the readers impatiently. Certainly, it's not too difficult to become a blogging addict and, surprisingly, personally I do not consider it to be very negative (of course, it isn't that good to have this "quality" but, compared to other problems, it is not the worst thing in the world). In fact, there are two sides of the same problem: if someone is skeptical, that person will have the tendency to say that spending too much time on a blog is a disaster and this "illness" needs to be corrected, but an optimistic person would say that the addictiveness is only a big passion and that is all.
Being objective takes a lot of effort but, my humble opinion, cumulated with the thoughts of other great bloggers, related to the problem of blogging, concludes to the fact that this is a time-consuming activity so the problem isn't the addictiveness, it is mostly about how to be more competitive. Being a good blogger or taking care of a successful blog is a difficult job and the competition is terrible; users have so many possibilities that almost these can almost be mentioned as countless.
WordPress! is an award-winning CMS, which enables you to build Blogs, Web sites and powerful online applications. Many aspects, including its ease-of-use and extensibility, have made WordPress the most popular blog software available. Best of all, WordPress is an open source solution that is freely available to everyone.
There are hundreds of WordPress themes online waiting to be paid for. Some of them are worth it, some are not. Just because many of our followers decided to stay with Premium themes, that doesn't mean Free Themes are ugly, cluttered, and boring.
Your social graph is determined by the quality of conversations, people on the network and information exchanged you and your network members. Hence, it's important to adopt some best practices (Dos) and refrain from indulging in certain kind of untoward behavior (Don'ts) while interacting on a day-to-day basis. Though, you may think that your posting does not make any difference on a 'casual' site like Facebook or MySpace, it all adds to your social image.
This social image building process may seem like a waste of time in the short term, but in the long run, this has the potential to yield rich dividends. For example, someone with whom you are interacting on Facebook can give you a lead to a potential job opening (may be his status update, it may be you reaching out to him outside Facebook etc) or in other case, someone may bounce a creative business idea and then you can team up and find a future business partner. Even someone's posts and views on particular topics may be liked by you and he/she may end up as a date and subsequently marriage.
Like any other profession or a technical job, photography as an art and as a science has some very distinct technical words which facilitate an easier communication of ideas and perceptions. Without them it would be almost impossible to communicate and get understood in an effort to do justice to our endeavors.
As a form of visual expression, photography is unique and it cannot be compared with any other branch of visual expression.
A Logo is a graphical element that, together with its logotype (a uniquely set and arranged typeface) form a trademark or commercial brand. Typically, a logo's design is for immediate recognition. The logo is one aspect of a company's commercial brand, or economic or academic entity, and its shapes, colors, fonts, and images usually are different from others in a similar market. Logos are also used to identify organizations and other non-commercial entities.
These types of corporate identities are often developed by large firms who specialize in this type of work. However, if you want to save some bucks and want to design your logo then there are many sources to get logo design inspiration. Infect, we might able to help you by presenting this showcase of Highly beautiful, original and creative logo designs for your design inspiration.


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Starting at $279.98
Size Chart
Make a vibrant statement in this gorgeous evening gown! With its mermaid taffeta skirt, strapless beaded bodice, and tiered back skirt, this long dress is a sure stunner. Finish the look with silver heels, a crystal stretch bracelet, and an oval silver clutch.• Strapless beaded bodice• Mermaid taffeta skirt• Center back zipper• Tiered back skirt
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Swiss Pork Steaks
Janice Karberg
I've been making it for 40 years. My husband loves it!
Featured Pinch Tips Video
- 3 medium
- boneless pork steaks
- 3
- lg. cans tomato sauce
- 1 medium
- onion cut in slices
- 4 sprig(s)
- lg. celery sliced
- olive oil, extra virgin
Directions Step-By-Step
1Salt & pepper pork steaks on both sides
2Brown in extra virgin olive oil in skillet on both sides
3Add 1/2 of the tomato sauce in an electric skillet
4Drain pork steaks after browning & place in electric skillet
5Add the remainder of the tomato sauce & pour some over the pork steaks.
6Add the celery & onion to the skillet, cover & cook at 200-300 degrees - depending on your skillet - for 1 hr.
About this Recipe
Course/Dish: Pork, Steaks and Chops


