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COPD  2010;7(4):262-268.
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes.
We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1) and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n=389) and smoking controls from the Normative Aging Study (NAS, n=472). We examined whether the SNPs were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Further, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n=3061) and the Boston Early-Onset COPD Study (EOCOPD, n=949).
In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p=0.029 and p=0.0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p=0.048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations.
In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
PMCID: PMC2923920  PMID: 20673035
2.  Delta‐aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini‐Mental Status Examination in older men: the Normative Aging Study 
To determine whether a polymorphism the in δ‐aminolevulinic acid dehydratase (ALAD) gene modifies the neurotoxicity of lead in older adults.
The authors studied men participating in the Department of Veterans Affairs' Normative Aging Study, assessing their recent exposure to lead by measuring blood lead (n = 915) at each triennial clinic visit, and, beginning in 1991, assessing their cumulative exposure by measuring lead levels in tibia (n = 722) and patella (n = 720), using K‐shell x ray fluorescence. Starting in 1993 and again at each triennial visit, the authors administered the Mini‐Mental State Examination (MMSE) to assess their cognitive functioning. The relation of the lead biomarkers to MMSE score was evaluated and this association was compared among men who carried the variant allele, ALAD‐2, versus men without the allele.
Sixteen per cent of men carried the ALAD‐2 allele. Median tibia and patella lead levels (first‐third quartile) were 19 (13–28) and 27 (18–39) μg/g. Blood lead levels were consistent with non‐occupational exposure: only 6% of men had levels ⩾10 μg/dl. In multivariable adjusted analyses, higher levels of blood lead were associated with poorer performance on the MMSE. This association was most pronounced among ALAD‐2 carriers, among whom a 3 μg/dl increment in blood lead (the interquartile range) was associated with a 0.26 point lower mean MMSE score (95% CI −0.54 to 0.01), compared with a 0.04 point lower score (95% CI −0.16 to 0.07) among non‐carriers. The modest 0.22 point difference in these associations did not attain statistical significance, however (pinteraction = 0.13). The associations between bone lead levels and MMSE score did not vary by ALAD‐2 status.
Although not statistically significant, these findings suggest that ALAD genotype may modify blood lead's adverse association with cognition among older men who had community exposures to lead. However, despite a relatively large sample size and the use of sensitive methods for measuring lead burden, the evidence overall was fairly weak.
PMCID: PMC2077996  PMID: 16757504
lead; delta‐aminolevulinic acid dehydratase; polymorphism, genetic; cognition; aging
3.  Angry breathing: a prospective study of hostility and lung function in the Normative Aging Study 
Thorax  2006;61(10):863-868.
Hostility and anger are risk factors for, or co‐occur with, many health problems of older adults such as cardiovascular diseases, all‐cause mortality, and asthma. Evidence that negative emotions are associated with chronic airways obstruction suggests a possible role for hostility in the maintenance and decline of pulmonary function. This study tests the hypothesis that hostility contributes to a faster rate of decline in lung function in older adults.
A prospective examination was undertaken of the effect of hostility on change in lung function over time. Data are from the VA Normative Aging Study, an ongoing cohort of older men. Hostility was measured in 1986 in 670 men who also had an average of three pulmonary function examinations obtained over an average of 8.2 years of follow up. Hostility was ascertained using the 50‐item MMPI based Cook‐Medley Hostility Scale. Pulmonary function was assessed using spirometric tests to obtain measures of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).
Baseline pulmonary function differed between high and medium/low hostility groups (mean (SE) percent predicted FEV1 88.9 (18.5) v 95.3 (16.9) and FVC 92.5 (16.5) v 98.9 (15.9), respectively; p<0.01 for both). This overall association between higher hostility and reduced lung function remained significant after adjusting for smoking and education, although the effect size was attenuated for both FEV1 and FVC. Higher hostility was associated with a more rapid decline in lung function, and this effect was unchanged and remained significant for FEV1 in multivariate models but was attenuated for FVC. Each standard deviation increase in hostility was associated with a loss in FEV1 of approximately 9 ml/year.
This study is one of the first to show prospectively that hostility is associated with poorer pulmonary function and more rapid rates of decline among older men.
