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BACKGROUND: Dysregulation of immunologic and coagulation systems is common in elderly persons and is associated with many diseases of aging. Thrombotic events are a major cause of morbidity and mortality in the elderly population. This study assesses whether D-dimer, a marker of fibrinolytic activity, varies systematically by demographic, health, and functional measures, and derives a prediction model for factors related to D-dimer in a sample of community-dwelling elderly persons. METHODS: D-dimer levels were assessed in a random sample of 1,727 community-dwelling elderly persons from five rural and urban counties in North Carolina in 1992, as part of the Established Populations for the Epidemiologic Studies of the Elderly (Duke University). All subjects were 72 years or older at the time of the blood draw. In addition, all subjects were surveyed yearly by telephone or in person each year from 1986 to 1992 for a variety of health, functional, and social factors. Levels of D-dimer in 1992 were related cross-sectionally to demographics (age, race, education, income, gender, smoking), function (Nagi, Rosow-Breslau, Katz, Older Americans Resources and Services procedures instrumental activities of daily living), life satisfaction and self-rated health, self-reported diseases (heart attack, cancer, stroke, diabetes, and hypertension), and weight change from 1986 to 1992. RESULTS: D-dimer levels increased with increasing age and functional disability. Among the health variables, only high blood pressure was predictive of D-dimer level. D-dimer levels were dramatically higher in blacks. Blacks were nearly four times more likely to have an extreme value of D-dimer (>600 microg/l) than whites when high D-dimer (yes/no) was analyzed, and blacks had an average level that was nearly 40% higher than whites in analyses of the continuous version of the outcome. This racial effect was not substantively affected in multivariable analyses with demographic and socioeconomic variables controlled. Race, age, functional status, current smoking, high blood pressure, and weight loss were related to level of D-dimer, and race, age, and functional status were related to the presence of a high D-dimer level (in the top 10% of the sample). CONCLUSIONS: Black, older, and functionally impaired persons had significantly higher levels of D-dimer in this sample of community-dwelling elderly persons. The findings for race were particularly striking and persisted even after controlling for smoking and other factors known to be related to thrombosis and were not mediated by social factors. This result may contribute to our understanding of the increased levels of thrombotic events found in these groups.

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OBJECTIVES: The prevalence of depression increases with age, as does the prevalence of higher levels of the cytokine interleukin-6 (IL-6). This analysis was performed to determine the association between increased levels of this cytokine and depression in a population-based sample. DESIGN: Cross-sectional cohort study. SETTING: Rural and urban counties in North Carolina. PARTICIPANTS: Community-dwelling older people. MEASUREMENTS: The association between IL-6 and other biologic variables with self-report depression was examined in 1686 persons aged 70 years and older in the third in-person survey wave (1991) of the Duke Established Population for Epidemiologic Studies of the Elderly (EPESE). Bivariate associations were established by the Spearman correlation, adjusted for age. A stepwise linear logistic regression model was used to derive a final model to assess multivariable effects on CES-D scores. RESULTS: Depression was correlated with IL-6 (P = .011), D-Dimer (P = .017), alpha-1-globulin (P = .023), alpha-2-globulin (P = .002), and beta globulin (P = .012). After controlling for age, race, and gender, IL-6 levels remained the only biologic variable significantly associated with depression (P = .035). CONCLUSION: These data suggest that the inflammatory marker, IL-6, is associated with depression in older people in this cross-sectional study. These results are compatible with the hypothesis of cytokine (IL-6) stimulation in geriatric depression as part of an overall immunoendocrine dysregulation.