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Mr. Agas noted that:
"It has become imperative for the Government of Delta State to make this clarification to avoid any confusion or misunderstanding regarding the status of Delta State in the renewed Biafra agitation.The SSG also warned against protests by Indigenous People of Biafra (IPOB) and Movement for the Actualization of Sovereign State of Biafra (MASSOB) on Delta State soil, threatening that anybody found flouting the orders will be punished.
"While some communities in the state may have cultural affinity with the people of the South-East, it is clearly a patent error for anybody or group to suggest or insinuate that Delta State, or more specifically, the Anioma people have been or are part of the South-East that is supposed to make up the proposed Biafra Republic."
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LIONEL GRIGSON was a jazz pianist, cornettist and teacher sure to provoke a reaction wherever he went. Whether he inspired or inflamed, Grigson's energies often acted as a catalyst and his interest in, and support for, young jazz musicians contributed significantly to the growth and consolidation of jazz education in Britain.
As a musicologist, Grigson did much to focus the analysis of jazz harmony and rhythm along the lines of Johann Fux, the great classical theoretician, whilst most of the time patiently sharing his insights in a non-academic and practical context. Within the context of a leading international conservatoire, the Guildhall School of Music, in London, Grigson did much to demonstrate and explain the underlying principles common to jazz, classical and indeed all music, and as a result produced a generation of jazz educators possessing a thorough grounding in an area where much educational work is left to chance. Alongside the folkloric tales of his exploits at the Guildhall School of Music (where he was Professor of Piano and Improvisation 1983-93), I suspect that Grigson's presence did much to sharpen the minds of students, colleagues and friends.
I first met Grigson at the 606 Club in the King's Road, London, a haunt of jazz musicians, in 1981. That night I heard his detailed and considered approach to the piano as he drew on the music of three of his 'masters' - Bill Evans, Bud Powell and Horace Silver. I also encountered the maverick academic shouting out his preferred chord changes. Later that night he switched to cornet and invited me to sit in. We played 'Autumn Leaves'. At the suggestion of the bass player I played some substitutions of my own, temporarily fazing Lionel, but moments later, mid-chorus, he shoved me off the piano muttering 'Yes, actually I knew that, but do you know these ones?' And off he went.
All his friends have favourite Lionel Grigson stories, some funny, some touching and some horrendous, but when we lose a man with such a skill to inflame and endear, there must be some lasting quality to have engendered such love. Much of this was born out of a shared experience as jazz musicians. We could identify with the symptomatic responses to the knock-backs and frustrations that Grigson suffered, forgiving the sometimes bizarre and extreme manifestations of his reactions.
On a more subtle level, I suspect that many of us empathise with Grigson's commitment. Here was a man passionate about music, literature (his father was the poet and critic Geoffrey Grigson), politics and justice. Generous with his knowledge, Grigson would share what he knew with anyone who was interested - an attitude not common to all jazz musicians. Courageous, misguided at times, Grigson communicated his ideas fearlessly, a man of principle, risking, often experiencing, rejection.
I myself experienced the whole range of emotions in my long relationship with Grigson. My early opportunities as a player and teacher were influenced by and, in some cases, provided by him - my appointment at the Guildhall in 1987 was not only on Grigson's recommendation but partly as a result of his own indiscretions - but what I owe him is not about which scale goes with which chord (although I'll always be grateful for the Fats Waller changes for 'Tea for Two'). What I owe to Lionel Grigson is having my mind challenged and the experience of a passionate and courageous man who took the step to be what he believed to be true.
- More about:
- Keyboard
- Pianists
- Teachers
- University Of The Arts London


