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Biomedical subjects

C Erik Hack

Publications and source records attributed to C Erik Hack.

At least 19 recordsLinked to original sources
PubMed2006

Serum levels of mannose-binding lectin and the risk of future coronary artery disease in apparently healthy men and women.

OBJECTIVE: To determine the association between serum levels of mannose-binding lectin (MBL) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women nested in the EPIC-Norfolk cohort. Baseline concentrations of MBL were measured in serum samples of 946 patients who experienced a myocardial infarction or died of CAD during follow-up, and 1799 matched controls who remained free of CAD. Among men, median MBL levels were 1.63 ng/mL (interquartile range [IQR]: 0.59 to 3.80) in cases and 1.20 ng/mL (IQR: 0.48 to 3.37) in controls. Among women, median MBL levels were 1.02 ng/mL (IQR: 0.43 to 2.95) in cases and 1.01 ng/mL (IQR: 0.43 to 2.94) in controls. After adjustment, the odds ratio in men for future CAD was 1.59 (95% confidence interval [CI]: 1.09 to 2.32; P for linearity=0.01) for those in the highest quartile compared with those in the lowest quartile. In women no such relation was observed. CONCLUSIONS: Elevated levels of MBL are associated with an increased risk of future CAD in apparently healthy men but not in women. The sex difference merits further exploration.

Aged↗
PubMed2006

Granzyme B, a novel mediator of allergic inflammation: its induction and release in blood basophils and human asthma.

Histamine, leukotriene C4, IL-4, and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the makeup of granules of human basophils by inducing de novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6 to 24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and -independent activation. In vitro, there is a close parallelism between GzmB, IL-13, and leukotriene C4 production. In vivo, granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.

Antibodies, Monoclonal↗
PubMed2006

Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein.

C-reactive protein (CRP) is the major acute phase protein in humans. It has been shown that CRP interacts with factor H, an inhibitor of the alternative pathway of complement, and now we demonstrate binding of CRP to the fluid-phase inhibitor of the classical pathway, C4b-binding protein (C4BP). C4BP bound to directly immobilized recombinant CRP as well as CRP attached to phosphorylcholine. The binding was sensitive to ionic strength and was enhanced in the presence of calcium. C4BP lacking beta-chain and protein S, which is a form of C4BP increasing upon inflammation, bound CRP with higher affinity than the C4BP-protein S complex. The binding could not be blocked with mAbs directed against peripheral parts of the alpha-chains of C4BP while the isolated central core of C4BP obtained by partial proteolytic digestion bound CRP, indicating that the binding site for CRP is localized in the central core of the C4BP molecule. Furthermore, we found complexes in serum from a patient with an elevated CRP level and trace amounts of CRP were also identified in a plasma-derived C4BP preparation. We were also able to detect C4BP-CRP complexes in solution and established that C4BP retains full complement regulatory activity in the presence of CRP. In addition, we found that C4BP can compete with C1q for binding to immobilized CRP and that it inhibits complement activation locally. We hypothesize that CRP limits excessive complement activation on targets via its interactions with both factor H and C4BP.

Binding, Competitive↗
PubMed2006

Competitive binding of pentraxins and IgM to newly exposed epitopes on late apoptotic cells.

A random distribution of phospholipids among the inner and outer leaflet of the cell membrane occurs during apoptosis and is known as membrane flip-flop. Flip-flopped cells have binding sites for various plasma proteins, such as IgM and the pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP). In this study, we investigated whether pentraxins and IgM antibodies recognize the same binding sites on apoptotic cells, and whether phospholipids constitute these binding sites. Except for SAP which also bound to early apoptotic cells, pentraxins and IgM preferentially bound to late apoptotic cells. Competition experiments with different phosphatemonoesters revealed that CRP and SAP as well as part of the IgM bound to the phospholipids head groups, SAP mainly to phosphorylethanolamine, CRP to phosphorylcholine and phosphorylethanolamine and to a lesser extent to phosphorylserine, and IgM to phosphorylcholine and phosphorylserine. These results were confirmed in experiments in which proteins were adsorbed from plasma with artificial phospholipids particles. IgM and the pentraxins variably competed for the same binding sites on late apoptotic cells, SAP having the highest and CRP the lowest apparent affinity. We conclude that CRP, SAP, and part of the IgM bind to the phospholipid head groups exposed on apoptotic cells. This shared specificity as well as their shared capability to activate complement, suggest that IgM and the pentraxins CRP and SAP exert similar functions in the removal of apoptotic cells.