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PURPOSE: To determine if there is an increased prevalence of monoclonal gammopathy in elderly blacks compared with whites, analogous to the difference in incidence of multiple myeloma reported for the two racial groups and to confirm age and gender relationships. PATIENTS AND METHODS: Subjects were from the Duke Established Populations for the Epidemiologic Study of the Elderly, selected on the basis of stratified random household sampling. Blacks were oversampled to allow for increased statistical precision in racial comparisons. In all, 1,732 subjects (aged > 70 years) consented to blood drawing and constitute the sample for this study. Monoclonal immunoglobulins were determined by agarose gel electrophoresis and immunofixation. RESULTS: One hundred six subjects (6.1%) had a monoclonal gammopathy. There was a greater than twofold difference in prevalence between blacks (8.4%) and whites (3.8%) (P < 0.001); monoclonal gammopathy prevalence increased with age, and was greater in men than women. Those with monoclonal gammopathy did not differ from those without in socioeconomic status, urban/rural residence, or education. The presence of monoclonal gammopathy was not associated with any specific diseases nor with impaired functional status. There was a slight increase in serum creatinine levels and decrease in hemoglobin and albumin levels in patients with monoclonal gammopathy, but no difference in interleukin-6 (IL-6) levels. Moreover, IL-6 levels were not correlated significantly with the level of monoclonal protein. CONCLUSION: Prevalence of monoclonal gammopathy is significantly greater among blacks than whites in a community-based sample, in approximately the same ratio that multiple myeloma has been reported in the two groups. Given the absence of correlation with environmental factors, there may be a biological racial difference in susceptibility to an early event in the carcinogenic process leading to multiple myeloma.

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BACKGROUND: IL-6 is a multifunctional cytokine that has been shown to increase with age. METHODS: Plasma IL-6 was measured by ELISA in 1,727 community-dwelling elderly subjects whose blood was drawn during the third in-person survey of the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE). Demographics, functional status (disability), and disease states were determined. Correlations of these factors with IL-6 were analyzed with Spearman's Rho while differences between groups were assessed by Wilcoxon test. RESULTS: IL-6 levels were higher with age (p = .0001) even in this older population (> 70 years). There was a positive correlation between IL-6 and functional disability for each of the functional status measures (p = .0001), as well as a correlation between self-rated health and IL-6. Significantly higher median levels of IL-6 were found in subjects reporting prevalent cancer, heart attack, and high blood pressure, but not diabetes or arthritis. The association between age and functional status with high IL-6 remained when all other variables were controlled, in multivariable analysis. CONCLUSIONS: This association between increased plasma IL-6 levels and functional status suggests that dysregulation of IL-6 may be related to the functional disability seen with aging, and that IL-6 may be useful as a component of an overall marker of health.

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OBJECTIVE: To determine the status of tumor necrosis factor (TNF) and other measures of immunity and inflammation in chronic heart failure (CHF) in the elderly. DESIGN: Comparative survey study of subjects with heart failure and age-matched controls. SETTINGS: University affiliated tertiary care VA Medical Center, Heart Failure Clinic. PATIENTS: Twenty men with New York Class II and III heart failure and 17 age-matched controls. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Levels of lymphocyte mitogenesis, TNF, natural killer (NK) cell activity, elastase-alpha 1-antitrypsin (E/alpha) and cross-linked fibrin D-dimers (XDP). RESULTS: TNF levels (p = 0.27), NK activity (p = 0.56), and lymphocyte mitogenesis (p = 0.67) were similar in patients and controls. E/alpha levels were somewhat lower in CHF patients (p = 0.05) and XDP were similar (p = 0.59). However, TNF levels were significantly related to NK activity and to E/alpha activity in elderly men with heart failure but not controls. XDP were positively related to NK in heart failure patients but not controls. CONCLUSION: TNF and other measures of immune function and inflammation do not appear to be significantly elevated in elderly patients with heart failure of moderate severity. However, significant relationships exist between TNF, NK activity, XDP and E/alpha in the heart failure patients only, suggesting that immune activation and subclinical inflammation does exist in these patients.

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Because obtaining multiple blood samples from individuals involved in epidemiologic studies is difficult, conclusions must be drawn on the basis of one or two samples. In this study, the authors attempted to determine the variability of two plasma markers over time, namely IL-6 levels and crosslinked fibrin degradation products (D-Dimers), in 16 elderly community-dwelling individuals. The study group included both men and women and black and white subjects (four in each group). Eight blood samples were obtained from each subject over a period of 36 days. Blood was separated within 1 hour after collection and aliquots of plasma were stored at -70 degrees C until all samples were collected. All samples from an individual were analyzed at one time. IL-6 and D-Dimers were measured by commercially available ELISA kits. The variability in the levels of plasma IL-6 and D-Dimers was assessed by means of intra-class correlation coefficient (ICC). The estimates of the ICCs for one measurement of IL-6 and D-Dimers were .87 and .86, respectively. Reliability values of this magnitude indicate excellent reproducibility in the measurement. These values indicate that obtaining a single sample from a subject is fairly representative of that individual's IL-6 and D-Dimer levels over an extended period of time.