PMCID: PMC2104760  PMID: 16950835
psychological factors; hostility; anger; pulmonary function; risk factor
4.  Controls on the distribution of productivity and organic resources in Antarctic Dry Valley soils 
The Antarctic Dry Valleys are regarded as one of the harshest terrestrial habitats on Earth because of the extremely cold and dry conditions. Despite the extreme environment and scarcity of conspicuous primary producers, the soils contain organic carbon and heterotrophic micro-organisms and invertebrates. Potential sources of organic compounds to sustain soil organisms include in situ primary production by micro-organisms and mosses, spatial subsidies from lacustrine and marine-derived detritus, and temporal subsidies (‘legacies’) from ancient lake deposits. The contributions from these sources at different sites are likely to be influenced by local environmental conditions, especially soil moisture content, position in the landscape in relation to lake level oscillations and legacies from previous geomorphic processes. Here we review the abiotic factors that influence biological activity in Dry Valley soils and present a conceptual model that summarizes mechanisms leading to organic resources therein.
PMCID: PMC1635502  PMID: 17015369
Antarctica; carbon; decomposition; Dry Valleys; respiration; soil
5.  Association of body mass index with the development of methacholine airway hyperresponsiveness in men: the Normative Aging Study 
Thorax  2002;57(7):581-585.
Background: The rising prevalence of asthma in developed nations may be associated with the rising prevalence of obesity in these same nations. The relationship between body mass index (BMI) and the development of an objective marker for asthma, methacholine airway hyperresponsiveness (AHR), was investigated in adult men.
Methods: Sixty one men who had no AHR at initial methacholine challenge testing but who developed AHR about 4 years later and 244 matched controls participated in the study. The effects of initial BMI and change in BMI on development of AHR were examined in conditional logistic regression models.
Results: Initial BMI was found to have a non-linear relationship with development of AHR. Compared with men with initial BMI in the middle quintile, men with BMI in the lowest quintile (BMI=19.8–24.3 kg/m2) and those with BMI in the highest quintile (BMI >29.4 kg/m2) were more likely to develop AHR: OR=7.0 (95% CI 1.8 to 27.7) and OR=10.0 (95% CI 2.6 to 37.9), respectively. These results remained significant after controlling for age, smoking, IgE level, and initial FEV1. In addition, there was a positive linear relationship between change in BMI over the period of observation and the subsequent development of AHR.
Conclusions: In this cohort of adult men, both a low BMI and a high BMI were associated with the development of AHR. For men with a low initial BMI the increased risk for development of AHR appears to be partly mediated by a gain in weight. The effect of BMI on AHR may suggest mechanisms in the observed associations between obesity and asthma.
PMCID: PMC1746377  PMID: 12096199
6.  Influence of bone resorption on the mobilization of lead from bone among middle-aged and elderly men: the Normative Aging Study. 
Environmental Health Perspectives  2001;109(10):995-999.
Bone stores of lead accrued from environmental exposures and found in most of the general population have recently been linked to the development of hypertension, cognitive decrements, and adverse reproductive outcomes. The skeleton is the major endogenous source of lead in circulating blood, particularly under conditions of accelerated bone turnover and mineral loss, such as during pregnancy and in postmenopausal osteoporosis. We studied the influence of bone resorption rate on the release of lead from bone in 333 men, predominantly white, middle-aged and elderly (mostly retired) from the Boston area. We evaluated bone resorption by measuring cross-linked N-telopeptides of type I collagen (NTx) in 24-hr urine samples with an enzyme-linked immunosorbent assay. We used K-X-ray fluorescence to measure lead content in cortical (tibia) and trabecular (patella) bone; we used graphite furnace atomic absorption spectroscopy and inductively coupled plasma mass spectroscopy to measure lead in blood and urine, respectively. After adjustment for age and creatinine clearance, the positive relation of patella lead to urinary lead was stronger among subjects in the upper two NTx tertiles (beta for patella lead > or =0.015) than in the lowest NTx tertile (beta for patella lead = 0.008; overall p-value for interactions = 0.06). In contrast, we found no statistically significant influence of NTx tertile on the relationship of blood lead to urinary lead. As expected, the magnitude of the relationship of bone lead to urinary lead diminished after adjustment for blood lead. Nevertheless, the pattern of the relationships of bone lead to urinary lead across NTx tertiles remained unchanged. Furthermore, after adjustment for age, the relation of patella lead to blood lead was significantly stronger in the upper two NTx tertiles (beta for patella lead > or =0.125) than in the lowest NTx tertile (beta for patella lead = 0.072). The results provide evidence that bone resorption influences the release of bone lead stores (particularly patella lead) into the circulation.
