Biomedical subjects

Jeremy Walston

Publications and source records attributed to Jeremy Walston.

16 recordsLinked to original sources

PubMed2006

Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events.

CONTEXT: C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD). OBJECTIVE: To assess whether polymorphisms in the CRP gene are associated with plasma CRP, carotid intima-media thickness (CIMT), and CVD events. DESIGN, SETTING, AND PARTICIPANTS: In the prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs) (1919A/T, 2667G/C, 3872G/A, 5237A/G) were genotyped in 3941 white (European American) participants and 5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003). MAIN OUTCOME MEASURES: Baseline CIMT; occurrence of MI, stroke, and CVD mortality during follow-up. RESULTS: In white participants, 461 incident MIs, 491 incident strokes, and 490 CVD-related deaths occurred; in black participants, 67 incident MIs, 78 incident strokes, and 75 CVD-related deaths occurred. The 1919T and 790T alleles were associated with higher CRP levels in white and black participants, respectively. The 3872A allele was associated with lower CRP levels in both populations, and the 2667C allele was associated with lower CRP levels in white participants only. There was no association between CIMT and any CRP gene polymorphism in either population. In white participants, the 1919T allele was associated with increased risk of stroke for TT vs AA (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.87) and for CVD mortality (HR, 1.40; 95% CI, 1.10-1.90). In black participants, homozygosity for the 790T allele was associated with a 4-fold increased risk of MI compared with homozygosity for the 790A allele (95% CI, 1.58-10.53). The minor alleles of the 2 SNPs associated with lower plasma CRP concentration in white participants (2667C and 3872A) were associated with decreased risk of CVD mortality. CONCLUSIONS: Genetic variation in the CRP gene is associated with plasma CRP levels and CVD risk in older adults.

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PubMed2006

Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.

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PubMed2006

Phenotype of frailty: characterization in the women's health and aging studies.

BACKGROUND: "Frailty" is an adverse, primarily gerontologic, health condition regarded as frequent with aging and having severe consequences. Although clinicians claim that the extremes of frailty can be easily recognized, a standardized definition of frailty has proved elusive until recently. This article evaluates the cross-validity, criterion validity, and internal validity in the Women's Health and Aging Studies (WHAS) of a discrete measure of frailty recently validated in the Cardiovascular Health Study (CHS). METHODS: The frailty measure developed in CHS was delineated in the WHAS data sets. Using latent class analysis, we evaluated whether criteria composing the measure aggregate into a syndrome. We verified the criterion validity of the measure by testing whether participants defined as frail were more likely than others to develop adverse geriatric outcomes or to die. RESULTS: The distributions of frailty in the WHAS and CHS were comparable. In latent class analyses, the measures demonstrated strong internal validity vis à vis stated theory characterizing frailty as a medical syndrome. In proportional hazards models, frail women had a higher risk of developing activities of daily living (ADL) and/or instrumental ADL disability, institutionalization, and death, independently of multiple potentially confounding factors. CONCLUSIONS: The findings of this study are consistent with the widely held theory that conceptualizes frailty as a syndrome. The frailty definition developed in the CHS is applicable across diverse population samples and identifies a profile of high risk of multiple adverse outcomes.

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PubMed2006

Low serum selenium and total carotenoids predict mortality among older women living in the community: the women's health and aging studies.

Selenium and the carotenoids play an important role in antioxidant defenses and in the redox regulation involved in inflammation. We tested the hypothesis that low selenium and carotenoids predict mortality in older women living in the community. Women who were enrolled in the Women's Health and Aging Studies I and II in Baltimore, MD (n = 632; 70-79 y old) had serum selenium and carotenoids measured at baseline and were followed for mortality over 60 mo. Median (minimum, maximum) serum selenium and carotenoids were 1.53 (0.73, 2.51) micromol/L and 1.67 (0.13, 9.10) micromol/L; 14.1% of the women died. The 5 major causes of death were heart disease (32.6%), cancer (18.0%), stroke (9.0%), infection (6.7%), and chronic obstructive pulmonary disease (5.6%). Adjusting for age, education, smoking, BMI, poor appetite, and chronic diseases, higher serum selenium [hazard ratio (HR) 0.71, 95% CI 0.56-0.90/1 SD increase in log(e) selenium; P = 0.005] and higher serum total carotenoids (HR 0.77, 95% CI 0.64-0.84/1 SD increase in log(e) total carotenoids; P = 0.009) were associated with a lower risk of mortality. Women living in the community who have higher serum selenium and carotenoids are at a lower risk of death.