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We determined L-selectin expression and elastase levels in neutrophils obtained from patients receiving granulocyte colony-stimulating factor (G-CSF) either alone (given for increasing peripheral progenitor cells for harvest) or in combination with high-dose chemotherapy with autologous bone transplantation support (BMT). Administration of G-CSF alone for 3-5 days produced a decrease in L-selectin expression in neutrophils (25 +/- 4 versus 7 +/- 1, mean +/- SEM; mean channel fluorescence, n = 10) with no effect on neutrophil elastase activity (3.1 +/- 0.3 versus 3.4 +/- 0.6; micrograms elastase/million cells; n = 9). In contrast, in patients in the BMT group the L-selectin expression was increased (26 +/- 2 versus 38 +/- 3; n = 20) and elastase activity was markedly decreased (2.9 +/- 0.2 versus 1.4 +/- 0.2, n = 12) compared with values before BMT. The changes in L-selectin expression correlated with the ability of neutrophils to adhere to human umbilical vein endothelial cells. The decrease in the neutrophil elastase activity was not associated with an increase in the plasma elastase/alpha 1-antitrypsin complex levels, indicating that the decrease in the neutrophil elastase activity is not caused by activation of neutrophils and release of the enzyme into the plasma. Administration of G-CSF alone did not cause a decrease in the neutrophil elastase activity but increased plasma elastase/alpha 1-antitrypsin complex levels. There was no change in CR3 expression on neutrophils under any of these conditions. These observations suggest that the changes seen in neutrophils during BMT are influenced by various factors associated with BMT other than the administered cytokine alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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OBJECTIVE: To report a case of thrombocytopenia associated with the use of extended-release procainamide hydrochloride in a geriatric patient. CASE SUMMARY: A 77-year-old man was admitted to the hospital for four-vessel coronary artery bypass surgery. He subsequently developed new onset atrial fibrillation and was started on extended-release procainamide on hospital day 7. The patient's platelet count on admission was 229 x 10(9)/L. The platelet count began to decrease on hospital day 22 and was 79 x 10(9)/L by day 30 and 13 x 10(9)/L by hospital day 37. The patient exhibited gross hematuria and lower extremity petechiae. There were no signs of splenic sequestration and other hematologic indices were normal. Procainamide was discontinued on hospital day 32. There was full recovery of the platelet count to baseline 33 days after procainamide was discontinued. DISCUSSION: Other possible medical and drug-related causes of thrombocytopenia are reviewed and ruled out. Previous reports of procainamide-associated thrombocytopenia describe an immune-mediated peripheral destruction of platelets with platelet recovery within three to eight days after drug discontinuation. However, the prolonged recovery period and the presence of antiplatelet antibodies suggest an immune-mediated process in the bone marrow of this patient. CONCLUSIONS: Clinicians should be aware of the possible adverse hematologic effects of procainamide in the elderly.

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OBJECTIVE: To measure markers of inflammation in a cohort of young and old subjects and relate these findings to the functional level of the individuals. DESIGN: For the pilot study, blood samples were obtained from 18 young (age 20-35 years) and 18 old (age 68-83 years) subjects. The main study population included community-dwelling subjects between the ages of 70 and 79. The group consisted of 282 subjects with minimal physical limitations, 17 subjects from the middle third, and 16 from the lower third of physical function rankings. METHODS: Plasma markers were measured by ELISA techniques, and certain biochemical values were obtained through routine clinical tests performed by a commercial laboratory. RESULTS: D-Dimers were higher for physically impaired subjects in all groups, but most prominently among black females, who also had significantly higher D-Dimer levels in every functional group. To inquire whether higher D-Dimers were associated with markers of inflammation, we also examined the macrophage metabolite, neopterin, the neutrophil product, elastase complexed to antitrypsin (E/a), and the albumin globulin ratio (A/G ratio). No differences were found in neopterin or E/a levels on the basis of gender, race, or functional status. The A/G ratio was significantly lower in functionally impaired subjects. CONCLUSION: These preliminary findings demonstrate racial/ethnic and gender differences in D-Dimers in a population of community-dwelling elderly, and suggest that factors influencing hemostasis may be particularly relevant to physical functional status in black women. A sample containing more subjects with lower physical function will be needed to establish the relationship between inflammation, altered hemostasis, and physical function decline.