PMCID: PMC1242074  PMID: 11675263
7.  The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study. 
Environmental Health Perspectives  2001;109(8):827-832.
Recent research has indicated that a polymorphic variant of delta-aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP). Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter), cortical bone (tibia) lead (micrograms per gram), and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1), 22.1 (13.5), and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1), and 5.7 (4.2), 21.2 (10.9), and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2). In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 microg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 microg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone.
PMCID: PMC1240411  PMID: 11564619
8.  Relationship of serum IgE concentration to level and rate of decline of pulmonary function: the Normative Aging Study. 
Thorax  1996;51(8):787-792.
BACKGROUND: Previous reports on the relationship between serum immunoglobulin E (IgE) concentration and the level and rate of decline of pulmonary function in the general population have produced conflicting results. The relationship between total serum IgE concentration and pulmonary function was therefore examined in 1078 men aged 41-86 years followed in the Normative Aging Study. METHODS: The serum IgE concentration determined at the start of the three year follow up period was examined in relation to both the level and longitudinal rate of decline of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: In a cross sectional analysis restricted to subjects who had ever smoked cigarettes, multiple linear regression models indicated an inverse association between total serum IgE concentration and both FEV1 (beta = -0.090 1/log10 IU/ml; SE = 0.030; p < 0.005) and FVC (beta = -0.110 1/log10 IU/ml; SE = 0.034; p < 0.005) but not FEV1/FVC, after adjustment for age and height. This relationship persisted when individuals with diagnosed asthma or methacholine hyperresponsiveness were excluded. In subjects who had never smoked cigarettes the total serum IgE concentration was unrelated to spirometric indices. No association was observed in smokers or non-smokers between the serum IgE concentration measured at the beginning of the period of follow up and the decline in FEV1, FVC, or FEV1/FVC. CONCLUSION: Increased levels of serum IgE measured at the beginning of the follow up period are associated with lower levels of pulmonary function but are not predictive of an accelerated rate in the decline of pulmonary function among middle aged and older men.
PMCID: PMC472538  PMID: 8795665
9.  Bovine polymorphonuclear neutrophil-mediated phagocytosis and an immunoglobulin G2 protease produced by Porphyromonas levii. 
Acute interdigital phlegmon (AIP) is a commonly occurring anaerobic bacterial infection in cattle. This study examined in vitro the interaction of bovine polymorphonuclear granulocytic neutrophils (PMN) from blood with bacterial species involved in AIP. Polymorphonuclear neutrophils were purified from whole bovine blood, exposed to one of the three putative etiologic agents of AIP and comparatively assessed for phagocytosis using light microscopy. Fusobacterium necrophorum and Prevotella intermedia were effectively phagocytosed by PMN, but Porphyromonas levii was phagocytosed significantly less effectively by PMN. The effect of high titre anti-P. levii bovine serum on antibody-mediated phagocytosis by PMN was also evaluated. High titre serum increased the efficiency of phagocytosis of P. levii by bovine PMN. This was independent of heat labile complement factors. Antibodies specific for P. levii were assessed for protease activity capable of cleaving bovine immunoglobulins (IgG, IgG1, IgG2, and IgM). Partially purified supernatant from broth cultures of P. levii were incubated with biotinylated immunoglobulins (Igs). Samples were taken from times 0 to 72 h and examined using SDS-PAGE followed by Western blot analysis. Streptavidin-alkaline phosphatase and NBT-BCIP were used to visualize the Igs for heavy and light chains as well as lower molecular weight fragments of these glycoproteins. Porphyromonas levii produced an immunoglobulin protease which readily cleaved bovine IgG into fragments, but did not act against IgM. Specifically, the enzyme may be a significant virulence factor as it may act to neutralize the antibodies demonstrated necessary for effective PMN-mediated phagocytosis.
PMCID: PMC1189529  PMID: 10369568
10.  The independent contribution of bone and erythrocyte lead to urinary lead among middle-aged and elderly men: the normative aging study. 
Environmental Health Perspectives  1999;107(5):391-396.