Apoptosis↗
PubMed2006

Detection of a soluble form of BACE-1 in human cerebrospinal fluid by a sensitive activity assay.

BACKGROUND: Formation of deposits of the insoluble amyloid beta-peptide is believed to be causally related with neurodegeneration in Alzheimer disease (AD). The beta-peptide originates from a larger amyloid precursor protein (APP) by the action of proteolytic enzymes. The first proteolytic event leading to amyloid formation is the cleavage of APP by the membrane-bound aspartyl protease BACE-1, also known as memapsin-2. Inhibition of BACE-1 is thought to be a therapeutic approach to AD. Measuring BACE-1 activity in biological samples would be useful to elucidate the mechanism of AD and for development of AD drugs. METHODS: We developed a sensitive and specific activity assay for BACE-1. The assay is based on a genetically engineered proenzyme that is specifically activated by BACE-1. The resulting active enzyme is measured with a chromogenic substrate. The use of 2 coupled reactions produces a detection limit as low as 0.4 pmol/L. RESULTS: The assay detected BACE-1 activity in extracts of human brain tissue as well as, unexpectedly, in human cerebrospinal fluid (CSF). Gel electrophoresis and Western blotting identified the BACE-1 present in CSF as a truncated soluble form of the originally membrane-bound BACE-1. CONCLUSION: Detection of the soluble form of BACE-1 in CSF, a relatively easily accessible biological fluid, may be useful for monitoring the effects of drug candidates in vivo and may have diagnostic or prognostic applications.

Amyloid Precursor Protein Secretases↗
PubMed2006

Factor XIII in severe sepsis and septic shock.

OBJECTIVE: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. Thus, clot stability might be a critical issue in the development of multiple organ dysfunction syndrome. Activated FXIII (FXIIIa) forms stable fibrin clots by covalently cross-linking fibrin monomers. Therefore, we investigated the impact of FXIII antigen and activity levels on disease severity and fatality in sepsis patients. PATIENTS AND METHODS: FXIII subunit A (FXIIIA) and FXIII cross-linking activity (FXIIICA) were measured in 151 controls, in 32 patients with severe sepsis and 8 with septic shock. In addition, FXIII subunit B (FXIIIB) was measured in the sepsis patients. Moreover, clotting parameters were determined. RESULTS: Patients suffering from sepsis (n=40) had significantly (p<0.005) lower FXIIIA levels (median [range]: 36.5% [8.8-127.4%]) and FXIIICA levels (76.5% [9.4-266%]) as compared to healthy controls (n=151, 119% [31.3-283.2] and 122.4% [40.6-485.3], respectively). No difference in FXIIIA, FXIIIB and FXIIICA levels between survivors and non-survivors, nor between patients with severe sepsis and septic shock was found. The specific activity of FXIII (FXIIICA/FXIIIA, SA(FXIII)) was significantly (p<0.001) higher in sepsis patients (2.0 [0.8-5.3]) as compared to healthy controls (1.0 [0.4-5.1]). SA(FXIII) significantly (p<0.05) increased with fatality (non-survivors [n=13] vs. survivors [n=27]: 3.3 [1.2-5.0] vs. 1.9 [0.8-5.3]) and disease severity (septic shock vs. severe sepsis: 3.4 [1.8-4.3] vs. 1.9 [0.8-5.3]). CONCLUSION: We show decreased FXIIICA and FXIIIA levels, but higher SA(FXIII) in sepsis as compared to controls. Increased SA(FXIII) correlates with disease severity and fatality in sepsis patients.

