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Biomedical subjects

A Roos

Publications and source records attributed to A Roos.

At least 19 recordsLinked to original sources
PubMed2006

Mannose-binding lectin levels during pregnancy: a longitudinal study.

BACKGROUND: Pregnancy is associated with changes in the immune system. Although previous studies have focussed mainly on adaptive immunity, there are indications that components of innate immunity, such as mannose-binding lectin (MBL), are associated with pregnancy outcome. Although this would suggest that pregnancy also involves adaptations in innate immunity, there are few studies in this area. Therefore, we aimed to determine whether MBL concentrations and the following steps in complement pathway activation are influenced by pregnancy. METHODS: MBL and Ficolin-2 concentrations, MBL-MBL-associated serine protease (MASP) complex activity, MBL pathway activity and classical complement pathway activity were determined by enzyme-linked immunosorbent assay (ELISA) in sera from pregnant women (n=32) during each trimester and post-partum. MBL genotyping was performed by PCR. RESULTS: During pregnancy, MBL concentrations increased to 140% [interquartile range (IQR) 116-181%, P < 0.0001]. This increase was already present at 12 weeks of pregnancy and was most pronounced in the high-production AA-genotype. Directly Post-partum MBL concentrations dropped to 57% of baseline (IQR 44-66%, P < 0.0001). Variations in MBL levels were reflected by similar changes in the following steps of complement activation, r > 0.93 (P < 0.01). Ficolin-2 levels and classical complement pathway activity were not similarly influenced by pregnancy. CONCLUSIONS: Pregnancy and the post-partum period profoundly influence MBL serum concentration and MBL complement pathway activity.

Adult↗
PubMed2006

Submicroscopic unbalanced translocation resulting in del10p/dup13q detected by subtelomere FISH.

Chromosomal rearrangements involving the (sub)telomeres are an important cause of human genetic diseases: with the development of advanced molecular cytogenetic methods they have been identified as a major cause of mental retardation and/or congenital malformation syndromes. We identified a cryptic unbalanced de novo translocation 10p/13q by subtelomere FISH in a boy with mental and growth retardation (karyotype: 46,XY,der(10)t(10;13)(p15.1;q34)(D10S2488-,D13S296+)). Craniofacial dysmorphisms included frontal bossing, epicanthal folds, long philtrum, thin upper lip, short nose, mild retrognathy and a flat midface. In addition the patient had ASDII, a pyloric stenosis, bilateral inguinal hernias and cryptorchidism. His psychomotor development was significantly delayed. Microsatellite typing revealed the paternal origin of the two chromosomes involved in the rearrangement. By comparing our case with previously published patients with similar aberrations we conclude that the congenital malformations in our case are associated with the partial 10p deletion. The craniofacial features might be attributed to the 13q duplication. The identification of a 10p/13q translocation in our case highlights the importance of searching for cryptic subtelomeric imbalances in mentally retarded patients and helps to further delineate genotype-phenotype correlations in rare chromosomal disturbances.

Abnormalities, Multiple↗
PubMed2006

A pathogenic role for secretory IgA in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by deposits of IgA in the renal mesangium. It is thought that deposits of IgA mainly involve high molecular weight (HMW) IgA1. However, there is limited information on the exact composition of HMW IgA in these deposits. In this study, we investigated the presence of secretory IgA (SIgA) in human serum and in the glomerular deposits of a patient with IgAN. Furthermore, we analyzed the interaction of SIgA with mesangial cells. With enzyme-linked immunosorbent assay, SIgA concentrations in the serum of IgAN patients and healthy controls were measured. Both patients and controls had circulating SIgA that was restricted to the HMW fractions. Patients tended to have higher levels of SIgA, but this difference was not significant. However, in patients with IgAN, high serum SIgA concentrations were associated with hematuria. Binding of size-fractionated purified serum IgA and SIgA to mesangial cells was investigated with flow cytometry. These studies showed stronger binding of SIgA to primary mesangial cells compared to binding of serum IgA. Importantly, after isolation and elution of glomeruli from a nephrectomized transplanted kidney from a patient with recurrent IgAN, we demonstrated a 120-fold accumulation of SIgA compared to IgA1 in the eluate. In conclusion, we have demonstrated that SIgA strongly binds to human mesangial cells, and is present in significant amounts in serum. Furthermore, we showed that SIgA is accumulated in the glomeruli of an IgAN patient. These data suggest an important role for SIgA in the pathogenesis of IgAN.