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The aging immune system, while showing little in the way of quantitative changes, demonstrates important functional changes, especially T-cell functions. In addition to increased susceptibility to some infections, there is an increased likelihood of autoantibody production, and the emergence of monoclonal antibodies and other lymphoproliferative disorders. The role of the immune system in degenerative processes, and susceptibility to malignant processes requires further investigation. Biotechnology is producing many new methods of modulating immune function, with ever increasing specificity. Thus the future holds great promise for overcoming the effects of immunosenescence.

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Rheumatoid arthritis is a complex inflammatory disease of unknown cause. Although various laboratory and clinical measurements are useful in managing these patients, there is a need for better tests to quantitatively assess disease activity. The purpose of this study was to investigate the association of certain immune and inflammation (I-I) parameters with four traditional disease severity measures and a functional measure in rheumatoid arthritis patients. A single set of patient blood samples was analyzed, and four traditional disease severity measures and patient functional statuses were determined from 64 consecutive outpatients with rheumatoid arthritis. Plasma tumor necrosis factor-alpha (TNF), soluble interleukin-2 receptor (sIL-2R), sCD4 and sCD8 (and the sCD4/sCD8 ratio), neopterin, and fibrin D-dimer were analyzed in relationship to Westergren erythrocyte sedimentation rate (ESR), physician assessment of disease activity, joint pain count, grip strength, and Arthritis Impact Measurement Scale (AIMS) scores. Rheumatoid arthritis patients had higher mean levels of all I-I measures (except sCD4) compared to healthy subjects. Initial significant correlations between TNF, sIL-2R, and D-dimer and several disease severity and functional measures were detected. When we controlled for the covariates age, gender, race, and medications, regression analyses indicated that, as a group, the I-I measures were significantly related to grip strength, physician disease severity rating, ESR, and total joint pain. When the predictive values of the I-I measures were tested controlling for the covariates and ESR, D-dimer was independently and significantly associated with variability in grip strength, physician disease severity, and AIMS physical disability, while TNF was associated with a significant amount of variability in total joint pain.(ABSTRACT TRUNCATED AT 250 WORDS)

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Dichlorofluorescein (DCFH) oxidation assay measures hydrogen peroxide (H2O2), which is a derivative of superoxide anion. We found that a calmodulin antagonist, W-13, which is known to inhibit superoxide anion generation enhanced the capacity of human neutrophils to oxidize DCFH. To investigate this discrepancy we studied the role of nitric oxide (NO) in DCFH oxidation. Pure NO was capable of oxidizing DCFH, and the product formed had spectral properties identical to oxidized DCFH produced by H2O2. The arginine analog, NG-monomethyl-L-arginine (NMMA), which inhibits NO production, in combination with W-13 completely inhibited the stimulus-induced increase in DCFH oxidation. We conclude that the oxidation of DCFH in human neutrophils can occur by either H2O2 or NO.