Factor XIIIa↗
PubMed2006

Neutrophil responsiveness to IgG, as determined by fixed ratios of mRNA levels for activating and inhibitory FcgammaRII (CD32), is stable over time and unaffected by cytokines.

We tested the hypothesis that the ratio between the activating and inhibitory Fcgamma receptor type II (FcgammaRII) in neutrophils determines their responsiveness to immune complexes. We measured mRNA levels of FcgammaRII isoforms and observed differences in the ratio of FcgammaRIIa to FcgammaRIIb2 mRNA in granulocytes of 50 white and 10 black healthy volunteers, and found 4 discrete groups of ratios (ie, 4:1; 3:1, 2:1, or 1:1). The response to either dimeric IgG or aggregated IgG (aIgG) was assessed. Up-regulation of CD11b on the surface as well as the elastase release was significantly more pronounced in neutrophils with a high FcgammaRIIa/FcgammaRIIb2 mRNA ratio of 4:1 compared with a 2:1 or 1:1 ratio. Individual ratios as well as the functional responsiveness of neutrophils were constant over time, as was tested over 12 months. Neutrophil stimulation with various agents in vitro did not alter the FcgammaRIIa/FcgammaRIIb2 mRNA ratio in the neutrophils of these donors, in clear contrast to the findings in their mononuclear cells. We found a strong association between the 2B.4 haplotype of the FCGR2B promoter with increased transcriptional activity in individuals with 1:1 ratios and the more common low-expression 2B.1 haplotype in individuals with FcgammaRIIa/FcgammaRIIb2 mRNA ratios of 2:1, 3:1, or 4:1.

Adolescent↗
PubMed2006

Evidence that complement protein C1q interacts with C-reactive protein through its globular head region.

C1q acts as the recognition unit of the first complement component, C1, and binds to immunoglobulins IgG and IgM, as well as to non-Ig ligands, such as C-reactive protein (CRP). IgG and IgM are recognized via the globular head regions of C1q (C1qGR), whereas CRP has been postulated to interact with the collagen-like region (C1qCLR). In the present study, we used a series of nine mAbs to C1q, five directed against C1qGR and four against C1qCLR, to inhibit the interaction of C1q with CRP. The F(ab')(2) of each of the five mAbs directed against C1qGR inhibited binding of C1q to polymerized IgG. These five mAbs also successfully inhibited the interaction of C1q with CRP. Moreover, these five mAbs inhibited C1 activation by CRP as well as by polymerized IgG in vitro. In contrast, none of the four mAbs against C1qCLR inhibited C1q interaction with CRP or IgG, or could reduce activation of complement by CRP or polymerized IgG. These results provide the first evidence that the interaction of C1q with CRP or IgG involves sites located in the C1qGR, whereas sites in the CLR do not seem to be involved in the physiological interaction of C1q with CRP.

Antibodies, Monoclonal↗
PubMed2006

Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency.

BACKGROUND: Administration of C1-inhibitor concentrate is effective for prophylaxis and treatment of severe angioedema attacks caused by C1-inhibitor deficiency. The concentrate should be administered intravenously and hence needs to be administered by health care professionals, which might cause considerable delay in treatment and inconvenience for patients. OBJECTIVE: The aim of this study was to investigate the feasibility, efficacy, and safety of on-demand and prophylactic self-administration of C1-inhibitor concentrate in patients with frequent attacks of angioedema. METHODS: Patients with hereditary or acquired C1-inhibitor deficiency who had very frequent angioedema attacks were trained to self-administer C1-inhibitor concentrate. The study consisted of 31 patients using on-demand treatment and 12 patients using prophylaxis with C1-inhibitor concentrate. Mean follow-up was 3.5 years. RESULTS: All patients were capable of self-administering the concentrate, with technical failure rates of self-injection being less than 2%. Times between the onset of the attack and the initiation of relief or complete resolution of symptoms in the on-demand group were significantly shortened (2.2 hours and 7.9 hours, respectively) compared with the situation before the start of self-administration. In the prophylaxis group self-administration of C1-inhibitor concentrate decreased the angioedema attack rate from 4.0 to 0.3 attacks per month. CONCLUSION: Intravenous self-administration of C1-inhibitor concentrate is a feasible and safe option and results in more rapid and more effective treatment or prevention of severe angioedema attacks in patients with C1-inhibitor deficiency. CLINICAL IMPLICATIONS: Self-administration of C1-inhibitor concentrate could be a valuable and convenient treatment modality to prevent or treat angioedema attacks in patients with C1-inhibitor deficiency.