Enzyme-Linked Immunosorbent Assay↗
PubMed2006

Design of a complement mannose-binding lectin pathway-specific activation system applicable at low serum dilutions.

Recently we showed that alternative pathway (AP) amplification was responsible for more than 80% of specific classical pathway-induced terminal pathway activation under physiological conditions. The present study aimed to design a system for specific lectin pathway (LP) activation applicable at low serum dilutions with a fully functional AP. Comparison between activation of normal human serum (NHS), a mannose-binding lectin (MBL) homozygous D/D-deficient serum, and sera deficient in C1q and C2, all diluted 1 : 2, was essential to document optimal conditions for LP specificity. Mannan on the solid phase of enzyme-linked immunosorbent assay (ELISA) plates was used for activation, showing 0.5 microg mannan/well to give optimal conditions because at this concentration a good signal was preserved for C4 and TCC deposition in NHS, whereas the C3 deposition observed in C2-deficient serum at higher mannan concentrations reached nadir at 0.5 microg/well, indicating a lack of direct AP activation under these conditions. Pooled NHS and C1q-deficient serum gave the same degree of C4 and terminal complement complex (TCC) deposition, whereas deposition of these products was not obtained with MBL-deficient serum. Reconstitution with purified MBL, however, restored the depositions. A blocking anti-MBL monoclonal antibody (mAb) completely abolished the complement deposition, in contrast to a non-inhibiting anti-MBL mAb. Activation of C2-deficient serum induced C4 deposition similar to NHS, but negligible deposition of C3 and TCC, confirming the lack of direct activation of AP. Thus, this assay is unique in being LP-specific at low serum dilution and thus particularly suitable to study LP activation mechanisms and the role of AP amplification under physiological conditions.

Antibodies, Monoclonal↗
PubMed2005

Evaluation of cardiac ischaemia in cardiac asymptomatic newly diagnosed untreated patients with primary hypothyroidism.

BACKGROUND: Hypothyroidism is regarded as a risk factor for coronary artery disease. Possible factors involved in this association are hyperlipidaemia and hypertension, both occurring with increased frequency in hypothyroid patients. The aim of our study was to evaluate signs/symptoms of cardiac ischaemia in untreated hypothyroid patients without angina pectoris, since this has never been performed before. METHODS: 51 consecutive cardiac asymptomatic patients (mean age 47, range 22 to 86 years) were studied by dobutamine stress echocardiography and bicycle ergometry. RESULTS: Mean values of body mass index, resting heart rate and blood pressure were 28.5 kg/m2, 68 beats/min and 129/81 mmHg, respectively. Median TSH was 51.9 mU/l, mean FT4 7.3 +/- 2.9 pmol/l (mean +/- SD), TT3 1.6 +/- 0.6 nmol/l and total cholesterol was 5.8 +/- 1.6 mmol/l. None of the patients had symptoms of angina pectoris during dobutamine stress echocardiography or bicycle ergometry and no evidence of myocardial ischaemia was demonstrated. Exercise tolerance, assessed by dividing the maximum achieved workload by the target performance (depending on body height, sex and age), was diminished in 38% of patients, and significantly related to the degree of hypothyroidism. CONCLUSION: No angina pectoris or cardiac ischaemia at exercise or stress was found in cardiac asymptomatic hypothyroid patients. The precise role of hypothyroidism as a risk factor for coronary artery disease should be further elucidated.

Adult↗
PubMed2004

Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA.

Primary defence against invading microorganisms depends on a functional innate immune system and the complement system plays a major role in such immunity. Deficiencies in one of the components of the complement system can cause severe and recurrent infections, systemic diseases, such as systemic lupus erythematosus (SLE) and renal disease. Screening for complement deficiencies in the classical or alternative complement pathways has mainly been performed by haemolytic assays. Here, we describe a simple ELISA-based format for the evaluation of three pathways of complement activation. The assays are based on specific coatings for each pathway in combination with specific buffer systems. We have standardized these assays and defined cut off values to detect complement deficiencies at the different levels of the complement system. The results demonstrate the value of these ELISA-based procedures for the functional assessment of complement deficiencies in clinical practice. The assay is now available commercially in kit form.

Complement Activation↗
PubMed2004

[The role of the complement system in the defence against infections and new ways of assessing the activation routes].