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PubMed2006

Variation in the ciliary neurotrophic factor gene and muscle strength in older Caucasian women.

OBJECTIVES: To determine whether genetic variants in the ciliary neurotrophic factor (CNTF) gene are associated with muscle strength in older women. DESIGN: Cross-sectional analysis of baseline data from the Women's Health and Aging Studies I (1992) and II (1994), complementary population-based studies. SETTING: Twelve contiguous ZIP code areas in Baltimore, Maryland. PARTICIPANTS: Three hundred sixty-three Caucasian, community-dwelling women aged 70 to 79. MEASUREMENTS: Participants were genotyped at the CNTF locus for eight single nucleotide polymorphisms (SNPs), including the null allele rs1800169. The dependent variables were grip strength and the frailty syndrome, identified as presence of three or more of five frailty indicators (weakness, slowness, weight loss, low physical activity, exhaustion). In addition to genotypes, independent variables of body mass index (BMI) and osteoarthritis of the hands were included. RESULTS: Using multivariate linear regression, single SNP analysis identified five SNPs significantly associated with grip strength (P<.05), after adjusting for age, BMI, and osteoarthritis. Haplotype analysis was performed, and a single haplotype associated with grip strength was identified (P<.01). The rs1800169 null allele fully explained the association between this haplotype and grip strength under a recessive model, with individuals homozygous for the null allele exhibiting a 3.80-kg lower (95% confidence interval=1.01-6.58) grip strength. No association was seen between the CNTF null allele and frailty. CONCLUSION: Individuals homozygous for the CNTF null allele had significantly lower grip strength but did not exhibit overt frailty. Larger prospective studies are needed to confirm this finding and extend it to additional populations.

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PubMed2006

Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults.

Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process.

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PubMed2005

Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study.

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.

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PubMed2005

Total and differential white blood cell counts and their associations with circulating interleukin-6 levels in community-dwelling older women.

BACKGROUND: Interleukin-6 (IL-6) is an inflammatory biomediator, and age-related increases in IL-6 levels are associated with osteoporosis, sarcopenia, disability, and mortality in older adults. Although white blood cells (WBC), or leukocytes, are known to produce IL-6 in vitro, their in vivo relationship with circulating IL-6 levels is not well established. METHODS: In this cross-sectional analysis of data from the Women's Health and Aging Study I, the authors evaluated the relationships of total WBC and WBC differential (neutrophil, monocyte, lymphocyte, eosinophil, and basophil) counts to circulating IL-6 levels in 619 community-dwelling older women. Potential associations of age, race, and cigarette smoking with total and differential WBC counts and IL-6 levels were also assessed. RESULTS: Except for lymphocyte and basophil counts, significant associations of total WBC, neutrophil, monocyte, and eosinophil counts with IL-6 levels were identified. These associations remained highly significant after adjustment for age, race, and smoking status. Total WBC, neutrophil, monocyte, and eosinophil counts had significant stepwise increases in four escalating quartiles of IL-6 levels. In addition, age, race, and cigarette smoking were differentially associated with total and differential WBC counts and IL-6 levels. CONCLUSIONS: Positive in vivo associations of total WBC and its specific subpopulations were identified, including neutrophils, monocytes, and eosinophils, with circulating IL-6 levels in community-dwelling older women. These findings suggest significant contributions of WBC and its subpopulations to circulating IL-6 levels and potential effects from chronic elevation of IL-6 levels to the function of these circulating immune cells that warrant further investigation.

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PubMed2005

Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women.