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'/gallery/other/fvjretro1x', '/gallery/other/fvjretro2x', '/gallery/other/fvjretro3x', '/gallery/other/fvjretro4x', '/gallery/other/fvjretro5x', '/gallery/other/fvjretro6x', '/gallery/other/fvjretro7x', '/gallery/other/fvjretro8x',
NECA is at it again! The action figure specialists are taking two of the greatest slashers of all time – A Nightmare on Elm Street's Freddy Krueger and Friday the 13th's Jason Voorhees – and are releasing them as 8-inch tall, retro-style poseable dolls with fabric clothing.
Jason is based on his first appearance with the infamous hockey mask in Friday the 13th Part 3 and comes with machete and harpoon gun accessories.
Freddy is based on his appearance in the original A Nightmare on Elm Street and comes with a removable hat and his razor glove. Both come on blister card packaging with removable protective clamshell.
Look for the Freddy and Jason retro-style figures this October priced at an SRP of $24.99 each.
Got news? Click here to submit it!
Go retro in the comments section below.


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Pear Bread
Total Time
1hr 30mins
Prep 0 mins
Cook 1 hr 30 mins
from www.allrecipes.com
Ingredients Nutrition
- 3 cups all-purpose flour
- 1⁄4 teaspoon baking powder
- 1 teaspoon baking soda
- 1 teaspoon salt
- 1 tablespoon ground cinnamon
- 3⁄4 cup vegetable oil
- 3 eggs
- 2 cups white sugar
- 2 cups peeled shredded pears
- 1 cup chopped pecans
- 2 teaspoons vanilla extract
- In a large mixing bowl combine flour, baking powder, baking soda, salt and cinnamon. Make well in the center of the bowl.
- In a separate bowl combine the oil, eggs, sugar, grated pears, pecans, and vanilla. Blend well. Add to well of dry ingredients. Stir until just moistened. Spoon batter into 2 greased and floured 8x5x3 inch loaf pans.
- Bake in a preheated 325 degree F oven for one hour and 15 minutes. Cool on wire rack before removing from the loaf pans.
Most Helpful
Very flavorful, moist bread. I subbed Splenda for half of the sugar and cut baking time about 15 minutes. I really liked the cinnamon and will try adding some cardamom next time, since it goes so well with pear. Made for Fall 2008 PAC.
Wonderful pear bread! The only ingredient I toned down by half is the cinnamon powder. Otherwise, this is just perfect! Thanks a tonne for posting :)


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Motilin (human, porcine)
Cat. No. 2264
Price and AvailabilityBy clicking submit you agree to accept a cookie from Tocris Bioscience. For details, please read our privacy and cookie policy.
Biological ActivityEndogenous motilin receptor ligand (Ki = 2.3 nM) that regulates gastrointestinal motor function. Stimulates contraction of gut smooth muscle (EC50 = 1 nM) and increases pepsin release.
Technical DataM.Wt:
The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis.
All Tocris products are intended for laboratory research use only.
Certificate of Analysis / Product Datasheet / Safety Data Sheet
Huang et al (2005) Signaling pathways mediating gastrointestinal smooth muscle contraction and MLC20 phosphorylation by motilin receptors. Am.J.Physiol.Gastrointest.Liver Physiol. 288 G23. PMID: 15591586.
Coulie et al (2001) Identification of peptide ligand-binding domains within the human motilin receptor using photoaffinity labeling. J.Biol.Chem. 276 35518. PMID: 11461914.
Itoh (1997) Motilin and clinical application. Peptides 18 593. PMID: 9210180.
If you know of a relevant reference for this product please let us know.
Citations are publications that use Tocris products. Selected citations for Motilin (human, porcine) include:
Broad and Sanger (2013) The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin. Br J Pharmacol 168 1859. PMID: 23190027.
Do you know of a great paper that uses Motilin (human, porcine) from Tocris? If so please let us know.
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Keywords: Motilin (human, porcine), supplier, Endogenous, peptide, regulator, gastrointestinal, motility, Motilin, Receptors, Tocris Bioscience, Motilin Receptor Agonist products
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Potent GAL2/3 agonist; exhibits anxiolytic effects in vivoMM 54
Potent apelin receptor antagonistMSG 606
Potent human MC1 receptor antagonist; also MC3 and MC5 partial agonist
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Looking for a vacation rental in Kangaroo Valley? Tripping.com has 164 rental homes available in Kangaroo Valley. Potential renters will find 0 studios, 61 1-bedroom, 32 2-bedroom and 71 rentals with 3 or more bedrooms ranging from $58 a night to $559 a night. Many of these properties are instantly bookable.
The average price of a nightly rental in Kangaroo Valley is $192 while the average price of a weekly rental is $25. For those looking for more than a short term rental such as corporate rentals, extended stays or long term rentals, the average monthly price of a Kangaroo Valley home is $25.
Wondering if you can bring your favorite dog or cat with you? We have 11 pet friendly vacation rentals available for you. In addition to accommodating pets, Kangaroo Valley rentals offer a variety of amenities. In particular, 22 rentals have internet and wifi, 141 have TV and/or cable and 14 have a pool or hot tub.
Search properties from 3 rental sites in Kangaroo Valley where the top providers in that area are TripAdvisor, Booking.com, and HomeStay. There are 93 TripAdvisor rentals, 70 Booking.com short term rentals and 1 HomeStay vacation rentals.


