Jana Uhrova

Depression, traumatic stress and interleukin-6

BACKGROUND Recent evidence indicates that various types of interactions between nervous and immune system are important in pathogenesis of depression. These findings show that a significant role in developing depression play pro-inflammatory cytokines that may mediate its psychological, and neurobiological manifestations. Great importance among these cytokine molecules plays interleukin-6 (IL-6). There is growing evidence that this inflammatory process related to depression may be influenced by psychological stress as well as organic inflammatory conditions. These findings suggest that specific influences related to traumatic stress and dissociation could be found in close relationship to increased level of cytokine IL-6. METHODS In the present study we have performed psychometric measurement of depression (BDI-II), traumatic stress symptoms (TSC-40) and dissociation (DES, SDQ-20), and immunochemical measure of serum IL-6 in 40 inpatients with unipolar depression (mean age 42.3+/-6.8). RESULTS The results show that IL-6 is significantly correlated to BDI-II (Spearman R=0.47, p<0.01), TSC-40 (Spearman R=0.32, p<0.05), SDQ-20 (Spearman R=0.34, p<0.05) but not to DES (Spearman R=0.25, p=0.11). CONCLUSION The findings of the present study indicate that increased level of IL-6 in depression could be directly related to symptoms of traumatic stress and somatoform dissociation.

Human Galectins Induce Conversion of Dermal Fibroblasts into Myofibroblasts and Production of Extracellular Matrix: Potential Application in Tissue Engineering and Wound Repair

Members of the galectin family of endogenous lectins are potent adhesion/growth-regulatory effectors. Their multifunctionality opens possibilities for their use in bioapplications. We studied whether human galectins induce the conversion of human dermal fibroblasts into myofibroblasts (MFBs) and the production of a bioactive extracellular matrix scaffold is suitable for cell culture. Testing a panel of galectins of all three subgroups, including natural and engineered variants, we detected activity for the proto-type galectin-1 and galectin-7, the chimera-type galectin-3 and the tandem-repeat-type galectin-4. The activity of galectin-1 required the integrity of the carbohydrate recognition domain. It was independent of the presence of TGF-β1, but it yielded an additive effect. The resulting MFBs, relevant, for example, for tumor progression, generated a matrix scaffold rich in fibronectin and galectin-1 that supported keratinocyte culture without feeder cells. Of note, keratinocytes cultured on this substratum presented a stem-like cell phenotype with small size and keratin-19 expression. In vivo in rats, galectin-1 had a positive effect on skin wound closure 21 days after surgery. In conclusion, we describe the differential potential of certain human galectins to induce the conversion of dermal fibroblasts into MFBs and the generation of a bioactive cell culture substratum.

Comparison of different immunoassays for CA 19-9.

Abstract We compared six routinely employed immunoassay kits: Architect i2000 and AxSYM, Abbott Laboratories; Elecsys 2010, Roche Diagnostics; ELSA, CIS-BioInternational; Immulite 1, Diagnostic Products Corporation; and IRMA-mat, Byk-Sangtec Diagnostica. Using all analytical systems, we measured identical groups of clinical samples completed with selected control samples. The repeatability of measurements (coefficient of variation) ranged from 2.1% (Elecsys 2010) to 6.7% (ELSA). The parameters of Passing-Bablok regression show significant systematic differences among analytical systems. Data from a Bland-Altman diagram suggest that these differences project onto other, still more significant individual differences among individual samples. Though the cut-off values differ between various systems, no similar clinical efficacy appears to be attained. The behavior of individual systems is quite different for identical control materials and does not necessarily duplicate the calibration for biological samples. The results of determining CA 19–9 cannot be extrapolated from one analytical technique to another, even in cases where the same monoclonal antibody is used. Standardization of CA 19–9 measurement systems is necessary to allow use of the results for the purposes of evidence-based medicine.