OBJECTIVES: To evaluate the association between asymptomatic chronic cytomegalovirus (CMV) infection and the frailty syndrome and to assess whether inflammation modifies this association. DESIGN: Cross-sectional analysis. SETTING: Women's Health and Aging Study I & II, Baltimore, Maryland. PARTICIPANTS: Seven hundred twenty-four community-dwelling women aged 70 to 79 with baseline measures of CMV, interleukin-6 (IL-6), and frailty status. MEASUREMENTS: CMV serology and IL-6 concentrations were measured using enzyme-linked immunosorbent assay. Frailty status was based on previously validated criteria: unintentional weight loss, weak grip strength, exhaustion, slow walking speed, and low level of activity. Frail women had three or more of the five components, prefrail women had one or two components, and women who were not frail had none of the components. Multinomial logistic regression adjusted for potential confounders. RESULTS: Eighty-seven percent of women were CMV seropositive, an indication of chronic infection. CMV was associated with prevalent frailty, adjusting for age, smoking history, elevated body mass index, diabetes mellitus, and congestive heart failure (CMV frail adjusted odds ratio (AOR)=3.2, P=.03; CMV prefrail AOR=1.5, P=.18). IL-6 interacted with CMV, significantly increasing the magnitude of this association (CMV positive and low IL-6 frail AOR=1.5, P=.53; CMV positive and high IL-6 frail AOR=20.3, P=.007; CMV positive and low IL-6 prefrail AOR=0.9, P=.73; CMV positive and high IL-6 prefrail AOR=5.5, P=.001). CONCLUSION: Chronic CMV infection is associated with prevalent frailty, a state with increased morbidity and mortality in older adults; inflammation enhances this effect. Further prospective studies are needed to establish a causal relationship between CMV, inflammation, and frailty.

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PubMed2004

Frailty--the search for underlying causes.

Research into the biological basis of frailty has been difficult to accomplish because of a lack of standardized definitions, disease and disability confounders, and complex multifactorial etiology. Multiple physiological systems are likely to be involved, including the skeletal muscle, endocrine, and immune/inflammation systems. Physiological characterization of frail older adults might provide etiologic clues. Translational research programs that connect mechanisms related to aging, such as oxidative damage and telomere shortening, to clinical aging-related syndromes will be necessary to further this critical area of geriatric research.

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PubMed2004

Clinical Global Impression of Change in Physical Frailty: development of a measure based on clinical judgment.

OBJECTIVES: To expand the ability to assess physical frailty by developing a Clinical Global Impression of Change in Physical Frailty (CGIC-PF) instrument. DESIGN: Qualitative and quantitative instrument development. SETTING: Academic centers. PARTICIPANT: s Six expert panel members, 46 clinicians, 24 patients, and 12 caregivers. MEASUREMENTS: Literature review and structured group processes with experts, clinicians, and consumers were used to generate an initial list of domains and indicators. Structured interviews with clinical experts in the area of frailty were used to establish relevance and feasibility of measurement of domains. Interrater reliability was assessed through a Web-based study. Geriatricians pilot tested the feasibility of the baseline CGIC-PF with 10 patients. RESULTS: The CGIC-PF includes six intrinsic domains (mobility, balance, strength, endurance, nutrition, and neuromotor performance) and seven consequences domains (medical complexity, healthcare utilization, appearance, self-perceived health, activities of daily living, emotional status, and social status). Each domain has two to four clinical indicators. Change is scored on a 7-point scale from markedly worse to markedly improved. Average interrater reliability of the CGIC-PF for the Web-based cases was 0.97. Geriatricians completed a baseline CGIC-PF on their own patients in 10 minutes or less. CONCLUSION: The CGIC-PF is a structured assessment of change in physical frailty with defined content and process. It has strong face validity, reliability, and feasibility for use in clinical research. It may be useful as one criterion of change and as an anchor for change in other measures.

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PubMed2003

Arg64 beta3-adrenoceptor variant and the components of energy expenditure.