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Tests & reviews
Icebreaker - Compass SS Shirt Plaid - Shirt tested
You are familiar with this product?
You have actually had one of these products? Tried and tested?
Other customers will be very happy to read your review – share what you know with them.
This is what customers from around the world say:
Wo ist der Unterschied zum Compass LS Shirt Plaid?


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Jabber Jaws
Every Wednesday at 9pm
Hosted by Apocryfiend and Cromaidz Productions1327 West Chew St
Allentown, PA
- ? HEY~ I live in Southern Ca. but I'm from Bethlehem. I do stand-up in the LA area. A friend suggested your place for Wed. June 25th. Will you be open & running that day? I will only be in town for a week. Please let me know! Thanks~ Nanciann Horvath
- reply to this commentNanciann Horvath (5/2014)
- ? how much to perform?
- reply to this commentRodney (4/2014)
Some of you may be familiar with Tuesday Night Trauma/Acoustic Trauma Tuesdays which has been occurring since December at The Eagle Hotel in Quakertown, PA, and if you're not check out the weekly youtube series of highlights at www.youtube.com/cromwellincident
Cromaidz Productions has expanded this model at Jabber Jaws in Allentown, PA (1327 W Chew St , Allentown, Pennsylvania 18102) on Wednesday Nights, except every week will be Full volume, all gear provided! All we ask is you bring yourself or your whole band and show us what you got. The whole night will be filmed and the highlights posted weekly on youtube! Feel free to bring whatever else you like, we provide House gear, not the greatest but it's there to use!
9pm till 12am, FREE, 21+, All genres welcome but mainly METAL, PUNK, and everything Underground encouraged, but no one will be singled out or made fun of, this is open mic, all are welcome! The house band every week will be Apocryfiend, so feel free to jam/sing along with us, do your own thing, or just plain bring your entire band, it's a very laid back yet fun atmosphere. This is not your grandfather's blues jam, although that of course is still welcomed!
www.cromaizproductions.com and here is the facebook invite with more details
- reply to this commentJoe Covell (9/2012)


text: After lots of hype, iOS hacker Grant Paul (chpwn) has released Zephyr, a multitasking gestures jailbreak tweak for iOS; the tweak can be purchased from the Cydia Store for three dollars. As one of its beta testers, iOS hacker Steven Troughton-Smith referred to Zephyr as the coolest jailbreak tweak for iOS. A video demonstration is above.