The complement system is of major importance in the defence against infections. Deficiencies in one of the three pathways of activation of the complement system can cause serious infections; the classical pathway, the alternative pathway and the lectin pathway. A new ELISA assay has been developed to enable the assessment of the functional activity of the whole lectin pathway and to determine the classical and the alternative pathway functional activity in a simple uniform design.

Bacterial Infections↗
PubMed2004

A role for mannose-binding lectin dysfunction in generation of autoantibodies in systemic lupus erythematosus.

OBJECTIVE: To investigate the possible association of the mannose binding lectin (MBL) pathway of complement activation with different disease parameters and disease activity in patients with systemic lupus erythematosus (SLE). METHODS: MBL genotype, MBL serum concentration, MBL complex activity and MBL pathway activity were assessed in 53 patients. The activity of the MBL-MASP complex was assessed on the basis of its ability to activate exogenous C4. For MBL pathway activity the formation of the terminal complex of complement activation (C5b-9) was measured. Results were analysed in relation to clinical variables and autoantibody profiles in these patients. RESULTS: MBL complex activity and MBL pathway activity were both reduced in patients carrying MBL variant alleles. Anticardiolipin and anti-C1q autoantibodies were observed significantly more frequently in patients with MBL variant alleles. Furthermore, the presence of these autoantibodies was associated with a decreased MBL concentration and function. In contrast, anti-MBL autoantibodies were not found in patients with MBL variant alleles, possibly related to impaired binding of variant MBL to apoptotic material. CONCLUSION: In patients with SLE, a reduced functional activity of the MBL pathway of complement, in relation to expression of MBL variant alleles, is associated with increased levels of autoantibodies against cardiolipin and C1q, but not against MBL. We hypothesize that an enhanced production of autoantibodies may be related to disturbed clearance of apoptotic material due to impaired MBL function.

Adult↗
PubMed2004

Anti-C1q autoantibodies in murine lupus nephritis.

Autoantibodies against C1q can be found in the circulation of patients with several autoimmune diseases including systemic lupus erythematosus (SLE). In SLE there is an association between the occurrence of these antibodies and renal involvement. How anti-C1q autoantibodies contribute to renal disease is currently unknown. Cohorts of MRL-lpr mice, which are known to develop age-dependent SLE-like disease, were used to study the relationship between levels of anti-C1q autoantibodies and renal disease. We collected serum, urine and renal tissue and analysed autoantibodies, complement levels and renal deposition as well as renal function. At 2 months of age all mice already had elevated levels of anti-C1q autoantibodies, and elution of kidneys revealed the presence of these antibodies in renal immune deposits in MRL-lpr mice and not in control MRL+/+ mice. In conclusion, anti-C1q antibodies are already present in serum and immune deposits of the kidney early in life and therefore can play a role in nephritis during experimental SLE-like disease in mice.

Animals↗
PubMed2003

Autoantibodies against mannose-binding lectin in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), autoantibodies directed against complement components of the classical pathway, especially against C1q, are associated with severe disease and are of prognostic value for flares of lupus nephritis. Mannose-binding lectin (MBL), the recognition unit of the MBL pathway of complement activation, has structural similarities to C1q. Deficiencies of MBL have been shown to predispose to the development of SLE and to influence the course of the disease. We hypothesized that the presence of autoantibodies to MBL, analogous to autoantibodies to C1q in patients with SLE, may contribute to disease development. The occurrence of anti-MBL autoantibodies was assessed by enzyme-linked immunosorbent assay (ELISA) of 68 serum samples from 20 patients with SLE and in serum from 70 healthy controls. Levels of antibodies directed against MBL were significantly higher in patients with SLE compared to healthy subjects. No significant difference was found between patients with active disease compared to those with inactive disease. While the occurrence of anti-C1q autoantibodies was associated with renal involvement, no such relationship was found for anti-MBL autoantibodies. A significant correlation was found between anti-MBL and anti-C1q antibody levels. The level of anti-MBL antibodies was negatively correlated with MBL-complex activity of circulating MBL. Anti-MBL autoantibodies were of the immunoglobulin G (IgG) isotype and the binding site of IgG anti-MBL was located in the F(ab')2 portion. We conclude that anti-MBL are present in sera from SLE patients and influence the functional activity of MBL.

Adult↗
PubMed2003

[A novel hirudin coating of vascular endoprostheses: experimental results].