OBJECTIVE: To determine Trp64Arg beta(3)-adrenoceptor genotype-specific differences in the components of energy expenditure. HYPOTHESIS: We hypothesized that resting metabolic rate (RMR) and physical activity levels would be lower and that thermic effect of feeding (TEF) would be higher in those with the Arg64 allele. RESEARCH METHODS AND PROCEDURES: RMR and TEF were measured by indirect calorimetry, physical activity by questionnaire, and total energy expenditure by the doubly labeled water method. Genotype-specific measures were compared using ANOVA and analysis of covariance (ANCOVA). RESULTS: RMR in Arg64 homozygotes was significantly lower than in Trp64 homozygotes [Arg64, 1373 +/- 259 kcal/d (n = 15) vs. Trp64Arg, 1538 +/- 238 kcal/d (n = 25) vs. Trp64, 1607 +/- 290 kcal/d (n = 22); p < 0.01]. TEF was significantly higher in Arg64 homozygotes compared with Trp64 homozygotes (Arg64, 359 +/- 28 kcal/d; Trp64Arg, 322 +/- 22 kcal/d; and Trp64, 279 +/- 23 kcal/d; p < 0.05). No differences were identified between genotypes in physical activity or in total energy expenditure. DISCUSSION: Our results suggest that the Arg64 beta(3)-adrenoceptor allele contributes significantly to the genetic variability in both RMR and TEF.

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PubMed2002

Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.

BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness. OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus. METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures. RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race. CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

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PubMed2002

Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia.

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6% vs 127.2 +/- 1.3%; all p <0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p < 0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged > 65 years.

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PubMed2002

Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study.

OBJECTIVES: To determine specific physiological correlates of the geriatric syndrome of frailty that warrant further investigation. DESIGN: Population-based case-control study. SETTING: General Clinical Research Center at Johns Hopkins Bayview Medical Center. PARTICIPANTS: Community-dwelling adults aged 74 and older from Baltimore, Maryland. MEASUREMENTS: Frailty status was determined using a recently validated screening tool that consists of weight loss, fatigue, low levels of physical activity, and measurements of grip strength and walking speed. Serum interleukin-6 (IL-6) was measured using enzyme-linked immunosorbent assay, and standard complete blood count was performed using a Coulter counter. RESULTS: Eleven frail and 19 nonfrail subjects with mean age +/- standard deviation of 84.9 +/- 6.7 vs 81.3 +/- 4.1 years, respectively, completed the study. The frail subjects had significantly higher serum IL-6 levels and significantly lower hemoglobin and hematocrit than the nonfrail subjects (4.4 +/-2.9 vs 2.8 +/- 1.6 pg/mL, 12.1 +/- 1.1 vs 13.9 +/- 1.0 g/dL, and 35.8% +/- 3.1% vs 40.6% +/- 2.8%, respectively). No significant difference was observed in mean corpuscular volume, red blood cell distribution width, or white blood cell and platelet counts between the frail and nonfrail groups. Furthermore, there was an inverse correlation between serum IL-6 level and hemoglobin (Pearson's correlation coefficient: -0.46) and hematocrit (-0.48) in the frail group but not in the nonfrail group. CONCLUSION: These results suggest that frail subjects have evidence of inflammation and lower hemoglobin and hematocrit levels. This subclinical anemia is normocytic and is hence unlikely due to myelosuppression or iron deficiency and is potentially related to the increased chronic inflammatory state marked by serum IL-6 elevation. Further studies are indicated to better characterize the immune and hematological changes that underlie frailty.

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PubMedDate not supplied

T cell subsets and mortality in older community-dwelling women.

The relationship between specific T cell subset alterations and mortality has not been well characterized in older adults. The specific aim was to determine whether specific T cell subsets are associated with an increased risk of death. We conducted a case-control study of T cell subsets (CD4+ and CD8+ T cells, and subsets of these cells defined by expression or non-expression of CD28, CD45RA, and CD45RO) nested within two complementary prospective cohorts of women aged 65 and over living in the community, the Women's Health and Aging Studies (WHAS). Cases consisted of 61 women who died during 5 years of follow-up, and controls consisted of 61 women matched by age, frailty, and morbidities who survived during 7 years of follow-up. There were no significant differences between cases and controls in any of the T cell subsets studied. When analyses were stratified by frailty status, these data suggest that CD8+CD28- lymphocyte counts were significantly higher among women who were frail compared with pre-frail and non-frail women.

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