PurposeAntifibrinolytics, used in cardiac surgery to abate postoperative blood loss, share anti-inflammatory properties by suppression of pro-inflammatory D-dimer and plasmin levels. Additional... Show morePurposeAntifibrinolytics, used in cardiac surgery to abate postoperative blood loss, share anti-inflammatory properties by suppression of pro-inflammatory D-dimer and plasmin levels. Additional drug specific immune modulating qualities are often mentioned in the discussion on which antifibrinolytic can best be used. To determine the extent and relevance of these effects, we investigated cytokine and growth factor plasma levels in cardiac surgery patients randomized to receive either tranexamic acid, aprotinin, or placebo. Corticosteroid-treated patients served to put the effects in perspective. MethodsUsing a biochip immunoassay, plasma of 36 cardiac surgery patients was quantified for 12 cytokines and growth factors, assessed preoperatively and 6, 12, 24, and 48h after the by Browse to Save" href="http://www.sciencedirect.com/science/article/pii/S1043466612007697#" mce_href="http://www.sciencedirect.com/science/article/pii/S1043466612007697#">start of cardiopulmonary bypass. Eight patients were treated with tranexamic acid, nine with aprotinin, and nine received placebo. Ten placebo-treated patients received corticosteroids. ResultsIL-1ß, IL-6, IL-8, IL-10, IFN-γ, TNF-α, VEGF, MCP-1, and EGF plasma concentrations significantly changed over time across all patients. Aprotinin-treated patients showed decreased pro-inflammatory TNF-α and peak MCP-1 plasma levels when compared with placebo. However, corticosteroids attenuated the inflammatory response to a much larger extent, lowering postoperative IL-6, IL-10, IFN-γ, and VEGF concentrations also. ConclusionsAprotinin attenuates postoperative pro-inflammatory levels TNF-α and MCP-1 whereas tranexamic acid does not. The majority of plasma proteins studied, however, were not affected by the use of antifibrinolytics when compared with placebo. A clinically relevant common anti-inflammatory effect through inhibition of fibrinolysis seems therefore unlikely. Highlights► Tranexamic acid and aprotinin hardly affect post-cardiac surgery cytokine levels. ► Only aprotinin significantly decreases postoperative plasma levels MCP-1 and TNF-α. ► When compared with corticosteroids, this effects seems of marginal importance. ► A common clinically relevant anti-inflammatory effect of antifibrinolytics seems unlikely. Show less
Giltay, E.J.; Enter, D.; Zitman, F.G.; Penninx, B.W.J.H.; Pelt, J. van; Spinhoven, P.; Roelofs, K. 2012
OBJECTIVE Low circulating levels of testosterone have been associated with major depression, but there is more limited evidence for differences in patients with anxiety disorders. The use of... Show moreOBJECTIVE Low circulating levels of testosterone have been associated with major depression, but there is more limited evidence for differences in patients with anxiety disorders. The use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants is associated with sexual side effects, warranting testing for interactions with testosterone. METHODS Data are from 722 male and 1380 female participants of The Netherlands Study of Depression and Anxiety (NESDA), who were recruited from the community, general practice care, and specialized mental health care. Depressive and anxiety diagnoses were assessed using the DSM-IV Composite International Diagnostic Interview. To smooth the episodic secretion, the four morning saliva samples per participant and the two evening samples were pooled before testosterone analysis. RESULTS Morning median testosterone levels were 25.2pg/ml in men and 16.2pg/ml in women, with lower evening levels of 18.2 and 14.1pg/ml, respectively. Significant determinants of testosterone levels were sex, age, time of the day, use of contraceptives, and smoking status. Female patients with a current (1-month) depressive disorder (effect size 0.29; P=0.002), generalized anxiety disorder (0.25; P=0.01), social phobia (0.30; P<0.001), and agoraphobia without panic disorder (0.30; P=0.02) had lower salivary testosterone levels than female controls. Higher testosterone levels were found in male and female participants using SSRIs than in non-users (effect size 0.26; P<0.001). CONCLUSION Salivary testosterone levels are lower in female patients with a depressive disorder, generalized anxiety disorder, social phobia, and agoraphobia as compared to female controls. SSRIs may increase salivary testosterone in men and women. Show less
Giltay, E.J.; Enter, D.; Zitman, F.G.; Penninx, B.W.J.H.; Pelt, J. van; Spinhoven, P.; Roelofs, K. 2012
The protein phosphatase calcineurin has been gradually revealing itself as the central controller of our immune response, although it is involved in a wide array of signaling pathways related to... Show moreThe protein phosphatase calcineurin has been gradually revealing itself as the central controller of our immune response, although it is involved in a wide array of signaling pathways related to cellular development and cell cycle progression. As such, calcineurin is an attractive, yet delicate, therapeutic target for the prevention of allograft rejection and treatment of several inflammatory skin conditions. However, calcineurin activity is not only sensitive to immunosuppressants such as cyclosporin A and tacrolimus, but also subject to modulation by reactive oxygen species. We have recently shown, both in vivo and in vitro, that UVA1 radiation suppresses calcineurin activity. In this paper, we present evidence that this activity loss is due to singlet oxygen and superoxide generated by photosensitization and show that a closely related phosphatase, PP2A, is not affected. Furthermore, a survey of this damage reveals oxidation of several Met and Cys residues as well as an overall conformational change. These findings provide a mechanistic basis for the hypothesis that UVA1 and calcineurin inhibitors both affect the same signal transduction pathway in skin. (C) 2011 Elsevier Inc. All rights reserved. Show less
Cortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present... Show moreCortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present study, associations were explored between CRP haplotypes with plasma CRP concentrations and basal salivary cortisol level. We included 266 physically healthy Caucasian subjects (103 females and 163 males) aged between 18 and 65 years of whom 94 had a psychiatric disorder in a genetic association study. Six tag single-nucleotide polymorphisms capturing the common genetic variation of the CRP gene were genotyped (i.e. rs2808628, rs2808630, rs1205, rs1800947, rs1417938, and rs3091244) to yield common CRP haplotypes. Plasma CRP concentrations, the salivary cortisol awakening response (CAR) (0, 30, 45, and 60?min after awakening), and the diurnal cortisol decline (11:00, 15:00, 19:00, and 23:00?h) were assessed for 2 days. rs2808628, rs1205, rs1417938, and rs3091244 showed expected associations not only with CRP concentrations, but also with salivary cortisol levels during the CAR. Five well-characterized CRP haplotypes were arranged in ascending order according to increasing CRP levels. There was an inverse linear association between CRP haplotypes and cortisol levels during the CAR, but no association with the diurnal cortisol decline. Hence, genetic variants in the CRP gene that are associated with lifetime plasma CRP levels were also associated with salivary cortisol levels after awakening, in basal, non-inflammatory conditions. Show less
The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety... Show moreThe Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety disorders. Continuous phenotypic dimensions may correlate better with underlying neuroendocrine dysregulations. We compared the categorical DSM-IV diagnoses with a dimensional approach in the same group of outpatients with depressive (n=36), anxiety (n=18), and comorbid depressive and anxiety (n=19) disorders, who were free of psychotropic medication, and in 36 healthy controls. The Mood and Anxiety Symptom Questionnaire (MASQ) was used to measure the three dimensions of the tripartite model, i.e., anhedonic depression, anxious arousal, and general distress. The salivary cortisol awakening response (CAR) (0, 30, 45, and 60 min after awakening), and diurnal cortisol decline (11:00 h, 15:00 h, 19:00 h, and 23:00 h) were analyzed for linear and nonlinear associations. The CAR showed statistically significant nonlinear relationships with two MASQ dimensions, i.e., anhedonic depression and general distress, but no differences between DSM-IV categories. The diurnal cortisol decline was linearly related to the MASQ dimensions anhedonic depression and general distress and significantly higher AUC(diurnal) levels and a steeper slope were found in depressive patients compared to controls using DSM-IV categories. The present study shows that linear and nonlinear associations with salivary cortisol are detected when using phenotypic dimensions and may be complementary to phenotypic DSM-IV categories when doing neuroendocrine research. Show less
Jacobs, G.; Grond, J. van der; Teeuwisse, W.; Langeveld, T.; Pelt, J. van; Verhagen, J.; ... ; Gerven, J.M.A. van 2010
The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus pituitary adrenal (HPA)... Show moreThe synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus pituitary adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis. (C) 2010 Elsevier B.V. and ECNP. All rights reserved. Show less
Dekter, H.E.; Romijn, F.P.H.T.M.; Temmink, W.P.M.; Pelt, J. van; Fijter, J.W. de; Smit, N.P.M. 2010
The mammalian target of rapamycin (mTOR) is an important mediator in the PI3K/AKT signaling pathway. mTOR is the target of immunosuppressive drugs, such as rapamycin and everolimus, that are used... Show moreThe mammalian target of rapamycin (mTOR) is an important mediator in the PI3K/AKT signaling pathway. mTOR is the target of immunosuppressive drugs, such as rapamycin and everolimus, that are used in transplant patients but also for the treatment of various cancers. We have developed a method for mTOR activity measurement in cell lysates that measures the phosphorylation of p70 S6 kinase by an enzyme linked immunosorbent assay (ELISA) protocol. Using an optimized lysis composition, activity could be measured in the peripheral blood mononuclear cells (PBMCs) isolated from blood. For the PBMCs, intra- and interassay variations of 7 and 10%, respectively, were found using one lot number of the kit. With different lot numbers, the interassay variation increased up to 21%. Activity remained constant for PBMC pool samples on storage for a period of more than 7 months. Activity could also be measured in CD3+ T-cells isolated from blood. In vitro experiments revealed maximum mTOR inhibition of 30% in PBMCs and 44% in T-cells. The in vitro inhibition in PBMCs could also be demonstrated by Western blotting. The mTOR activity measurements may be used to show in vivo inhibition in renal allograft patients during everolimus treatment and to study mTOR activity in various (tumor) cell types. (C) 2010 Elsevier Inc. All rights reserved. Show less