Effect of Hemodiafiltration on Pregnancy-Associated Plasma Protein A (PAPP-A) and Related Parameters

Background. Dialysis patients are at high risk of vascular/cardiovascular complications with multifactorial pathogenesis, and pregnancy-associated plasma protein A (PAPP-A) is one of the new markers related to cardiovascular risk. Because hemodiafiltration (HDF) is supposed to be better for cardiovascular status, the aim of this study was to describe whether it has any advantage concerning changes of PAPP-A and related molecules during the session in comparison with hemodialysis (HD). Methods. The studied group consisted of 20 chronic hemodialysis patients. In each patient, PAPP-A and related parameters—IGFBP-4 (insulin like growth factor binding protein), IGF-I (insulin like growth factor), and two MMPs (matrix metalloproteinases)-2 and 9—were determined both during a single online HDF session (high-flux polysulfone membrane HF80, postdilution) and during a single HD session (low-flux polysulfone membrane F6, F7) at time 0 (start), 15 min, 120 min, and 240 min (end) of the session. Results. PAPP-A, elevated at baseline in dialysis patients, changes significantly both during HDF and HD without significant differences between these two procedures (mean levels during HDF were 24.3, 53.9, 24.3, and 27.3 mIU/L). It increases more than two-fold from 0 to 15 min of the session (p < 0.001) and then decreases until the end of the session (p < 0.001). MMP-2 decreased slightly during both sessions (p < 0.001), and changes of other molecules were only minimal. Conclusion. A single HDF session compared to HD has no advantage in the decrease of PAPP-A and other tested molecules, all of them related to cardiovascular risk. Studies aimed at a long-term effect of both procedures on these parameters would be needed to further evaluate these therapeutical strategies.

Dissociative symptoms reflect levels of tumor necrosis factor alpha in patients with unipolar depression

Recent evidence indicates that the nature of interactions between the nervous system and immune system is important in the pathogenesis of depression. Specifically, alterations in pro-inflammatory cytokines have been related to the development of several psychological and neurobiological manifestations of depressive disorder, as well as to stress exposure. A number of findings point to tumor necrosis factor alpha (TNF-α) as one of the central factors in these processes. Accordingly, in the present study, we test the hypothesis that specific influences of chronic stressors related to traumatic stress and dissociation are related to alterations in TNF-α levels. We performed psychometric measurement of depression (Beck Depression Inventory [BDI]-II), traumatic stress symptoms (Trauma Symptom Checklist [TSC]-40), and psychological and somatoform dissociation (Dissociative Experiences Scale [DES] and Somatoform Dissociation Questionnaire [SDQ]-20, respectively), and immunochemical measure of serum TNF-α in 66 inpatients with unipolar depression (mean age 43.1 ± 7.3 years). The results show that TNF-α is significantly related to DES (Spearman R=−0.42, P<0.01), SDQ-20 (Spearman R=−0.38, P<0.01), and TSC-40 (Spearman R=−0.41, P<0.01), but not to BDI-II. Results of the present study suggest that TNF-α levels are related to dissociative symptoms and stress exposure in depressed patients.

Comparability of Eight Immunoassay Procedures for the Determination of CA 15-3 and Related Markers

Abstract MUC1 mucins are tumour markers that are frequently indicated and examined, particularly as part of the treatment of breast cancer. Relatively large differences were observed in external quality assessment (EQA) between the results that were obtained by different immunoassay technologies. Thus, we compared eight routinely employed immunoassay sets for the determination of MUC1 mucins in the serum: six closed automated systems (AxSYM, Centaur, ECi Vitros, Elecsys 2010, Immulite 2000 and Kryptor), and two IRMA kits (ELSA CIS and IRMA-mat Byk-Sangtec). Using all analytical systems, we measured identical groups of clinical samples complete with selected calibrator and control samples. The repeatability of measurements (presented as coefficients of variation) ranged from 0.7% (Kryptor) to 6.9% (Immulite 2000). Even though the cut-off values differ among various systems, no similar clinical efficacy appears to be attained. In the region of cut-off values, the highest specificity that was set as a standard was found for the AxSYM analyser, while the sensitivity was highest for the Elecsys 2010. Data from Bland-Altman differential plots suggest the presence of significant individual differences among individual samples, mainly in the region of high concentrations of MUC1 mucins. The parameters of Passing-Bablok regression show significant systematic differences between some of the analytical systems as well as an increase of the differences with increasing MUC1 mucin concentrations. The effect of the combination of antibodies used on the extent of differences among results obtained with individual systems is more obvious than the effect of the matrix of analysed materials.

