Suppression of retinal neovascularization by intravitreal injection of cryptotanshinone.

Neovascular eye diseases, including proliferative diabetic retinopathy and retinopathy of prematurity, is a major cause of blindness. Laser ablation and intravitreal anti-VEGF injection have shown their limitations in treatment of retinal neovascularization. Identification of a new therapeutic strategies is in urgent need. Our study aims to assess the effects of Cryptotanshinone (CPT), a natural compound derived from Salvia miltiorrhiza Bunge, in retina neovascularization and explore its potential mechanism. Our study demonstrated that CPT did not cause retina tissue toxicity at the tested concentrations. Intravitreal injections of CPT reduced pathological angiogenesis and promoted physical angiogenesis in oxygen-induced retinopathy (OIR) model. CPT improve visual function in OIR mice and reduced cell apoptosis. Moreover, we also revealed that CPT diminishes the expression of inflammatory cytokines in the OIR retina. In vitro, the administration of CPT effectively inhibited endothelial cells proliferation, migration, sprouting, and tube formation induced by the stimulation of human retinal vascular endothelial cells (HRVECs) with VEGF165. Mechanistically, CPT blocking the phosphorylation of VEGFR2 and downstream targeting pathway. After all, the findings demonstrated that CPT exhibits potent anti-angiogenic and anti-inflammatory effects in OIR mice, and it has therapeutic potential for the treatment of neovascular retinal diseases.

Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin-Mediated Mitophagy.

BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury. METHODS: We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion models and AML12 cells subjected to hypoxia/reoxygenation. Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response. RESULTS: Our findings reveal that PCSK9 is up-regulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy. CONCLUSIONS: Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species and mitochondrial DNA by promoting PINK1-Parkin-mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.

Insights into adeno-associated virus-based ocular gene therapy: A bibliometric and visual analysis.

BACKGROUND: Adeno-associated virus (AAV) plays a vital role in ocular gene therapy and has been widely studied since 1996. This study summarizes and explores the publication outputs and future research trends of AAV-based ocular gene therapy. METHODS: Publications and data about AAV-based ocular gene therapy were downloaded from the Web of Science Core Collection or ClinicalTrials.gov database. The publications and data were analyzed by Microsoft Excel, CiteSpace, VOS viewer, and a free online platform (http://bibliometric.com). RESULTS: Totally 832 publications from the Web of Science Core Collection relevant to AAV-based ocular gene therapy were published from 1996 to 2022. These publications were contributed by research institutes from 42 countries or regions. The US contributed the most publications among these countries or regions, notably the University of Florida. Hauswirth WW was the most productive author. "Efficacy" and "safety" are the main focus areas for future research according to the references and keywords analysis. Eighty clinical trials examined AAV-based ocular gene therapy were registered on ClinicalTrials.Gov. Institutes from the US and European did the dominant number or the large proportion of the trials. CONCLUSIONS: The research focus of the AAV-based ocular gene therapy has transitioned from the study in biological theory to clinical trialing. The AAV-based gene therapy is not limited to inherited retinal diseases but various ocular diseases.

Combined Anti-Angiogenic and Anti-Inflammatory Nanoformulation for Effective Treatment of Ocular Vascular Diseases.

Background: Ocular vascular diseases are the major causes of visual impairment, which are characterized by retinal vascular dysfunction and robust inflammatory responses. Traditional anti-angiogenic or anti-inflammatory drugs still have limitations due to the short-acting effects. To improve the anti-angiogenic or anti-inflammatory efficiency, a dual-drug nanocomposite formulation was proposed for combined anti-angiogenic and anti-inflammatory treatment of ocular vascular diseases. Methods : CBC-MCC@hMSN(SM) complex nanoformulation was prepared by integrating conbercept (CBC, an anti-angiogenic drug) and MCC950 (MCC, an inhibitor of inflammation) into the surface-modified hollow mesoporous silica nanoparticles (hMSN(SM)). CBC-MCC@hMSN(SM) complex nanoformulation was then characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, zeta potentials, and nitrogen adsorption-desorption measurement. CBC and MCC release profile, cytotoxicity, tissue toxicity, anti-angiogenic effects, and anti-inflammatory effects of CBC-MCC@hMSN(SM) were estimated using the in vitro and in vivo experiments. Results:  CBC-MCC@hMSN(SM) complex had no obvious cytotoxicity and tissue toxicity and did not cause a detectable ocular inflammatory responses. CBC-MCC@hMSN(SM) complex was more effective than free CBC or MCC in suppressing endothelial angiogenic effects and inflammatory responses in vitro. A single intraocular injection of CBC-MCC@hMSN(SM) complex potently suppressed diabetes-induced retinal vascular dysfunction, choroidal neovascularization, and inflammatory responses for up to 6 months. Conclusion : Combined CBC and MCC nanoformulation provides a promising strategy for sustained suppression of pathological angiogenesis and inflammatory responses to improve the treatment outcomes of ocular vascular diseases.