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We studied a number of parameters, which may all depend upon cytoskeletal function, comparing lymphocytes and granulocytes (PMN) from young and old healthy donors. F-actin content was measured by NBD-phallacidin staining, followed by flow cytometry and was expressed as mean channel fluorescence (MCF). There were no differences in the basal F-actin content of PMN obtained from young (under 35 years old) and old donors (above 65 years). In contrast, the basal F-actin content was higher in lymphocytes obtained from the old donors (MCF, 56.8 +/- 2.9 vs 48.1 +/- 2.6 in the young; mean +/- SEM, n = 20, p less than .03). Stimulus-induced actin polymerization was slightly lower in the older age-group both in PMN and lymphocytes, but a significant difference was found only in PMN stimulated with the chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (MCF 97.9 +/- 4.7 vs 88.6 +/- 3.4; young vs old, mean +/- SEM, n = 20, p less than .05). Interleukin-2 receptor expression was measured by staining with FITC-conjugated anti-CD25 antibodies and flow cytometry, following stimulation with phytohemagglutinin (PHA) or pokeweed mitogen (PWM). Perturbation of the cytoskeletal system with pentoxifylline, which has been shown to decrease F-actin content and inhibit the expression of several cell surface receptors, had similar effects on leukocytes from young and old donors.(ABSTRACT TRUNCATED AT 250 WORDS)

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We studied the changes in actin state and chemotactic peptide receptor expression in granulocytes from patients receiving different cytokines following high dose chemotherapy and autologous bone marrow transplantation (ABMT). The F-actin content in granulocytes was higher in all patients following ABMT. However, in patients receiving granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) the increase in F-actin content was much greater than in those not receiving these cytokines (159, 149, and 90% for G-CSF, M-CSF, and noncytokine group, respectively). Patients receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) had only a 62% increase in the F-actin content, which was not statistically significant from patients undergoing ABMT without any cytokines. Although the basal level of F-actin was high following ABMT, granulocytes from all patients showed an additional increase in F-actin content after stimulation with either the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA). The chemotactic peptide receptor expression was significantly higher in patients treated with ABMT alone or ABMT plus G-CSF. These observations suggest that the granulocytes generated following ABMT and cytokine administration may have different functional potential depending on the cytokine administered. Further studies to evaluate these potential differences are essential to devise optimal therapeutic protocols for maximizing the granulocyte protective function in this clinical setting.

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Complement activity has been linked to decompression sickness (DCS), but the effects of intravascular bubbles on complement activation are poorly understood. We have investigated intravascular complement activation by measuring red blood cell (RBC)-bound C3d after repetitive air diving in man. Subjects were exposed to a single, 20 min, 170 fsw (feet of sea water) dive, or to 2 such dives with a 6-h surface interval. Doppler monitoring for venous gas emboli was performed postdive. Predive blood samples were studied to determine sensitivity of complement to activation by air bubbles. Other predive and postdive venous samples were evaluated for intravascular complement activation. No cases of DCS occurred in 39 dives. Baseline complement sensitivity appeared normally distributed, thus "sensitive" and "insensitive" subjects were not clearly distinguishable. RBC-bound C3d did not increase after 1 dive but did increase after the repetitive dive (P less than 0.05). Furthermore, maximum bubble grade was independent of complement activation.

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Addition of pentoxifylline to lymphocytes caused a dose-dependent decrease in PHA-induced interleukin-2 receptor (IL-2R) expression. Expression of IL-2R protein and mRNA were inhibited by 60% at a concentration of 1 mM. Pentoxifylline also inhibited release of IL-2R into the medium by 85%. Treatment with recombinant IL-2 (50 U/ml) did not abrogate the effect of pentoxifylline. In addition to inhibition of IL-2R expression, pentoxifylline also decreased the expression of transferrin receptors and class I MHC antigens. Pentoxifylline also inhibited cell proliferation. However, aphidicolin, an inhibitor of DNA polymerase alpha inhibited cell proliferation to the same extent as pentoxifylline, but had no effect on IL-2R expression, indicating that inhibition of cell proliferation does not necessarily lead to inhibition of IL-2R expression. The inhibitory effect on IL-2R expression was also noted with other methylxanthines, theophylline and isobutylmethylxanthine, and with dbcAMP and forskolin. The inhibitory activity of pentoxifylline was prevented by W-13, a calmodulin antagonist, but not by HA-1004, a cyclic AMP-dependent protein kinase inhibitor. This suggests that pentoxifylline might act in part through a Ca2+/calmodulin-dependent mechanism. Pentoxifylline and other methylxanthines may prove useful in delineating the biochemical pathways involved in induction and expression of cell surface receptors.