text: News & Events keep updated NewsEvents Australian firm innovates product offering with new mobile technology Sydney, Australia – 17 November 2010 – Elcom, one of Australia's largest independently owned web developers, has launched version 7.2 of CommunityManager.NET – its flagship enterprise Web Content Management System (WCMS). The company's product is used by hundreds of local and international organisations to streamline processes and improve information architecture. According to CEO John Anstey, "this is achieved through simplifying the development, publishing and management of online content in the form of websites, intranets, extranets, membership systems, web applications, e-commerce processes and mobile platforms." Version 7.2 of CommunityManager.NET has a host of new features and upgrades from previous versions. One of the company's most significant enhancements was based on the emerging trend of web accessibility via mobile platforms. According to leading technology research body, Gartner; "By 2013, mobile phones will overtake PCs as the most common Web access device worldwide". Elcom's version 7.2 has capitalised on this trend and been able to provide businesses with a synergised mobile functionality, which is built upon highly innovative user-agent detection technology. Mr Anstey states "this means that organisations no longer need to develop separate content and sites for an infinite number of platforms such as iphones, ipads and blackberrys. Our system has complete separation of content and presentation, so our customers do not need to repurpose content, as specified templates will be embedded into the system – ensuring a more automated process which saves time and money". Some of Version 7.2's other enhancements also include a new analytics engine which enables marketers to collect, analyse and report on variety of campaign metrics, while owning all data – unlike other service providers that keep this information for industry analysis. The new version also includes an office connector with the ability to publish content from within Microsoft Word or Outlook; this extends the existing functionality of the SharePoint connector allowing CommunityManager.NET to seamlessly co-exist with an existing SharePoint solution. Elcom is an exciting Australian company which is continuing to drive product innovation within the enterprise Web Content Management sector. Through the pursuit of an aggressive release schedule which involves quarterly updates, it is confidently growing its customer base and market presence, locally and internationally. About Elcom Founded by John Anstey in 1996, Elcom is a globally recognised enterprise web content management developer assisting mid-market organisations achieve their online objectives for corporate websites, intranets, ecommerce and training through one powerfully simple, secure platform: the CommunityManager.NET Enterprise Web Content Management System. For more information about version 7.2 of CommunityManager.NET and Elcom's suite of web application products please visit www.elcomcms.com or call Kevin Oliver on (02) 8064 0999 to arrange a product demonstration.


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14th February 2014
Miller Tripods recently published an engaging story on their website about the life and career of Director of Photography David Wright. Very interesting. Well worth a few minutes of your time to read. Sharpshooters.
David Wright is an award winning Director of Photography and producer, with recent accolades
including an Emmy for Cinematography. He works on high profile television series, features and
commercials, also specializing in shooting high speed / slow motion imagery.
He is a regular contributor to National Geographic, the BBC, Discovery and PBS.


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Product Info
- SKU : GG-d13assortedkatlisbox
- A beautiful gift box containing all time favourite Pure Kaju katlis, Kesari Katlis, Strawberry katlis, and Pista Katlis made from best Goanese cashews.
- This mithai has been specially packed using Italian technology for an extended shelflife.
- Net Weight: 400 gms.
Delivery Info
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|Please Note


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Kafelnikov faces Rafter and Joyce in fascinating draw
The draw for next month's Marlboro Championships has tossed up intriguing preliminary matches between four big names and young emerging talents ready to upset the odds at the Victoria Park from October 15-20.
The men's singles will comprise 12 players who will be divided into four groups of three playing preliminary round-robin matches. The winners of each group will advance to the semi-finals.
World number one Peter Sampras, American Richey Reneberg, reigning French Open champion Yevgeny Kafelnikov and 1995 French Open champion Thomas Muster are seeded to reach the last four.
But the big four have all been drawn against up-and-coming young players who are ready to upset their more illustrious opponents.
US Open champion Sampras has been drawn against Zimbabwe's Byron Black and Canadian Grant Connell in the Silver Group but the best preliminary round-robin matches are expected to come in the Red Group where Russian Kafelnikov should have his hands full against Australia's Patrick Rafter and another young gun, American Michael Joyce.
Joyce has one of the best records of the younger players competing in the territory, having reached the fourth round of last year's Wimbledon with victories over Michael Stich and Jim Courier.
Reneberg's Blue Group should also provide entertainment as the highly rated American youngster Vince Spadea looks to claim a scalp or two.
Spadea will make his debut in the territory with considerable interest on him after his exploits at the US Open where he took finalist Michael Chang, the world number two, to five sets.
Sweden's Kenneth Carlsen completes the lineup in the Blue Group.
Muster makes his appearance in a match against rapidly emerging Neville Godwin of South Africa in the Gold Group which is completed by Sweden Jonas Bjorkman.
Godwin reached the fourth round of this year's Wimbledon after German star Boris Becker withdrew from their match injured.
Sampras will have to overcome Black who is known for his tenacity and who reached the quarter-finals of the US Open last year while Connell is no pushover and can also do well.
Organisers are anticipating a mouth-watering showdown between Sampras and Muster who have made inopportune comments about each other, adding extra flavour to what should be a classic battle between two top players.
GROUPS Silver: Pete Sampras, Byron Black, Grant Connell.
Blue: Richey Reneberg, Kenneth Carlsen, Vince Spadea.
Red: Yevgeny Kafelnikov, Patrick Rafter, Michael Joyce.
Gold: Thomas Muster, Jonas Bjorkman, Neville Godwin.
Most Popular
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Fair Hotel. Close to the city center and train stations. Warm service and cheap WiFi. Clean bathroom.
Guest Review Highlights
- Great location
- Train station is close
- Near city centre
- Great shopping
- Wonderful sightseeing
- Average parking
- Free internet
- Clean
- Clean rooms
- Clean bathroom