Identification of differentially expressed genes and functional annotations associated with metastases of the uveal melanoma.

Uveal melanoma (UVM) is an adult intraocular malignancy which is the most frequent and has a high tendency for metastasis. This study aims to develop significant differential gene subnetwork between primary and metastatic UVM to identify potential prognostic biomarkers. Differentially expressed genes (DEGs) among three chip datasets were downloaded from Gene Expression Omnibus and identified according to standardization annotation information. Genetic enrichment analyses were utilized to describe biologic functions. The protein-protein interaction network of DEGs was developed and the module analysis was constructed by STRING and Cytoscape. Kaplan-Meier method of the integrated expression score was applied to analyze survival outcomes. Functional annotation was assessed to perform GO and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, ClueGO and gene set enrichment analysis were analyzed to detect underlying significant genes and involved signaling pathways. A total of 103 DEGs with function enrichment were recognized and might be considered as candidate prognostic biomarkers between primary and metastatic UVM. Furthermore, Kaplan-Meier method suggested that SCD5, SPTBN1, FABP5, SQLE, PTPLA (HACD1), and CDC25B were independent prognostic factors in UVM. Functional annotations indicated that the most involved significant pathways including interferon-gamma response, IL-6 JAK STAT3 signaling, TNFA signaling via NFKB and inflammatory response. Significant DEGs between primary and metastatic UVM tissue were identified and might have involved in the metastasis of UVM. SCD5, SPTBN1, FABP5, SQLE, PTPLA (HACD1), and CDC25B transcription levels were of high prognostic value, which might assist us to understand the underlying carcinogenesis or advancement of UVM better.

shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis.

Bmi-1 has been implicated in cancer cell growth and metastasis in a variety of tumor types. In this study, we sought to evaluate the expression of Bmi-1 in lung adenocarcinoma samples, and to determine if a correlation exists between Bmi-1 expression and clinical features of lung cancer, such as metastasis. Our results showed that Bmi-1 expression is increased in lung cancer tissues compared to adjacent non-cancerous tissues, and is associated with clinical features of lung cancer, including clinical stage and distant metastasis. We were then interested in determining if shRNA-mediated knockdown of Bmi-1 would inhibit metastasis of lung adenocarcinoma cells. To this end, we chose the most efficient shRNA duplexes targeting Bmi-1, and constructed two stably transfected lung adenocarcinoma cell lines (A549 and SPCA1). The shRNA-mediated knockdown of Bmi-1 significantly reduced migration in vitro, and metastasis in vivo, of A549 and SPCA1 cells. More importantly, knockdown of Bmi-1 also upregulated PTEN expression, and downregulated p-Akt and VEGF expression. These data support the hypothesis that Bmi-1 regulates key pathways involved in the metastasis of lung adenocarcinoma cells.

Association of cumulative lead exposure with Parkinson's disease.

BACKGROUND: Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson's disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead. OBJECTIVES: We sought to assess the association between bone lead and PD. METHODS: Bone lead concentrations were measured using 109Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression. RESULTS: The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17-8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11-5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01-3.60). We found no association with patella bone lead. CONCLUSIONS: These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.

Cumulative lead exposure and age-related hearing loss: the VA Normative Aging Study.