Plasma is the component of blood from which lead is free to cross cell membranes and cause organ toxicity. Plasma lead levels, however, are extremely low and difficult to measure. Urinary lead originates from plasma lead that has been filtered at the glomerular level; thus, urinary lead adjusted for glomerular filtration rate serves as a proxy for plasma lead levels. In this investigation we examined the interrelationships of lead levels in whole blood corrected by hematocrit [i.e., erythrocyte lead (EPb)], trabecular bone (TBoPb), cortical bone (CBoPb), and urine excreted over 24 hr (UPb); all samples were obtained from 71 middle-aged and elderly men with no known occupational lead exposures. Lead was measured by graphite furnace atomic absorption spectroscopy (blood), K-X-ray fluorescence (bone), and inductively coupled plasma mass spectroscopy (urine). Lead levels were generally low, with mean EPb, TBoPb, and CBoPb values of 13.8, 31.1, and 21.7 microg/g, respectively, and a median UPb value of 6.15 microg/day. In generalized additive models adjusted for body weight and creatinine clearance rate, both EPb and bone lead variables remained independently and significantly associated with UPb. This finding suggests that bone influences plasma lead in a manner that is independent of the influence of erythrocytic lead on plasma lead. Thus, the superiority of bone lead over blood lead in predicting some chronic forms of toxicity may be mediated through bone's influence on plasma lead. In addition, this study suggests that measurement of urinary lead might be useful as a proxy for plasma lead levels in studies of lead toxicity.
PMCID: PMC1566410  PMID: 10210695
11.  The relationship of blood lead to systolic blood pressure in a longitudinal study of policemen. 
We examined the relationship of blood lead level to systolic and diastolic blood pressure in a longitudinal study of 89 Boston, MA, policemen. At the second examination blood lead level and blood pressure were measured in triplicate. Blood pressure measurements were taken in a similar fashion in years 3, 4, and 5. Multivariate analysis using a first-order autoregressive model revealed that after adjusting for previous systolic blood pressure, body mass index, age, and cigarette smoking, an elevated blood lead level was a significant predictor of subsequent systolic blood pressure. Bootstrap simulations of these models provided supporting evidence for the observed association. These data suggest that blood lead level can influence systolic blood pressure even within the normal range.
PMCID: PMC1474617  PMID: 3203646
12.  Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study. 
Journal of Clinical Investigation  1987;80(6):1527-1534.
In view of the known association of vascular disease with increasing age, we have conducted an analysis of hemostatic system activity with respect to perturbations induced by aging phenomena. We have utilized an immunochemical assay for prothrombin fragment F1 + 2 to quantify Factor Xa activity upon prothrombin in the plasma of 199 healthy males between the ages of 42 and 80. The levels of F1 + 2 in this population generally increased as a function of age (P less than 0.0001). The metabolic behavior of this marker was determined in 10 individuals greater than 65 yr of age with varying levels of F1 + 2, which ranged from 1.28 to 5.85 nM. The elevations in the concentration of this component were not due to diminished clearance of the fragment. Radio-immunoassays for fibrinopeptide A (FPA) and the protein C activation peptide (PCP) were subsequently employed to measure thrombin activity upon fibrinogen and thrombin-thrombomodulin activity upon protein C, respectively, in 82 members of this population ranging in age from 42 to 80. Significant positive correlations were again observed between increasing age and the level of F1 + 2 (P less than 0.0001) as well as FPA (P less than 0.01) and PCP (P less than 0.002). The results of this cross-sectional study indicate that many apparently normal males of increasing age with normal immunologic levels of antithrombin III and protein C exhibit a biochemical defect that denotes the presence of an acquired prethrombotic state.
PMCID: PMC442420  PMID: 2824564
13.  MEF2 proteins, including MEF2A, are expressed in both muscle and non-muscle cells. 
Nucleic Acids Research  1995;23(21):4267-4274.
The MEF2 proteins are involved in regulation of many muscle specific genes. Although MEF2 RNAs encoding the MEF2A and MEF2D isoforms are ubiquitously expressed, the presence of MEF2 proteins in non-muscle cell types has been controversial. Here we use a well-characterised antibody in conjunction with DNA binding studies to provide evidence that members of the MEF2 family are widely expressed in the nuclei of cultured cells and are competent to bind DNA. The data show that non-muscle MEF2 complexes contain MEF2A, and that another MEF2 protein, probably MEF2D, is also present. These results suggest that MEF2 proteins fulfil functions in addition to muscle-specific gene expression.
PMCID: PMC307379  PMID: 7501445

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