Circadian interrelationships among levels of plasma fibrinogen, blood platelets, and serum interleukin-6.

Circadian (24 h) rhythms of fibrinogen, interleukin-6 (IL-6), and platelet levels were studied in 11 males ages 46 to 72 years. Since there is a known circadian rhythm for fibrinogen and IL-6, we postulated that the peak level (acrophase) of fibrinogen would follow the acrophase of IL-6, based on the fact that IL-6 is the stimulus for fibrinogen production in the liver. Platelet levels were measured to show whether there was any correlation with the IL-6 acrophase because it has been reported that IL-6 affects megakaryocytes and platelets in dogs. We found that the acrophase for IL-6 occurred at 02:03 h and the acrophase for fibrinogen occurred at 09:16 h. Platelet counts peaked at 16:56 h. Thus, there was a positive correlation between IL-6 and fibrinogen acrophases and a negative correlation of each with the acrophase for platelets. The positive linkage of IL-6 with fibrinogen in this study suggests that suppression of IL-6 production would lower those peak fibrinogen levels that occur in the morning in association with arterial ischemic events. This could result in fewer arterial ischemic events, especially in the morning.

Measurement of soluble transferrin receptor in serum of healthy adults.

The concentration of soluble transferrin receptor (sTfR) in serum is reported to be useful in the diagnosis of iron deficiency, especially for patients with concurrent chronic disease, where routine tests of iron status are compromised by the inflammatory condition. A new diagnostic assay for sTfR is calibrated against natural plasma sTfR, thus minimizing calibration discrepancies that result from differences between the analyte and the cellular transferrin receptor used in other assays. Use of the new assay to measure sTfR concentrations in 225 healthy, hematologically normal adults provided a reference interval against which pathological samples could be compared. There was no difference in the reference intervals for men and women and no correlation of [sTfR] with the age of the subject. Black subjects had significantly higher concentrations than nonblacks, and people living at high altitude had higher concentrations than those living closer to sea level. These differences were additive.

Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men.

BACKGROUND: The intercellular adhesion molecule ICAM-1 mediates adhesion and transmigration of leucocytes to the vascular endothelial wall, a step proposed to be critical in the initiation and progression of atherosclerosis. Whether concentrations of soluble ICAM-1 (sICAM-1) are raised in apparently healthy individuals who later suffer acute myocardial infarction is unknown. METHODS: We obtained baseline plasma samples from a prospective cohort of 14,916 healthy men enrolled in the Physicians' Health Study. With a nested case-control design, we measured sICAM-1 concentrations for 474 participants who developed a first myocardial infarction, and 474 controls (participants who remained healthy throughout the 9-year follow-up). Cases were matched to controls according to age and smoking status at the time of myocardial infarction. FINDINGS: We found a significant association between increasing concentration of sICAM-1 and risk of future myocardial infarction (p = 0.003), especially among participants with baseline sICAM-1 concentrations in the highest quartile (> 260 ng/mL; relative risk 1.6 [95% Cl 1.1-2.4], p = 0.02). This association was present overall as well as among non-smokers, and persisted after control for lipid and non-lipid risk factors. In multivariate analyses, the risk of future myocardial infarction was 80% higher for participants with baseline sICAM-1 concentrations in the highest quartile (relative risk 1.8 [1.1-2.8], p = 0.02). Similar risk estimates were seen among non-smokers. We found slight but significant correlations between sICAM-1 and fibrinogen, high-density-lipoprotein cholesterol, homocysteine, triglycerides, tissue-type plasminogen-activator antigen, and C-relative protein, but adjustment for these altered the risk little. The risk of myocardial infarction associated with raised concentrations of sICAM-1 seemed to increase with length of follow-up. INTERPRETATION: Our data support the hypothesis that cellular mediators of inflammation have a role in atherogenesis and provide a clinical basis to consider antiadhesion therapies as a novel means of cardiovascular disease prevention.

Maternal serum interleukin-6 during pregnancy and during term and preterm labor.