Adult↗
PubMed2006

P-selectin- and CD63-exposing platelet microparticles reflect platelet activation in peripheral arterial disease and myocardial infarction.

BACKGROUND: Platelet-derived microparticles (PMPs) are generally considered a marker of platelet activation in cardiovascular disease. We studied the extent to which PMP subpopulations parallel platelet activation in vitro and in vivo. METHODS: Using flow cytometry, we analyzed PMP subpopulations from resting and activated platelets in vitro (n = 6) as well as from plasma samples of patients with stable angina, peripheral arterial disease, or myocardial infarction [non-ST-elevation (NSTEMI) and ST-elevation (STEMI)] and from older, age- and sex-matched and young healthy individuals [n = 10 for all groups except NSTEMI (n = 11)]. Coagulation markers prothrombin fragment F(1 + 2) and thrombin-antithrombin complexes were determined by ELISA. The PMP-associated fraction of soluble (s)P-selectin was estimated by ELISA. RESULTS: In vitro, stimulation of platelets with thrombin receptor-activating peptide (15 micromol/L) or the calcium ionophore A23187 (2.5 micromol/L) increased fractions of both platelets and PMPs exposing P-selectin or CD63 (P <0.001 for all). Whereas the number of PMPs released by A23187-stimulated platelets increased significantly (P <0.001), the number of PMPs released from thrombin receptor-activating peptide-stimulated platelets remained constant (P >0.05). Ex vivo, numbers of circulating PMPs were comparable in all groups. Compared with young persons, P-selectin-exposing PMPs were increased in older persons (P = 0.02) and were further increased in patients with NSTEMI (P = 0.007) and STEMI (P = 0.045). CD63-exposing PMPs were increased in patients with peripheral arterial disease (P = 0.041), NSTEMI (P = 0.001), and STEMI (P = 0.049). Subpopulations exposing P-selectin or CD63 correlated with each other (r = 0.581; P <0.001), but neither correlated with the plasma concentrations of F(1 + 2) or thrombin-antithrombin complexes. The PMP-associated fraction of sP-selectin constituted only 2.2 (4.7)% [mean (SD)] of total sP-selectin. CONCLUSIONS: PMP subpopulations reflect platelet activation status better than the total number of PMPs. Increased concentrations of circulating PMP subpopulations are found in aging, and further increases are encountered in peripheral arterial disease and myocardial infarction.

Adult↗
PubMed2006

Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q-C4 complexes as novel activation products.

OBJECTIVE: Novel activation products that are stable and minimally susceptible to in vitro artefacts have recently been described in the classical complement pathway. The present study assessed circulating levels of these products, i.e., covalent complexes between the recognition molecule of the classical pathway (C1q) and activated C4, in plasma samples from patients with rheumatoid arthritis (RA) to establish the relationship between these levels and the clinical and immunologic parameters in these patients. METHODS: C1q-C4 levels were measured in plasma samples from 41 patients with active RA and 43 patients with inactive RA. These levels were related to other complement activation products and to disease activity according to the Disease Activity Score in 28 joints (DAS28), using Spearman's rank correlations. RESULTS: C1q-C4 plasma levels were significantly higher in patients with active RA as compared with patients with RA in clinical remission (median 3.3 arbitrary units [AU], range 0.4-13.4 versus 1.7 AU, range 0.2-5.5; P=0.0001), suggesting that activation of the classical complement pathway reflects disease activity. This was supported by a significant correlation between C1q-C4 levels and the DAS28 (r=0.398, P=0.0002). Levels of other complement activation products, such as activated C4 (C4b/c), were also significantly elevated in patients with active disease compared with patients with inactive disease (P=0.03), and were correlated with C1q-C4 levels (r=0.329, P=0.002). Levels of C1q-C4 complexes were higher in synovial fluid samples than in plasma samples from the 4 patients tested. CONCLUSION: Systemic complement activation via the classical pathway in patients with RA correlates with disease activity. These results indicate that C1q-C4 complexes may be used as a biomarker for RA.

