Components of biological variation in plasma haptoglobin: relationships to plasma fibrinogen and immune variables, including interleukin-6 and its receptor.

We investigated the components of biological variation, including seasonality, in plasma haptoglobin (Hp) levels and the relationships between plasma Hp and interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6), sIL-2R, fibrinogen (Fb) and absolute number of peripheral blood mononuclear cells, such as leukocytes, neutrophils, monocytes, lymphocytes, CD4+, CD8+, CD25+ T cells and CD20+ B cells. Monthly blood samples were taken from 26 normal volunteers during one calendar year. The estimated inter- and intra-individual C.V. values for plasma Hp were 27.9% and 20.0%, respectively; the index of individuality was 0.72. No significant seasonal rhythms could be detected in plasma Hp levels. The yearly mean values in plasma Hp were significantly and positively related to those in plasma Fb, absolute number of leukocytes, neutrophils, CD4+ T cells and the CD4+/CD8+ T cell ratio. 49.0% of the variance in the yearly mean values of plasma Hp could be explained by variances in serum IL-6 and number of CD4+ (positively related) and CD8+ (negatively related) T cells. There were significant and positive time relationships between plasma Hp, on the one hand, and plasma Fb, sIL-6R, sIL-2R and number of leukocytes, neutrophils and monocytes, on the other. A smaller part of the within-subject variability in plasma Hp (i.e. 6.0%) could be explained by serum sIL-6R and sIL-2R. It is concluded that there are (1) important between-subject differences in the homeostatic setpoints of plasma Hp, which are related to those in plasma Fb and in immune status and (2) significant within-subject, time relationships between plasma Hp and indicators of immune activation and plasma Fb.

Components of biological, including seasonal, variation in hematological measurements and plasma fibrinogen concentrations in normal humans.

This study has been carried out in order to examine the components of biological and, in particular, seasonal variation in hematologic measurements in normal humans. Toward this end, 26 normal volunteers had monthly blood samplings during one calendar year for determination of number of red blood cells (RBC) and platelets, hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), MC Hb (MCH), MC Hb concentration (MCHC), RBC distribution width (RDW), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), and plasma fibrinogen concentrations. The data were analyzed by means of spectral analyses of a group of time series or a single time series, and by means of repeated measures analyses of variance. Most of the hematologic variables show seasonal rhythms, such as annual rhythms or harmonics, which are expressed as a group phenomenon. An important part of the variance ( > 15%) in Ht, MCV, MCH, MCHC, RDW, number of platelets, MPV and plasma fibrinogen was explained by a yearly variation. The peak-trough differences (expressed as a percentage of the mean) in the yearly variations in number of RBC, Ht, MCV, MCH, MCHC and RDW were very low (all < 8.5%). Number of platelets (14.4%) and plasma fibrinogen values (28%) showed a high-amplitude yearly variation. All hematological variables, except MCHC, show a high interindividual variability which exceeds by far the intraindividual variability.

Psychomotor retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobinemia during major depression.

Recently, we have established that major depression is characterized by hyperhaptoglobinemia, which may be regarded as an index of an "acute" phase response in that illness. The present study investigates the psychopathological correlates of increased plasma concentrations of haptoglobin (Hp) in major depression. To this end, the authors studied the Hp levels in relation to depressive items of the Structured Clinical Interview for DSM-III (SCID) and the Hamilton Rating Scale for Depression (HRSD) in 90 depressed subjects. There was a significant positive relationship between the SCID symptoms anorexia/weight loss, sleep, and psychomotor disorders and Hp plasma concentrations. Hp plasma levels were significantly and positively correlated with overall severity of illness (HRSD). The HRSD symptom correlates of higher Hp levels were loss of interest, middle insomnia, and psychomotor retardation. Up to 31.4% of the variance in Hp plasma values could be explained by psychomotor disorders, anorexia, weight loss, middle insomnia, and less diurnal variation of mood. It is suggested that hyperhaptoglobinemia, as an index of an "acute" phase response in major depression, is related to the somatic dimension of depressive illness.

The presence of antibodies against extractable nuclear antigens in serum: a comparison of immunoblotting versus radial immunodiffusion.

A commercial immunoblotting kit has recently been introduced to determine auto-antibodies against extractable nuclear antigens. We compared this new test with radial immunodiffusion for its usefulness in the routine laboratory procedures of a general hospital. Antigen preparation in immunoblotting includes a protein denaturation step prior to electrophoretic separation of the different proteins. In this way antigenic determinants that depend heavily on the protein superstructure are lost. In theory, auto-antibodies against these epitopes may be missed. In our series of 100 samples that had tested positively for antinuclear antibodies, radial immunodiffusion was able to detect one SSA positive sample that was negative by immunoblotting. However, 47 samples positive in immunoblotting, 37 positive for UBP, seven for anti-SSA, are for anti-Jo-1, one for anti-RNP and one for anti-Sm were missed by radial immunodiffusion. Most of these samples had low antinuclear antibody titres (1/80 or 1/160).

Spuriously low concentrations of serum iron measured with generation 14 Kodak Ektachem slides: prevalence, possible causes, and partial improvement with generation 16 slides.