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We measured neutrophil elastase/alpha 1 proteinase inhibitor complex (E/alpha) levels by ELISA in plasma samples drawn from 19 patients with claudication, before and at 1 and 2 months after initiation of pentoxifylline (PTF), 400 mg. p.o. tid. Plasma E/alpha levels declined in all eight patients whose initial values were more than 300 ng elastase per ml. Whole blood viscosity (wbv) was reduced by two months' treatment in 12 of 14 patients tested. The relative change in wbv was significantly related to the relative change in E/alpha (R2 = 0.8), for patients with elevated initial E/alpha levels, suggesting a common or related mechanism for the two effects. Plasma crosslinked fibrin D-dimer fragments (XDP) measured by ELISA as indicators of coagulation activity were lower compared to pretreatment levels in 9 of 10 samples drawn when symptoms were improved on PTF, whereas they were increased in 6 of 9 samples drawn when symptoms were worse or unchanged. Plasma viscosity, C-reactive protein and alpha 1-acid-glycoprotein did not change significantly with PTF treatment. Together these findings are consistent with the possibility that reduced microvascular neutrophil activation and coagulation play a role in the clinical efficacy of PTF in intermittent claudication.

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We have previously shown that pentoxifylline, a drug used in intermittent claudication, causes depolymerization of actin in leukocytes in vitro. In this study we evaluated several parameters in peripheral blood obtained from 17 patients receiving pentoxifylline, before therapy and at 1 and 2 months after initiation of drug therapy. Total blood viscosity decreased at 1 month and was further reduced at 2 months. The plasma viscosity remained unchanged during the course of the therapy (1.770 +/- 0.147, 1.776 +/- 0.162, and 1.772 +/- 0.164 centipoise at 0, 1, and 2 months, respectively; mean +/- SD, n = 14 to 17). No changes were observed in stimulus-induced actin polymerization in granulocytes, concanavalin A-induced capping in granulocytes and lymphocytes, and anti-IgG-induced caps in lymphocytes, before and after therapy. Similarly, there was no difference in the magnitude of depolymerization caused by pentoxifylline when added in vitro. Thus none of the parameters altered by pentoxifylline treatment in vitro have been observed ex vivo in patients receiving this drug. However, the decrease in total blood viscosity along with unaltered plasma viscosity suggests that the rheology of the cellular elements is being affected by the administered drug. In addition to the direct effects on the cell membrane and the cytoskeleton, pentoxifylline may exert indirect effects through its inhibitory action on cytokine production. Subtle changes in a number of parameters in leukocytes, which taken alone fail to show demonstrable changes, might ultimately be responsible for the therapeutic benefit noted with pentoxifylline.

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Erythrocyte CR1, a C3b/C4b-binding complement-regulatory protein, is sensitive to proteolysis in vitro. To test the hypothesis that in vivo erythrocyte CR1 reduction results from intravascular proteinase activities, we used enzyme-linked immunosorbent assays to measure gamma-crosslinked fibrin degradation products (D-dimers) as indicators of coagulation/fibrinolytic activity, and complexes of neutrophil elastase with alpha 1 proteinase inhibitor (E/A) as indicators of neutrophil enzyme release in malignant and inflammatory disorders. Erythrocyte CR1, measured by monoclonal anti-CR1 antibody binding, was inversely related to disease activity and blood proteinase markers. Levels of erythrocyte CR1 were significantly lower for patients with active versus remittent squamous and small cell lung cancers, Hodgkin's and diffuse large cell lymphomas, and acute myelogenous leukemias. In patients with active thoracic cancers, elevated D-dimer levels correlated with reduction of CR1. In patients with rheumatoid arthritis, CR1 reduction was correlated with elevated levels of elastase complexes. Our findings substantiate the relationship of acquired CR1 reduction to the activity of certain diseases and provide circumstantial support for the hypothesis that erythrocyte CR1 is lost to proteolysis in vivo. Although heritable differences in CR1 expression reduce the interpretability of single measurements of erythrocyte CR1 levels, disease-associated CR1 reduction may be a useful indicator of disorders with chronically increased blood proteinase activity.

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