Adult↗
PubMed2006

Phosphorylcholine coating of bypass systems used for young infants does not attenuate the inflammatory response.

BACKGROUND: Contact of blood with the artificial surfaces of the cardiopulmonary bypass (CPB) system is considered to be a main cause of complement activation. Improving the biocompatibility of the system by reduction of contact activation of blood elements and thereby producing less inflammatory response is evidently desired, especially for neonates and infants who are more susceptible to the deleterious effects of CPB. A phosphorylcholine coating, Phisio, is designed to mimic the natural interfaces of blood. The aim of this study is to compare the influence of a phosphorylcholine-coated CPB system versus an uncoated CPB system on complement activation and clinical outcomes. METHODS: In this prospective, randomized, blind, one-center study, 28 neonates and infants with a bodyweight between 3 and 6 kg who were undergoing cardiopulmonary bypass were divided in two groups, the phosphorylcholine group and the control group. Thirteen patients were assigned to the phosphorylcholine group and 15 patients to the control group. Patients with Down syndrome, prematurity, cyanosis, or reoperation were excluded. Complement factor C3b/c, human neutrophil elastase (HNE), interleukin-6, and C-reactive protein were measured before, during, and after CPB. Duration of intensive care stay, ventilation time, highest body temperature, and inotropic medication were the clinical variables. RESULTS: No significant differences were found between the groups for complement factor C3b/c, HNE, interleukin-6, or C-reactive protein during and after CPB. No clinical differences were observed between the groups. CONCLUSIONS: Phosphorylcholine coating does not attenuate the complement activation during CPB in neonates and infants.

Cardiopulmonary Bypass↗
PubMed2006

Structure and function of C1-inhibitor.

C1-INH belongs to the family of serpins. Structural studies have yielded a clear understanding of the biochemical principle underlying the functional activities of these proteins. Although the crystal structure of C1-INH has yet to be revealed, homology modeling has provided a three-dimensional model of the serpin part of C1-INH. This model has helped us understand the biochemical consequences of mutations of the C1-INH gene as they occur in patients who have HAE. The structure of the N-terminal domain of C1-INH remains unknown; however, this part of the molecule is unlikely to be important in the inhibitory activity of C1-INH toward its target proteases. Mutations in this part have not been described in patients who have HAE, except for a deletion containing two cysteine residues involved in the stabilization of the serpin domain. Recent studies suggest some anti-inflammatory functions for this N-terminal part, possibly explaining the effects of C1-INH in diseases other than HAE.

Amino Acid Sequence↗
PubMed2006

Inhibition of sPLA2-IIA, C-reactive protein or complement: new therapy for patients with acute myocardial infarction?

Reperfusion of ischemic myocardium after acute myocardial infarction (AMI) induces a local activation of inflammatory reactions that results in ischemia/reperfusion (I/R)-injury. I/R-injury contributes considerably to the total cell damage in the heart after AMI. Secretory phospolipase A2-IIA (sPLA2-IIA), C-reactive protein (CRP) and complement are inflammatory mediators that have been demonstrated to play key roles in I/R injury. From studies by us and others a mechanism emerged in which sPLA2-IIA binds to reversibly damaged cardiomyocytes and subsequently induces cell death, partly by potentiating binding of CRP and subsequent complement activation. Next to this, sPLA2-IIA also has a direct toxic effect, independent of CRP or complement. Therefore, these studies indicate a crucial role of inflammatory mediators in ischemia/reperfusion injury. This review will focus on the pathogenic effects of sPLA2-IIA, CRP and complement and on the putative therapeutic effects of inhibitors of these inflammatory mediators in acute myocardial infarction.