OBJECTIVE: To determine the normal concentrations of maternal serum interleukin-6 during the second and third trimesters of pregnancy and the different stages of term and preterm labor, and to examine the clinical usefulness of measuring this cytokine in the serum of women in preterm labor to diagnose asymptomatic intrauterine infections. METHODS: Maternal serum interleukin-6 concentrations were measured cross-sectionally in 315 gravidas in their second and third trimesters and during term and preterm labor. Placentas from women who delivered preterm were examined for histologic chorioamnionitis. RESULTS: At term, women in labor had significantly elevated median maternal serum interleukin-6 concentrations compared with those at term not in labor (4.7 pg/mL versus 2.2 pg/mL, P < .001). Women admitted in preterm labor who delivered had significantly higher median interleukin-6 concentrations than did those in preterm labor who responded to tocolysis (9.3 pg/mL versus 1.9 pg/mL, P < .001). Women in preterm labor who delivered preterm with evidence of chorioamnionitis had significantly higher serum concentrations of interleukin-6 than did those in preterm labor who delivered in the absence of chorioamnionitis (15.9 pg/mL versus 4.6 pg/mL, P = .006). CONCLUSION: Compared with antepartum gravidas, those in term or preterm labor had significantly higher concentrations of maternal serum interleukin-6 concentrations; extremely elevated levels were found in patients whose preterm labor was associated with intrauterine infection.

Maternal serum interleukin-6 concentrations in patients with preterm premature rupture of membranes and evidence of infection.

OBJECTIVE: Our purpose was to determine whether maternal serum interleukin-6 concentrations are elevated in patients with preterm premature rupture of membranes and intrauterine infection. STUDY DESIGN: By use of a sensitive enzyme-linked immunosorbent assay maternal serum interleukin-6 concentrations were measured in 110 samples from patients at 22 to 34 weeks gestation with the following conditions: nonlaboring, uninfected controls (n = 46), preterm premature rupture of membranes > 48 hours before delivery without infection (n = 27), preterm premature rupture of membranes 24 to 48 hours before delivery with subsequent clinical or histologic infection (n = 11), and preterm premature rupture of membranes < 24 hours before delivery with infection present by clinical or histologic criteria (n = 26). The Mann-Whitney U test was used for statistical analysis. RESULTS: Compared with that of nonlaboring controls, serum interleukin-6 was significantly higher in patients with preterm premature rupture of membranes < 24 hours before delivery with evidence of infection (17.2 vs 1.6 pg/ml, p < 0.0001). Patients with preterm premature rupture of membranes 24 to 48 hours before delivery who had infection had significantly higher interleukin-6 concentrations than did nonlaboring controls (3.6 vs 1.6 pg/ml, p = 0.006). There was no significant difference in interleukin-6 concentrations in nonlaboring controls compared with patients with preterm premature rupture of membranes when serum was obtained > 48 hours before delivery (1.6 vs 1.6 pg/ml, p = 0.90). A serum interleukin-6 level > or = 8 pg/ml yielded a sensitivity of 81%, a specificity of 99%, a positive predictive value of 96%, and a negative predictive value of 95% for identifying intrauterine infection in patients with preterm premature rupture of membranes on the day of delivery. CONCLUSIONS: Maternal serum interleukin-6 concentrations are elevated in patients with preterm premature rupture of membranes with clinical or histologic chorioamnionitis.

Circadian characteristics of interleukin-6 in blood and urine of clinically healthy men.

The cytokine interleukin-6 (IL-6) is a multi-functional small peptide molecule that is produced by various types of lymphoid and non-lymphoid cells and plays a central role in hematopoiesis, host defense mechanisms, and acute phase reactions, including regulation of inflammatory and immune responses. A high-sensitivity ELISA assay was applied to serum (S) and urine (U) samples available from 10 men (median age = 50y, range = 46-71y) in order to compare circadian characteristics of IL-6 between assays and in 2 biological fluids. S and U samples were collected at 3-h intervals for 24hrs beginning at 19:00h on May 14, 1993 (8 samples/subj) and frozen at -25 degrees C until analysis. IL-6 in U was adjusted for time & volume (pg/hr) and assigned to midpoint of collection interval. A significant time-effect was found by ANOVA and a high-amplitude circadian rhythm was detected by the least-squares fit of a 24-hr &/or 24+12-hr cosine for each assay. Higher serum IL-6 values were detected throughout the night, with a peak at 01:00h, and lower values throughout the day, with a nadir at 10:00h. In contrast, IL-6 values in urine were highest during the day, with a major peak in the afternoon at 17:30h and a minor peak at 08:30h, and lowest values overnight, with a nadir at 23:30h. Of interest, the rhythm in urinary IL-6 concentration (pg/ml) was more prominent than hourly excretion rate (pg/hr). Thus, endogenous IL-6 (and possibly other cytokine) levels may be significantly influenced by their large and predictable day-night variations and the biological fluid used.

Circadian characteristics of circulating interleukin-6 in men.