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Long Sleeve Flowy Tee!
$26.99 $14.99
Brand: Lucy and Lyla
We can't get over how cute these tees are for your little ones! For boys layer it under a button down collared shirt & cargo shorts. For girls pair it with cute patterned leggings, a light cardigan & headband! Graphic tees are so fun to dress up or down & your littles will get a kick out of the saying!
This product is expected to ship by July 15th. $2.99 for the first item and $2.29 for each additional.
We understand that sometimes purchases just don't work out. If you are not 100% satisfied with your item please contact our customer service team at firstname.lastname@example.com within 14 days of receiving your item. Please note we do not accept returns for swimsuits, undergarments, or personalized items.
This item is sold by Lucy and Lyla and they are solely responsible to customers for the fulfillment, delivery, care, and quality of the advertised goods and services. U.S. shipments only. This product is new.
Long Sleeve Flowy Tee!
$26.99 $14.99
Baseball Tunic/Dress | Extended Sizes
$29.99 $14.99
Fringed Cardigans - New Colors- Up to 3XL!
$45.00 $20.99
Classy But I Cuss A Little Crewneck Sweatshirt
$40.00 $19.99


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Service area
Zip codes we service: 83656
How much does basement waterproofing cost in ID?
There are a few methods to keep water away from your cellar or remove what gets in. The most expensive, in addition to the most effective, may require substantial excavation, our researchers learned in selecting highly rated contractors and home-owners.
Interior-based waterproofing approaches, frequently called aspect jobs that were damaging, involve moving out water that's within the home. Fixing a water problem from the interior might be an alternative that is more affordable, notably in cases where exterior function is't useful or possible.
Drain: This program moves water through a hole in the foundation, combined with a sump pump out of the home. Such a system should also contain insulation of basement walls, having a steam barrier to protect against condensation. Drainage techniques start at around $2, 000.
Sealants: We do 't recommend sealants because they state they fail too readily. The cost of a sealant-established waterproofing job may possibly range from $4to $8 a square foot.
Epoxy injection: Like sealants, this option isn't always favored because it might provide only a temporary treatment for fill cracks in added-concrete partitions. $300 can be started at by shots that are adhesive.
Outdoor water proofing projects are occasionally called side jobs that were positive because the objective will be to avoid water from getting inside your home.
Excavation: We consider installing an underground trench or margin drain if done accurately, to function as the method that is most reliable. However, the typical array for an excavation job is $20, 000 to $30,000, and can be as large as $80,000, according to how accessible the targeted places are, how much digging is required and must be. restored work how much landscaping or other
Sodium bentonite: This process consists of adding a clay material to the dirt around the house absorb water and to fill splits. It's an option that is temporary and hard to manage, since outdoor empties may clog. Costs with this strategy start at around $500.


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Blue Boutique Hotel is located at Mursel Pasa Bulvari 1265, Sok. No. 13 Basmane, Izmir. It is home to stylish bedrooms perfectly furnished to ensure maximum comfort. Featuring a nice blend of vibrant colors and sleek fittings each room is fully equipped with a host of state of the art facilities. O...
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