Mark S. Currie

Association of Interleukin-6 and Other Biologic Variables with Depression in Older People Living in the Community

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.

Flow cytometric analysis of nitric oxide production in human neutrophils using dichlorofluorescein diacetate in the presence of a calmodulin inhibitor

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, N G‐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.

Racial Differences in the Prevalence of Monoclonal Gammopathy in a Community-based Sample of the Elderly

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.

Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production.

The effects of pentoxifylline (Trental) on human neutrophil CR3 up‐modulation, degranulation, and superoxide production were studied. We used the chemotactic peptide fMLP and the phorbol ester PMA as soluble stimuli, and β‐glucan particles as a CR3‐specific solid phase stimulus of neutrophil superoxide production. Since neutrophils have adenosine A2 receptors, we compared effects of pentoxifylline to effects of adenosine, and we also looked at the effect of cytochalasin B, which breaks up actin filaments. Pentoxifylline inhibited both CR3 up‐modulation and degranulation of myeloperoxidase and lysozyme. Pentoxifylline is a more potent inhibitor of fMLP‐ compared to PMA‐induced degranulation, and is especially potent against superoxide production. While pentoxifylline is less potent than adenosine in its inhibiton of fMLP‐induced superoxide production, it is more potent in its inhibition of PMA‐ and β‐glucan particle‐stimulated superoxide production. Cytochalasin B, which enhances degranulation and fMLP‐stimulated superoxide production, was found to inhibit β‐glucan particle‐stimulated superoxide production. These findings are consistent with the hypothesis that pentoxifylline can affect both the cytoskeletal architecture of unstimulated neutrophils and the activation and responses of neutrophils which involve actin polymerization and receptor‐cytoskeletal interactions.

Pentoxifylline and other methyl xanthines inhibit interleukin-2 receptor expression in human lymphocytes

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.

Age and functional correlations of markers of coagulation and inflammation in the elderly : functional implications of elevated crosslinked fibrin degradation products (D-dimers)

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.

Granulocyte antibodies in leukaemic chronic lymphoproliferative disorders.

The anti‐granulocyte activity of serum from patients with B‐cell chronic lymphocytic leukaemia (CLL) and other lymphoproliferative disorders was investigated. Granulocyte‐binding IgG was measured in 34 patients with CLL, 13 patients with hairy cell leukaemia, one patient with prolymphocytic leukaemia, two patients with Sézary cell leukaemia, and seven patients with chronic T‐cell lymphocytosis who had a predominance of circulating large granular lymphocytes. Anti‐granulocyte activity was absent in CLL and its variants, but present in the majority of granulocytopenic patients with chronic T‐cell lymphocytosis. In one of these patients, granulocytopenia was associated with complement activating IgG granulocyte antibody. Thus, antibody mediated granulocyte injury appears to be an unusual occurrence in chronic lymphocytic leukaemia, but is a frequent complication of chronic T‐cell lymphocytosis.

Activation of human complement by immunoglobulin G antigranulocyte antibody.

The ability of antigranulocyte antibody to fix the third component of complement (C3) to the granulocyte surface was investigated by an assay that quantitates the binding of monoclonal anti-C3 antibody to paraformaldehyde-fixed cells preincubated with Feltys syndrome serum in the presence of human complement. The sera from 7 of 13 patients with Feltys syndrome bound two to three times as much C3 to granulocytes as sera from patients with uncomplicated rheumatoid arthritis. The complement-activating ability of Feltys syndrome serum seemed to reside in the monomeric IgG-containing serum fraction. For those sera capable of activating complement, the amount of C3 fixed to granulocytes was proportional to the amount of granulocyte-binding IgG present in the serum. Thus, complement fixation appeared to be a consequence of the binding of antigranulocyte antibody to the cell surface. These studies suggest a role for complement-mediated injury in the pathophysiology of immune granulocytopenia, as has been demonstrated for immune hemolytic anemia and immune thrombocytopenia.

Tumor necrosis factor, natural killer activity and other measures of immune function and inflammation in elderly men with heart failure

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.

Effect of Pentoxifylline and Analogs on Actin State and Cell Surface Receptor Expression in Human Leukocytes

AbstractWe have shown previously that pentoxifylline causes a decrease in the F-actin content, inhibits ligand-induced capping (Rao et al., J. Cell Physiol. 137:577, 1988) and CR3 expression (Currie e