Although lead has been associated with hearing loss in occupational settings and in children, little epidemiologic research has been conducted on the impact of cumulative lead exposure on age-related hearing loss in the general population. We determined whether bone lead levels, a marker of cumulative lead exposure, are associated with decreased hearing ability in 448 men from the Normative Aging Study, seen between 1962 and 1996 (2264 total observations). Air conduction hearing thresholds were measured at 0.25-8 kHz and pure-tone averages (PTA) (mean of 0.5, 1, 2 and 4 kHz) were computed. Tibia and patella lead levels were measured using K X-ray fluorescence between 1991 and 1996. In cross-sectional analyses, after adjusting for potential confounders including occupational noise, patella lead levels were significantly associated with poorer hearing thresholds at 2, 3, 4, 6 and 8 kHz and PTA. The odds of hearing loss significantly increased with patella lead levels. We also found significant positive associations between tibia lead and the rate change in hearing thresholds at 1, 2, and 8 kHz and PTA in longitudinal analyses. Our results suggest that chronic low-level lead exposure may be an important risk factor for age-related hearing loss and reduction of lead exposure could help prevent or delay development of age-related hearing loss.

HFE H63D polymorphism as a modifier of the effect of cumulative lead exposure on pulse pressure: the Normative Aging Study.

BACKGROUND: Cumulative lead exposure is associated with a widened pulse pressure (PP; the -difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function. OBJECTIVES: We examined whether the HFE mutations modify the impact of lead on PP in -community-dwelling older men. METHODS: We examined 619 participants with a total of 1,148 observations of PP from a substudy of bone lead levels (a measure of cumulative exposure, measured by in vivo K-shell X-ray fluorescence) and health in the Normative Aging Study between 1991 and 2001. Linear mixed-effects regression models with random intercepts were constructed. RESULTS: Of the 619 subjects, 138 and 72 carried the HFE H63D and C282Y variants, respectively. After adjusting for age; education; alcohol intake; smoking; daily intakes of calcium, sodium, and potassium; total calories; family history of hypertension; diabetes; height; heart rate; high-density lipoprotein (HDL); total cholesterol:HDL ratio; and waist circumference, baseline bone lead levels were associated with steeper increases in PP in men with at least one H63D allele (p-interaction = 0.03 for tibia and 0.02 for patella) compared with men with only the wild types or C282Y variant. CONCLUSIONS: The HFE H63D polymorphism, but not the C282Y mutation, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.

Interaction of stress, lead burden, and age on cognition in older men: the VA Normative Aging Study.

BACKGROUND: Low-level exposure to lead and to chronic stress may independently influence cognition. However, the modifying potential of psychosocial stress on the neurotoxicity of lead and their combined relationship to aging-associated decline have not been fully examined. OBJECTIVES: We examined the cross-sectional interaction between stress and lead exposure on Mini-Mental State Examination (MMSE) scores among 811 participants in the Normative Aging Study, a cohort of older U.S. men. METHODS: We used two self-reported measures of stress appraisal--a self-report of stress related to their most severe problem and the Perceived Stress Scale (PSS). Indices of lead exposure were blood lead and bone (tibia and patella) lead. RESULTS: Participants with higher self-reported stress had lower MMSE scores, which were adjusted for age, education, computer experience, English as a first language, smoking, and alcohol intake. In multivariable-adjusted tests for interaction, those with higher PSS scores had a 0.57-point lower (95% confidence interval, -0.90 to 0.24) MMSE score for a 2-fold increase in blood lead than did those with lower PSS scores. In addition, the combination of high PSS scores and high blood lead categories on one or both was associated with a 0.05-0.08 reduction on the MMSE for each year of age compared with those with low PSS score and blood lead level (p < 0.05). CONCLUSIONS: Psychological stress had an independent inverse association with cognition and also modified the relationship between lead exposure and cognitive performance among older men. Furthermore, high stress and lead together modified the association between age and cognition.

Bone lead level prediction models and their application to examine the relationship of lead exposure and hypertension in the Third National Health and Nutrition Examination Survey.

OBJECTIVE: We developed prediction models for bone lead using blood lead levels and other standard covariates in a community-based cohort of older men. METHODS: Participants having bone lead levels measured by K X-ray fluorescence were included in the model selection process (n = 825). Predictors of each tibia and patella lead were identified in three quarters of the population and then predicted the bone lead levels in the remaining one quarter and in the Community Lead Study. RESULTS: Eighteen predictors were selected for tibia (blood lead, age, education, occupation, smoking status, pack-years of cigarette, serum levels of phosphorus, uric acid, calcium, creatinine and total and high-density lipoprotein cholesterols, hematocrit, body mass index, systolic and diastolic blood pressure, and diagnoses of cancer and diabetes; R2 = 0.32) and 16 for patella lead (among the predictors included in the tibia model diagnosis of cancer, serum levels of calcium, and total cholesterol were not included in patella lead model, but diagnosis of hypertension was included; R2 = 0.34), respectively. The correlation coefficients between the observed and predicted values were 0.43 to 0.50 for tibia and 0.52 to 0.58 for patella lead in internal and external validation. We applied these predicted bone lead models to the Third National Health and Nutrition Examination Survey (NHANES-III) to examine associations with hypertension and found relatively more significant associations compared with blood lead. CONCLUSIONS: This study suggests that the prediction equations may be used to predict bone lead levels in other community-based cohorts with reasonable accuracy.