For sera with iron (Fe) concentrations < 4 mumol/L, Kodak Ektachem slides Generation (GEN) 14 (without ascorbic acid) yielded systematically lower results for Fe than did liquid Ferrozine-based reagents from Baker containing ascorbic acid (10 g/L, final concentration) and adapted to Cobas-Bio. During an 8-month comparison period, outliers (defined as [Fe]Cobas - [Fe]Kodak > 4 mumol/L) were seen in 21 of the 8731 sera (0.24%) tested, corresponding to < 5% of the sera with [Fe]Kodak < 4 mumol/L. In vitro addition of ascorbic acid and (or) Fe identified at least two types of outliers: type 1 (approximately 70%), characterized by [Fe]Kodak > 0.4 mumol/L, by (supra)normal Fe recovery in Kodak slides in the presence or absence of ascorbic acid (10 g/L), and by between-method differences in serum Fe (Cobas - Kodak) that were significantly correlated with serum Zn content (P < 0.0004); and type 2 (approximately 30%), tentatively ascribed to contamination by EDTA, with serum Fe by Kodak < 0.4 mumol/L and Fe recovery near 0%, both of which could be significantly and dose-dependently increased by addition of ascorbic acid (5-20 g/L). For both types of outliers, flameless atomic absorption spectrometry (AAS) yielded results that were significantly higher than concentrations by Kodak with GEN 14. Use of GEN 16 slides (containing ascorbic acid) improved concordance of Kodak results with Cobas, and hence with flameless AAS, for both types of outliers; abolished Zn dependency of results; and increased Fe results in sera with type 2 outliers, although these remained substantially lower than by Cobas. However, like other ascorbic acid-containing reagents, GEN 16 slides were more sensitive to interference by dextran-bound Fe, as assessed during in vitro addition experiments and comparisons involving samples from Fe-dextran-treated patients. GEN 16 slides are hence expected to more frequently overestimate the physiologically available protein-bound Fe in hemodialysis patients. In hospital laboratories, this new interference will probably arise more frequently than the spuriously low results with GEN 14, hence warranting further efforts in optimizing Fe slides.

Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness.

1. Leukocyte enumeration through flow cytometry has revealed that severe depression may be accompanied by a systemic immune activation, indicative of an inflammatory response. The latter condition allegedly involves an important modification of acute phase plasma protein (APP) equilibrium. 2. In order to elucidate whether the state of severe depression is represented by alterations in APPs, the authors measured: alpha 1 antitrypsin (alpha 1 AT), alpha 2 macroglobulin (alpha 2 M), haptoglobin (Hp), alpha 1 acid glycoprotein (alpha 1 S), transferrin (Tf), complement component 4 (C4) and C-reactive protein (CRP). Interleukin-1-beta (II-1 beta) and interleukin-6 (II-6) circulating levels were determined. 3. Hyperhaptoglobinemia and hypotransferrinemia are hallmarks for major depression and depression per se, respectively. The disorders in Hp and Tf circulating levels are highly sensitive to (83%) and specific for (100%) melancholia as opposed to the healthy state. 4. Disorders in both APPs are significantly related to the absolute number of blood monocytes. 5. The authors observed a trend towards lower alpha 2M and higher alpha 1S values in severely depressed subjects. Severity of depression was significantly related to Hp and alpha 1S (both positively) and to alpha 2M and Tf (both negatively) values. 6. No significant intercategory differences in C4 could be established, whilst only a few subjects exhibited measurable CRP, II-1 beta and II-6 circulating levels. 7. Our findings may support the hypothesis that depression is accompanied by an inflammatory response.

Higher alpha 1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: further evidence for the existence of an inflammatory response during that illness.

Recently, a few reports have shown that severe depression may be associated with higher levels of positive acute phase proteins (APPs), such as haptoglobin (Hp), alpha 1-acid glycoprotein (alpha 1S) and lower levels of negative APPs (visceral proteins), such as albumin (Alb) and transferrin (Tf). In order to reassess whether depression is related to alterations in the expression of plasma APP concentrations, we measured in 84 normal controls and depressed inpatients positive APPs such as Hp, alpha 1-antitrypsin (alpha 1AT), hemopexin (Hpx), ceruloplasmin (Cp), complement component C3C and one visceral protein, i.e., retinol binding protein (RBP). We found increased plasma concentrations of Hp, alpha 1AT, and Cp in major depressed subjects as compared with healthy controls, with minor depressives exhibiting an intermediate position. RBP was significantly lower in minor and major depressives than in normal controls. The disorders in these proteins were rather sensitive (62%) for major depression, with a specificity equalling 96%. Our findings are compatible with the hypothesis that major depression may be accompanied by inflammatory changes with higher levels of positive APPs (i.e., alpha 1AT, Hp, Cp, alpha 1S) and lower levels of visceral proteins (i.e., RBP, Tf, Alb).

Urine analysis of European moles Talpa europaea and white rats Rattus norvegicus kept on a carnivore's diet.

1. The urine compositions of the European mole Talpa europaea and of the white rat Rattus norvegicus (albino) kept on a carnivore's diet were compared. 2. The urine of moles contained bicarbonate while that of rats kept on a carnivore's diet did not. 3. Urine volume per 100 g body mass over 24 hr was significantly higher in the mole than in the rat. 4. The results of this study suggest that the mole, like other subterranean mammals on the one hand and caecal fermenters on the other, may use its kidneys as a pathway for releasing bicarbonate in its hypercapnic environment.

alpha-1-Anti-trypsin, an inhibitor of renin.

A naturally occurring competitive inhibitor of pig kidney renin has been identified in human plasma. The inhibitor was shown to be alpha-1 anti-trypsin and the effect in vitro on the renin activity was examined. The slope in the Hill plot is compatible with the assumption of one-site competitive inhibition. Other proteinase inhibitors, such as alpha-2-macroglobulin and C1 inactivator, however, have no inhibitory effect on the renin-angiotensinogen reaction.