PURPOSE: Does hirudin coating improve the patency of iliac artery endoprostheses in comparison to non-hirudin-coated endoprostheses? MATERIALS AND METHODS: Nitinol stents and stentgrafts covered with polytetrafluoroethylene (PTFE) were coated with the polymer polyamino-p-xylylene-co-poly-p-xylylene using chemical vapor deposition (CVD) technique. Hirudin was covalently bound to the surface of the endoprostheses via the amino-group. External factors (mounting of the prosthesis, sterilization, storage time and temperature, release) affecting the hirudin activity were evaluated in vitro. Five types of prostheses were compared in vivo: (1) plain and (2) CVD- and hirudin-coated stents; (3) plain, (4) CVD-coated, and (5) CVD- and hirudin-coated PTFE-stentgrafts. In 20 sheep, 16 protheses of each type were inserted in arteries pretreated with a Fogarty maneuver. The animals were followed for either 1 (n = 10) or 6 (n = 10) months. Immediately after implantation and after 1, 3, and 6 months, intravascular ultrasound (IVUS) and angiography were performed. The vascular specimens were analyzed histologically. RESULTS: Within 10 weeks, the hirudin activity of coated stents dropped 60 % due to external factors; the activity of coated PTFE stentgrafts dropped 20 %. After 1, 3, and 6 months, IVUS and histology revealed a significantly reduced patency of the hirudin-coated stentgrafts compared to the other prostheses. Only IVUS showed a significantly reduced patency of hirudin coated stents after 1 and 3 months compared to plain and CVD-coated PTFE-stentgrafts. The reduced patency was caused by neointimal hyperplasia. CONCLUSIONS: In an experimental setting, hirudin coating did not improve the patency of vascular endoprostheses.

Angiography↗
PubMed2002

Are the strokes in moyamoya syndrome associated with Down syndrome due to protein C deficiency?

Moyamoya syndrome has occasionally been seen in association with Down syndrome. We report a child with moyamoya syndrome and Down syndrome who was admitted with repeated episodes of strokes; his magnetic resonance imaging and magnetic resonance angiography findings confirmed the presence of occlusive cerebrovascular disease with basal collateral vessels. His protein C levels were significantly decreased during the stroke. Complete clinical recovery was seen during follow-up. This raises the possibility of a link between protein C deficiency and Down syndrome with moyamoya syndrome.

Child, Preschool↗
PubMed2002

Comparison of predictive models for postoperative nausea and vomiting.

BACKGROUND: In order to identify patients who would benefit from prophylactic amtiemetics, six predictive models have been described for the risk assessment of postoperative nausea and vomiting (PONV). This study compared the validity and practicability of these models in patients undergoing general anaesthesia. METHODS: Data were analysed from 1566 patients who underwent balanced anaesthesia without prophylactic antiemetic treatment for various types of surgery. A systematic literature search identified six predictive models for PONV. These models were compared with respect to validity (discriminating power and calibration characteristics) and practicability. Discriminating power was measured by the area under the receiver operating characteristic curve (AUC) and calibration was assessed by weighted linear regression analysis between predicted and actual incidences of PONV. Practicability was assessed according to the number of factors to be considered for the model (the fewer factors the better), and whether the score could be used in combination with a previously applied cost-effective concept. RESULTS: The incidence of PONV was 600/1566 (38.1%). The discriminating power (AUC) obtained by the models (named according to the first author) using the risk classes from the recommended prophylactic concept were as follows: Apfel, 0.68; Koivuranta, 0.66; Sinclair, 0.66; Palazzo, 0.63; Gan, 0.61; Scholz, 0.61. For four models, the following calibration curves (expressed as the slope and the offset) were plotted: Apfel, y=0.82x+0.01, r2=0.995; Koivuranta, y=1.13x-0.10, r2=0.999; Sinclair, y=0.49x+0.29, r2=0.789; Palazzo, y=0.30x+0.30, r2=0.763. The numbers of parameters to be considered were as follows: Apfel, 4; Koivuranta, 5; Palazzo, 5; Scholz, 9; Sinclair, 12; Gan, 14. CONCLUSION: The simplified risk scores provided better discrimination and calibration properties compared with the more complex risk scores. Therefore, simplified risk scores can be recommended for antiemetic strategies in clinical practice as well as for group comparisons in randomized controlled antiemetic trials.

Adult↗
PubMed2001

Specific inhibition of the classical complement pathway by C1q-binding peptides.