Dissociation and immune dysregulation: a preliminary report

Recent evidence indicates that various types of interactions between nervous and immune system are important in pathogenesis of depression. These findings show that a significant role in developing depression play proinflammatory cytokines that may mediate its psychological and neurobiological manifestations. Great importance among these cytokines plays tumor necrosis factor alpha (TNF-a) and there is growing evidence that inflammatory processes related to depression may be influenced by psychological stress as well as organic inflammatory conditions. These findings suggest that specific influences related to traumatic stress and dissociation could be found in close relationship to increased level of cytokine TNF-a. In the present study we have performed psychometric measurement of depression (BDI-II), traumatic stress symptoms (TSC-40) and dissociation (DES), and immunochemical measure of serum TNF-a in 40 inpatients with unipolar depression (mean age 38.4±8.2). The results show that TNF-a is significantly related to DES (Spearman R= -0.36, p<0.05), but not to BDI-II and TSC-40. Results of the present study suggest that TNF-a alterations related to dissociation could present a specific process of immunomodulation that may be explained by mutual influences between stress and neuroimmune system.

Contents Vol. 194, 2011

Stem Cells and Tissue Engineering S.F. Badylak, Pittsburgh, Pa. E-Mail: badylaks@msx.upmc.edu U. Just, Kiel E-Mail: ujust@biochem.uni-kiel.de L.E. Niklason, New Haven, Conn. E-Mail: laura.niklason@yale.edu A. Ratcliffe, San Diego, Calif. E-Mail: anthonyratcliffe@synthasome.com A.M. Wobus, Gatersleben E-Mail: wobusam@ipk-gatersleben.de Tumor Cell Plasticity E. Thompson, Melbourne E-Mail: rik@medstv.unimelb.edu.au

Myelin basic protein in multiple sclerosis and other neurological disorders

Sirs: Myelin basic protein (MBP) is one of the specific proteins of the central nervous system (CNS). The gene for the MBP is expressed by oligodendrocytes and Schwann cells, and it represents 30 % of the protein component of myelin. When there is damage of the CNS, MBP or its peptides, which represent an important part of the myelin, can appear in the cerebrospinal fluid (CSF), blood and urine. According to some data from the literature, MBP or myelin basic protein-like material (MBPLM) levels in the CSF could be a marker of the damage of the myelin [2–4, 7]. We evaluated MBP levels in CSF and serum using radioimmunoassay (RIA) in the patients with multiple sclerosis (MS) and in patients with other neurological disorders: cerebrovascular accidents (CVA), CNS trauma, polyneuropathy and other disorders of the peripheral nervous system, non-purulent infections of the CNS, malignant meningeal infiltration, lumbar disc herniation, narcolepsy, dementia, and systemic autoimmune disorders. MS patients were divided according to the clinical course of the disease into relapsing-remitting form (RR) in relapse, RR in remission, secondary progressive (SP) or primary progressive (PP) form. 191 CSF and 51 serum samples were evaluated. Further, we established correlations of the MBP levels with the CSF cell count, CSF total protein (TP) level, albumin quotient, IgG, IgM and IgA indices, the presence of intrathecal immunoglobulin synthesis according to Reiber’s formula, the presence of oligoclonal IgG, and the presence of plasma cells and lipophages. MBP levels in the CSF were increased in 17 of 78 patients with MS (22 %) and in 2 of 16 patients with ON (13 %). CSF levels of MBP during relapse of the RR form of MS were increased in 9 of 29 patients (31 %), and this difference was statistically significant compared with the reference group. The lowest MBP levels in the CSF were found in the patients with the progressive form of MS (both primary and secondary progression), which were even lower than in normal controls (Table 1). MBP levels showed negative correlation with the duration of the disease, even in the RR subgroup of MS patients during relapse (P = 0.001). MBP levels in the CSF correlated positively with the cell count (P < 0.001), TP level (P < 0.001), albumin quotient (P < 0.001), IgM index (P = 0.004), and IgA index (P = 0.026). The levels of MBP in the CSF were significantly higher in the patients with the positive finding of two and more CSF-restricted oligoclonal IgG bands (OCBs). No correlation was found between MBP levels and the IgG index. Markedly increased MBP concentrations in the CSF and serum were found in CVA and CNS trauma. Normal or borderline MBP levels in serum and CSF were found in all the patients with other neurological disease. The significance of the MBP assessment in the CSF is controversial. The methodology used may be of importance: Ohta et al. [6] reported excellent correlation with the activity of the disease using an ELISA method. MBP levels in the CSF in the reference group were lower than those obtained by RIA, but in the range of highly elevated levels ELISA showed higher levels than RIA. In our study surprisingly high serum MBP – or MBP-like material (MBPLM) – were found with the RIA method. The presence of interfering substances in serum can be hypothesized. In accordance with the data from the literature [2, 7, 8, 9, 11] we conclude from our experience that the examination of MBP in the CSF LETTER TO THE EDITORS