Cumulative lead exposure and tooth loss in men: the normative aging study.

BACKGROUND: Individuals previously exposed to lead remain at risk because of endogenous release of lead stored in their skeletal compartments. However, it is not known if long-term cumulative lead exposure is a risk factor for tooth loss. OBJECTIVES: We examined the association of bone lead concentrations with loss of natural teeth. METHODS: We examined 333 men enrolled in the Veterans Affairs Normative Aging Study. We used a validated K-shell X-ray fluorescence (KXRF) method to measure lead concentrations in the tibial midshaft and patella. A dentist recorded the number of teeth remaining, and tooth loss was categorized as 0, 1-8 or > or = 9 missing teeth. We used proportional odds models to estimate the association of bone lead biomarkers with tooth loss, adjusting for age, smoking, diabetes, and other putative confounders. RESULTS: Participants with > or = 9 missing teeth had significantly higher bone lead concentrations than those who had not experienced tooth loss. In multivariable-adjusted analyses, men in the highest tertile of tibia lead (> 23 microg/g) and patella lead (> 36 microg/g) had approximately three times the odds of having experienced an elevated degree of tooth loss (> or = 9 vs. 0-8 missing teeth or > or = 1 vs. 0 missing teeth) as those in the lowest tertile [prevalence odds ratio (OR) = 3.03; 95% confidence interval (CI), 1.60-5.76 and OR = 2.41; 95% CI, 1.30-4.49, respectively]. Associations between bone lead biomarkers and tooth loss were similar in magnitude to the increased odds observed in participants who were current smokers. CONCLUSION: Long-term cumulative lead exposure is associated with increased odds of tooth loss.

A prospective study of bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the Department of Veterans Affairs Normative Aging Study.

BACKGROUND: Blood lead concentration has been associated with mortality from different causes in several studies. Many effects of lead exposure that might increase risk of death are likely to result from cumulative exposure, for which bone lead is a better biomarker than blood lead. The association between bone lead levels and mortality has not been explored. METHODS AND RESULTS: We prospectively assessed the association between both blood lead and bone lead, analyzed with the use of K-shell x-ray fluorescence, and mortality among 868 men in the Normative Aging Study. We identified 241 deaths over an average of 8.9 (SD=3.9) years of follow-up. We calculated adjusted hazard ratios and 95% confidence intervals using Cox proportional hazards. Compared with the lowest tertile of patella bone lead, the fully adjusted hazard ratios in the highest tertile for all-cause and cardiovascular mortality (n=137 deaths) were 2.52 (95% confidence interval, 1.17 to 5.41) and 5.63 (95% confidence interval, 1.73 to 18.3), respectively. The age-, smoking-, and race-adjusted hazard ratio for ischemic heart disease mortality (n=62 deaths) in the highest tertile was 8.37 (95% confidence interval, 1.29 to 54.4). Results were similar for tibia lead. Bone lead was not associated with cancer, and blood lead was not associated with any mortality category. CONCLUSIONS: We found bone lead to be associated with all-cause and cardiovascular mortality in an environmentally exposed population with low blood lead levels. This study suggests that cumulative lead exposure from prior decades of high environmental exposures continues to significantly affect risk of death despite recent declines in environmental lead exposure.

Bone lead and endogenous exposure in an environmentally exposed elderly population: the normative aging study.

OBJECTIVE: The objective of this study is to investigate the mobilization of lead from bone to blood (endogenous exposure) in a large epidemiologic population. METHODS: Study subjects were 776 participants in the Normative Aging Study. The subjects had their tibia lead, patella lead, blood lead, and urinary N-telopeptide (NTx) levels measured 1 to 4 times from 1991 to 2002. Regression models were estimated to quantify the association between tibia and patella lead and blood lead. We studied nonlinearity of the association, and explored possible factors that may modify it, including age and NTx levels. RESULTS AND CONCLUSIONS: There is significant association between bone lead and blood lead, and the association is nonlinear. The nonlinear associations between blood lead and bone lead are not significantly modified by age and NTx.