BACKGROUND: The cytokine interleukin-6 (IL-6) is a multifunctional small-peptide molecule that is produced by various types of lymphoid and nonlymphoid cells. It plays a central role in hematopoiesis, host defense mechanisms, and acute-phase reactions, including regulation of inflammatory and immune responses. METHODS: Because a circadian time structure has been shown to characterize nearly every biologic function tested in human beings, including some cytokines, we sought to investigate the 24-hour pattern of circulating IL-6 in a group of 11 clinically symptom-free men (median age, 50 years; range, 46 to 72 years). Blood samples were obtained every 3 hours for 24 hours (eight samples per subject), and serum was frozen until analysis for IL-6 with a solid-phase ELISA. RESULTS: Average IL-6 values ranged from 1.66 to 5.38 pg/ml, with lowest to highest values within 24 hours ranging from 1.20 to 7.58 pg/ml (120% to 531%) between subjects. On average, values were greater than the mean throughout the night, with a peak at 01:00 hours and less than the mean throughout the day, with a nadir at 10:00 hours. A significant time effect was found by analysis of variance; and a high-amplitude circadian rhythm was described by the least-squares fit of a 24-hour cosine (p < 0.001; amplitude, 41% +/- 5%; acrophase, 02:16 +/- 00:28 hours). In addition, a positive correlation between mean IL-6 levels and age was found (r = 0.63, p = 0.037). CONCLUSIONS: Because monitoring of endogenous cytokine levels is suggested for assessing immune function and pathologic condition, clinical decisions and immunotherapies may be significantly influenced by the large and predictable day-night variations in endogenous cytokine production and bioactivity.

Circadian rhythmometry of serum interleukin-2, interleukin-10, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor in men.

Serum levels of four cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-10 (IL-10)] were measured in nine diurnally active healthy adult male subjects at 3-h intervals during a 24-h period. Statistical evaluation by analysis of variance and/or the least- squares fit of a cosine model revealed significant 24-h rhythms for each cytokine. Although the amount of IL-2 in the serum was low, the levels fluctuated to form a single peak at approximately noon. In contrast, the other three cytokines exhibited a biphasic temporal pattern. In subjects with detectable TNF-alpha levels, the first peak occurred at 07:30 and the second at 13:30. IL-10 levels also exhibited a biphasic pattern, with one peak at 07:30 and the second 12 h later at 19:30. GM-CSF levels were last to rise, first peaking at approximately 13:30 and then again at 19:30. These results suggest temporal patterns that are unique for each cytokine, generally with daytime highs and nighttime lows.

Genetic analysis of atopy in three large kindreds: no evidence of linkage to D11S97.

Both genetic and environmental influences have been implicated in the pathogenesis of atopic disease. A recent report suggested that a major gene providing susceptibility to atopy was transmitted in a pattern consistent with autosomal dominant inheritance and evidence was presented that places the disease locus near the D11S97 marker on human chromosome 11q. In this report, we present three large, highly characterized pedigrees in which atopy is transmitted in a pattern consistent with autosomal dominant inheritance. Genotypes at the D11S97 and HLA loci were evaluated using both lod score and sib pair methods of analysis. In these pedigrees, we reject close moderate linkage (up to 10 cM) of atopy with both D11S97 and HLA.

Atopic disease and immunoglobulin E in twins reared apart and together.

Both genetic and environmental influences have been implicated in the etiology of atopic disease and in the determination of serum IgE levels. To quantify the relative contribution of these influences, we studied the prevalence of asthma and seasonal rhinitis, skin-test response, total serum IgE levels, and specific IgE, as measured by RAST, in a sample of MZ and DZ twins reared apart or together. Concordance rates for asthma, rhinitis, positive skin tests, and RAST were calculated. MZ twins, whether reared apart or together, showed a greater concordance than dizygotic twins reared apart or together. Maximum-likelihood tests of genetic and environmental components of the variation of total IgE levels revealed a substantial genetic component and a negligible contribution from common familial environmental effects.

Aging and serum immunoglobulin E levels, immediate skin tests, RAST.

The changes of the serum IgE levels, specific immediate skin-test responses, and RAST measurements with age were evaluated. A total of 331 unrelated individuals were studied, consisting of 166 subjects with ragweed allergic rhinitis and/or asthma, 67 with idiopathic (intrinsic) asthma, and 98 who appeared in good health with no clinical evidence of atopic diseases. All subjects were evaluated by history and physical examination, intradermal skin testing to the common aeroallergens, measurements of IgE antibody to common aeroallergens with the RAST, and serum IgE levels. Results demonstrated a significant decrease in serum IgE levels with aging in atopic individuals. This decline was exponential in character. In addition, a tendency for RAST and immediate type skin-test responses for selected antigens and histamine to decrease with age was observed.