Undesired activation of the complement system is a major pathogenic factor contributing to various immune complex diseases and conditions such as hyperacute xenograft rejection. We aim for prevention of complement-mediated damage by specific inhibition of the classical complement pathway, thus not affecting the antimicrobial functions of the complement system via the alternative pathway and the lectin pathway. Therefore, 42 peptides previously selected from phage-displayed peptide libraries on basis of C1q binding were synthesized and examined for their ability to inhibit the function of C1q. From seven peptides that showed inhibition of C1q hemolytic activity but no inhibition of the alternative complement pathway, one peptide (2J) was selected and further studied. Peptide 2J inhibited the hemolytic activity of C1q from human, chimpanzee, rhesus monkey, rat, and mouse origin, all with a similar dose-response relationship (IC(50) 2-6 microM). Binding of C1q to peptide 2J involved the globular head domain of C1q. In line with this interaction, peptide 2J dose-dependently inhibited the binding of C1q to IgG and blocked activation of C4 and C3 and formation of C5b-9 induced via classical pathway activation, as assessed by ELISA. Furthermore, the peptide strongly inhibited the deposition of C4 and C3 on pig cells following their exposure to human xenoreactive Abs and complement. We conclude that peptide 2J is a promising reagent for the development of a therapeutic inhibitor of the earliest step of the classical complement pathway, i.e., the binding of C1q to its target.

Amino Acid Sequence↗
PubMed2001

Human IgA activates the complement system via the mannan-binding lectin pathway.

The recently identified lectin pathway of the complement system, initiated by binding of mannan-binding lectin (MBL) to its ligands, is a key component of innate immunity. MBL-deficient individuals show an increased susceptibility for infections, especially of the mucosal system. We examined whether IgA, an important mediator of mucosal immunity, activates the complement system via the lectin pathway. Our results indicate a dose-dependent binding of MBL to polymeric, but not monomeric IgA coated in microtiter plates. This interaction involves the carbohydrate recognition domain of MBL, because it was calcium dependent and inhibited by mannose and by mAb against this domain of MBL. Binding of MBL to IgA induces complement activation, as demonstrated by a dose-dependent deposition of C4 and C3 upon addition of a complement source. The MBL concentrations required for IgA-induced C4 and C3 activation are well below the normal MBL plasma concentrations. In line with these experiments, serum from individuals having mutations in the MBL gene showed significantly less activation of C4 by IgA and mannan than serum from wild-type individuals. We conclude that MBL binding to IgA results in complement activation, which is proposed to lead to a synergistic action of MBL and IgA in antimicrobial defense. Furthermore, our results may explain glomerular complement deposition in IgA nephropathy.

Antibodies, Monoclonal↗
PubMed2001

Autoantibodies to complement components.

The complement system is a major component of innate immunity. Under normal conditions the contribution of the complement system is beneficial, but when inappropriately activated it may cause damage to the host and under certain conditions it may even be the target of an autoantibody response. Autoantibodies directed against individual complement components, convertases, complement regulators and complement receptors have been described. The presence of autoantibodies in individuals may be associated with manifestations of disease, but only for some autoantibodies have clear causal relations been described. Autoantibodies against complement components can even be present in healthy individuals, indicating that the development of pathology most likely requires the simultaneous action of multiple processes. Since autoantibodies against complement components may cause depletion of circulating complement levels, leading to a secondary complement deficiency, it is imaginable that this process leads to an increased susceptibility to infections. In the present review, we describe autoantibodies against complement components and their subsequent effects.

Autoantibodies↗
PubMed2001

The otter (Lutra lutra) in Sweden--population trends in relation to sigma DDT and total PCB concentrations during 1968-99.

Polychlorinated biphenyl (PCB) has been suggested as the major cause of the European otter (Lutra lutra) population decline. This study investigates temporal and geographical changes in otter numbers as well as total PCB and sigma DDT concentrations in otters and their food in different parts of Sweden with various pollution impacts during three decades. In Sweden, rare species belong to the State and carcasses of such specimens are sent to the authorities. Two-hundred and eight specimens have been used to investigate temporal and spatial variation in the otter populations during 1968 and 1999. One-hundred and twenty-five of them have been chemically analysed. The population trends in northern Sweden coincide with the temporal trends of the contaminants. When concentrations of PCBs decrease in the environment, otter population increases. Neither aldrin/dieldrin nor mercury pollution seem to explain why the Swedish otter populations decreased dramatically during the 1960s-1980s. In southern Sweden total PCB concentrations are still high and the indications of improvement of the population are weak.

Animals↗