Cumulative exposure to lead in relation to cognitive function in older women.

BACKGROUND: Recent data indicate that chronic low-level exposure to lead is associated with accelerated declines in cognition in older age, but this has not been examined in women. OBJECTIVE: We examined biomarkers of lead exposure in relation to performance on a battery of cognitive tests among older women. METHODS: Patella and tibia bone lead--measures of cumulative exposure over many years--and blood lead, a measure of recent exposure, were assessed in 587 women 47-74 years of age. We assessed their cognitive function 5 years later using validated telephone interviews. RESULTS: Mean +/- SD lead levels in tibia, patella, and blood were 10.5 +/- 9.7 microg/g bone, 12.6 +/- 11.6 microg/g bone, and 2.9 +/- 1.9 microg/dL, respectively, consistent with community-level exposures. In multivariable-adjusted analyses of all cognitive tests combined, levels of all three lead biomarkers were associated with worse cognitive performance. The association between bone lead and letter fluency score differed dramatically from the other bone lead-cognitive score associations, and exclusion of this particular score from the combined analyses strengthened the associations between bone lead and cognitive performance. Results were statistically significant only for tibia lead: one SD increase in tibia lead corresponded to a 0.051-unit lower standardized summary cognitive score (95% confidence interval: -0.099 to -0.003; p = 0.04), similar to the difference in cognitive scores we observed between women who were 3 years apart in age. CONCLUSIONS: These findings suggest that cumulative exposure to lead, even at low levels experienced in community settings, may have adverse consequences for women's cognition in older age.

Radiation dose to trabecular bone marrow stem cells from (3)H, (14)C and selected alpha-emitters incorporated in a bone remodeling compartment.

A Monte Carlo simulation of repeated cubic units representing trabecular bone cavities in adult bone was employed to determine absorbed dose fractions evaluated for (3)H, (14)C and a set of alpha-emitters incorporated within a bone remodeling compartment (BRC). The BRC consists of a well-oxygenated vascular microenvironment located within a canopy of bone-lining cells. The International Commission on Radiological Protection (ICRP) considers that an important target for radiation-induced bone cancer is the endosteum marrow layer adjacent to bone surface where quiescent bone stem cells reside. It is proposed that the active stem cells and progenitor cells located above the BRC canopy, the 'BRC stem cell niche', is a more important radiation-induced cancer target volume. Simulation results from a static model, where no remodeling occurs, indicate that the mean dose from bone and bone surface to the 50 microm quiescent bone stem cell niche, the current ICRP target, was substantially lower (two to three times lower) than that to the narrower and hypoxic 10 microm endosteum for (3)H, (14)C and alpha-particles with energy range 0.5-10 MeV. The results from a dynamic model indicate that the temporal alpha-radiation dose to active stem/progenitor cells located in the BRC stem cell niche from the material incorporated in and buried by forming bone was 9- to 111-fold greater than the dose to the quiescent bone stem cell niche. This work indicates that the remodeling portion of the bone surface, rather than the quiescent (endosteal) surface, has the greatest risk of radiation-induced bone cancer, particularly from short-range radiation, due to the elevated dose and the radiosensitizing oxygen effect.

Interaction of the delta-aminolevulinic acid dehydratase polymorphism and lead burden on cognitive function: the VA normative aging study.

OBJECTIVE: We evaluated the modifying influence of a delta-aminolevulinic acid dehydratase (ALAD) polymorphism on the relation between lead burden and cognition among older men. METHODS: Information on ALAD genotype, lead measurements, potential confounders, and cognitive testing was collected from 982 participants. For each cognitive test and lead biomarker, we fit separate multiple linear regression models, which included an interaction term for ALAD genotype and the lead biomarker and adjusted for potential confounders. RESULTS: With higher levels of tibia lead, ALAD 1-2/2-2 carriers exhibited worse performance on a spatial copying test in comparison with ALAD 1-1 carriers (P interaction = 0.03). However, there was no consistent pattern of an ALAD genotype-lead interaction for the other tests. CONCLUSIONS: The results provide some evidence that ALAD genotype may modify the relation between lead and cognition among older men with low lead burden. However, future work in this area is needed to confirm these suggestive findings.