Animals↗
PubMed2005

C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993-2003.

INTRODUCTION: Measurement of C-reactive protein (CRP) levels has been proposed as a useful marker to improve the prediction of future coronary artery disease (CAD) risk, but this notion has been challenged recently. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women. The odds ratio (OR) for future CAD incidence was 2.49 (95% CI=2.02-3.08, p for linearity <0.0001) unadjusted, and 1.66 (95% CI=1.31-2.12, p for linearity <0.0001), after adjustment for classical cardiovascular risk factors, for top versus bottom quartile of the CRP distribution. Notably, the risk factor adjusted predictive value was substantially stronger for fatal CAD (OR=2.92, 95% CI=1.83-4.67, p for linearity <0.0001) than for non-fatal CAD (OR=1.25, 95% CI=0.93-1.66, p for linearity=0.06). CRP levels were among the strongest predictors of CAD incidence and mortality. CRP levels remained a statistically significant predictor of future CAD, even after adjustment for the Framingham risk score. CONCLUSIONS: In this British cohort with risk factor levels representative of a contemporary Western population, CRP concentration was among the strongest predictors of CAD incidence and mortality. We suggest that current guidelines on CRP measurement in clinical practice should be based on contemporary and representative populations.

Aged↗
PubMed2005

The granzyme B inhibitor SERPINB9 (protease inhibitor 9) circulates in blood and increases on primary cytomegalovirus infection after renal transplantation.

SERPINB9 is the only known human intracellular inhibitor of granzyme B (GrB), the effector molecule in immunity against cytomegalovirus (CMV) and in renal allograft rejection. Therefore, using specific enzyme-linked immunosorbent assays, we addressed the presence of circulating SERPINB9 during primary CMV infection, subclinical rejection, acute rejection, and uncomplicated posttransplantation course. Soluble (s) SERPINB9 circulates in blood and increases on primary CMV infection. This increase was significantly higher in symptomatic than in asymptomatic patients. In contrast, sSERPINB9 levels did not change in response to subclinical or acute rejection. We demonstrated the presence of circulating sSERPINB9/sGrB complexes, which suggests that SERPINB9 has extracellular functions as well.

Adult↗
PubMed2005

Elastase and granzymes during meningococcal disease in children: correlation to disease severity.

OBJECTIVE: To investigate the levels of human neutrophil elastase and lymphocyte-derived granzymes A and B in relation to disease severity in children with meningococcal disease. DESIGN: Clinical observational cohort study. SETTING: Paediatric intensive care unit. PATIENTS: All patients with meningococcal disease during the study period were included. MEASUREMENTS AND RESULTS: Blood sampling was done on the day of admission and on days 3 and 7. Assays for elastase and granzymes were done with ELISA. Sixty-one patients were included: 19 having distinct meningitis; 17 meningitis and shock; and 25 fulminant septicaemia. On admission levels of elastase were increased in all patients, being highest in those with fulminant septicaemia and lowest in those with distinct meningitis. Granzyme A (although marginally) and granzyme B levels were only increased in patients with shock. In 20 of the 28 patients admitted for > or = 3 days elastase decreased from admission ("rapid-decrease" group). In the remaining 8 patients, elastase started to decrease after 2 days ("slow-decrease" group). Patients of the "slow-decrease" group had a higher temperature up to day 4, needed more respiratory support (mean airway pressure in cm H2O on days 3 and 4: p=0.02 and p<0.01, respectively), and more circulatory support (>2 inotropic agents on day 3; p=0.04) compared with the "rapid-decrease" group. CONCLUSIONS: Human neutrophil elastase and granzyme B are related with disease severity during the initial phase of meningococcal disease and prolonged neutrophil activation is associated with the extent of organ dysfunction during the period thereafter.

Child↗