Air pollution and heart rate variability: effect modification by chronic lead exposure.

BACKGROUND: Outdoor air pollution and lead exposure can disturb cardiac autonomic function, but the effects of both these exposures together have not been studied. METHODS: We examined whether higher cumulative lead exposures, as measured by bone lead, modified cross-sectional associations between air pollution and heart rate variability among 384 elderly men from the Normative Aging Study. We used linear regression, controlling for clinical, demographic, and environmental covariates. RESULTS: We found graded, significant reductions in both high-frequency and low-frequency powers of heart rate variability in relation to ozone and sulfate across the quartiles of tibia lead. Interquartile range increases in ozone and sulfate were associated respectively, with 38% decrease (95% confidence interval = -54.6% to -14.9%) and 22% decrease (-40.4% to 1.6%) in high frequency, and 38% decrease (-51.9% to -20.4%) and 12% decrease (-28.6% to 9.3%) in low frequency, in the highest quartile of tibia lead after controlling for potential confounders. We observed similar but weaker effect modification by tibia lead adjusted for education and cumulative traffic (residuals of the regression of tibia lead on education and cumulative traffic). Patella lead modified only the ozone effect on heart rate variability. CONCLUSIONS: People with long-term exposure to higher levels of lead may be more sensitive to cardiac autonomic dysfunction on high air pollution days. Efforts to understand how environmental exposures affect the health of an aging population should consider both current levels of pollution and history of lead exposure as susceptibility factors.

Cumulative community-level lead exposure and pulse pressure: the normative aging study.

BACKGROUND: Pulse pressure increases with age in industrialized societies as a manifestation of arterial stiffening. Lead accumulates in the vasculature and is associated with vascular oxidative stress, which can promote functional and structural vascular disease. OBJECTIVES: We tested the hypothesis that cumulative community-level lead exposure, measured with K-X-ray fluorescence, is associated with pulse pressure in a cohort of adult men. METHODS AND RESULTS: In a cross-sectional analysis of 593 men not treated with antihypertensive medication, tibia lead was positively associated with pulse pressure (p < 0.001). Adjusting for age, race, diabetes, family history of hypertension, education, waist circumference, alcohol intake, smoking history, height, heart rate, fasting glucose, and total cholesterol-to-HDL ratio, increasing quintiles of tibia lead remained associated with increased pulse pressure (ptrend = 0.02). Men with tibia lead above the median (19.0 microg/g) had, on average, a 4.2-mmHg (95% confidence interval, 1.9-6.5) higher pulse pressure than men with tibia lead level below the median. In contrast, blood lead level was not associated with pulse pressure. CONCLUSIONS: These data indicate that lead exposure may contribute to the observed increase in pulse pressure that occurs with aging in industrialized societies. Lead accumulation may contribute to arterial aging, perhaps providing mechanistic insight into the observed association of low-level lead exposure with cardiovascular mortality.

Lead burden and psychiatric symptoms and the modifying influence of the delta-aminolevulinic acid dehydratase (ALAD) polymorphism: the VA Normative Aging Study.

The authors evaluated the association between lead burden and psychiatric symptoms and its potential modification by a delta-aminolevulinic acid dehydratase (ALAD) polymorphism. Lead measurements in blood or bone and self-reported ratings on the Brief Symptom Inventory from 1991 to 2002 were available for 1,075 US men participating in the Department of Veterans Affairs (VA) Normative Aging Study. The authors estimated the prevalence odds ratio for the association between interquartile-range lead and abnormal symptom score, adjusting for potential confounders. An interquartile increment in tibia lead (14 microg/g) was associated with 21% higher odds of somatization (95% confidence interval of the odds ratio: 1.01, 1.46). An interquartile increment in patella lead (20 microg/g) corresponded to a 23% increase in the odds of global distress (95% confidence interval of the odds ratio: 1.02, 1.47). An interquartile increment in blood lead (2.8 microg/dl) was associated with 14% higher odds of hostility (95% confidence interval of the odds ratio: 1.02, 1.27). In all other analyses, lead was nonsignificantly associated with psychiatric symptoms. The adverse association of lead with abnormal mood scores was generally stronger among ALAD 1-1 carriers than 1-2/2-2 carriers, particularly regarding phobic anxiety symptoms (p(interaction) = 0.004). These results augment evidence of a deleterious association between lead and psychiatric symptoms.