Biomedical subjects

A J Duits

Publications and source records attributed to A J Duits.

At least 19 recordsLinked to original sources

PubMed2004

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease.

In recent years an important role has been ascribed to a reduced nitric oxide (NO) availability in the pathophysiology of sickle cell disease (SCD). Endogenously produced inhibitors of NO synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various vascular disease states characterized by reduced NO availability. We determined ADMA levels in plasma of 12 adult sickle cell patients (eight HbSS and four HbSC), and compared these to plasma levels in race- and age-matched controls. Sickle cell patients were characterized by strongly elevated levels of ADMA [HbSS: median 0.63 micromol/l (interquartile range 0.54-0.85), HbSC: 0.43 micromol/l (0.40-0.46), HbAA: 0.33 micromol/l (0.32-0.35) p<0.001]. ADMA levels were highest in HbSS patients with lowest hemoglobin levels and highest leukocyte counts, and in HbSS patients ADMA levels were positively associated with serum levels of soluble vascular cell adhesion molecule-1. These results suggest an important role of ADMA in limiting NO availability in SCD, and its role in the pathophysiology of SCD should be further investigated.

Adult↗

PubMed2004

Protein C and S and inflammation in sickle cell disease.

Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCD. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels.

Adult↗

PubMed2004

Sickle cell disease; a general overview.

Sickle cell disease (SCD) is a heterogeneous disorder, with clinical manifestations including chronic haemolysis, an increased susceptibility to infections and vaso-occlusive complications often requiring medical care. Patients with SCD can develop specific and sometimes life-threatening complications, as well as extensive organ damage reducing both their quality of life and their life expectancy. Proven effective treatment options for sickle cell patients are limited to hydroxyurea, blood transfusions and bone marrow transplantation. With the increasing prevalence of SCD in the Netherlands, a fundamental understanding of its pathophysiology and clinical syndromes is of importance for local medical practitioners.

Anemia, Sickle Cell↗

PubMed2003

[Kidney transplant program facilitated by airlift between the Netherlands Antilles and the Netherlands; 1998-2001].

OBJECTIVE: To describe the results of a structured kidney-transplantation programme available to dialysis patients in Curaçao (Dutch Caribbean), involving transplantation in the Netherlands and follow-up in Curaçao. DESIGN: Descriptive. METHOD: In 1998, a joint venture was begun with the Academic Medical Center (AMC) in Amsterdam, the Eurotransplant Foundation, the Dutch Transplantation Working Party and the Diagnostic Division of the Sanquin Foundation in Amsterdam, the Netherlands. Its aim was to achieve a structural kidney transplantation programme for patients in the Dutch Caribbean in general and patients in Curaçao in particular. An airlift programme between Curaçao and the AMC was instituted. RESULTS: Between 1998-2001 19 patients underwent a kidney transplant, three of which failed. In most of the transplants the cold ischaemia time was less than 48 hours; the average cold ischaemia time was 32 hours. All patients returned to the Antilles within 3 months where their treatment was continued. Post-transplantation follow-up was on average 13.9 months (limits 3-36); three patients died.

Adult↗

PubMed2003

Erythropoiesis and serum sVCAM-1 levels in adults with sickle cell disease.

Sickle cell patients are characterized by stress erythropoiesis involving cytokines, growth factors, and adhesion molecules. We set out to determine whether serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, which are inversely related to red blood cell counts in sickle cell disease (SCD), reflect erythropoietic activity in adult HbSS patients. Serum levels of sVCAM-1 were compared to erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and soluble transferrin receptor (sTfR) levels in 29 adults with HbSS, and their respective levels were also compared to 29 race- and age-matched HbAA controls. EPO and sTfR levels were increased as compared to healthy controls, whereas IL-3 and GM-CSF were not. No significant correlation of sVCAM-1 levels could be detected with any of the measured erythropoietic markers. Patients, but not controls, with detectable IL-3 levels had lower sTfR and GM-CSF levels as compared to patients with undetectable IL-3 levels. Even though a link of sVCAM-1 to erythropoiesis could not be established, it cannot be ruled out that sVCAM-1 levels reflect the release of young red blood cells into the circulation. IL-3 and GM-CSF levels suggest that different rates of erythropoiesis may be characterized by specific cytokine profiles in SCD. Further research should focus on the potential cytokines and adhesion molecules involved in sickle cell erythropoiesis, as this may increase our understanding of sickle cell complications and may provide us with potential markers for risk assessment in sickle cell disease as well.

Adult↗

PubMed2003

Steady-state sVCAM-1 serum levels in adults with sickle cell disease.

Cytokines and adhesion molecules play an important role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), and their in vivo profiles are potential tools for assessing SCD severity. We compared steady-state soluble vascular cell adhesion molecule-1 (sVCAM-1) serum levels to clinical (painful crisis frequency, occurrence of acute chest syndrome, leg ulcers, and cerebrovascular disease) and related hematological parameters of SCD severity (such as HbF%, hemoglobin levels, and leukocyte counts) in 29 HbSS adults. Serum sVCAM-1 levels were not related to clinical severity, but an inverse correlation was demonstrated between sVCAM-1 and hemoglobin levels (r=-0.71, p<0.001) with a positive correlation to serum lactate dehydrogenase levels (r=0.59, p=0.008). Based upon these results, steady-state serum sVCAM-1 levels do not seem to reflect clinical disease severity. However, as VCAM-1 is involved in hematopoiesis, sVCAM-1 levels might reflect bone marrow activity in SCD. This underlies the pleiotropic nature of adhesion molecules in vivo and the need for further research in this area, especially since therapies targeting (cellular) adhesive interactions involving the endothelium are emerging for SCD.

Adult↗

PubMed2002

No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease.

Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.

Acenocoumarol↗

PubMed2001

Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study.

Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of low-adjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6-2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20-59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical benefit (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing specific events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study.

Acenocoumarol↗

PubMed2000

Duffy phenotype does not influence the clinical severity of sickle cell disease.

The red blood cell Duffy antigen receptor for chemokines serves as a sink for the clearance of chemokines such as interleukin-8 (IL-8) from the circulation. We analyzed the impact of the Duffy phenotype on sickle cell disease (SCD) severity and serum IL-8 levels in 15 Duffy-positive and 36 Duffy-negative sickle cell patients. There was no difference in clinical severity between Duffy-positive and Duffy-negative sickle cell patients. In asymptomatic sickle cell patients the upward deviation of mean serum IL-8 levels was significantly greater in Duffy-negatives (n = 20) than in Duffy-positives (n = 8) (P = 0.011). However, during a vasoocclusive episode, serum IL-8 levels were similar between Duffy-negatives (n = 11) and Duffy-positives (n = 3). Although the Duffy phenotype seems to influence steady-state serum IL-8 levels, it does not seem to have an effect on SCD severity.

Adolescent↗

PubMed2000

Two common endoglin mutations in families with hereditary hemorrhagic telangiectasia in the Netherlands Antilles: evidence for a founder effect.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleeding disorder characterized by localized angiodysplasia. Mutations in either of two genes, endoglin or ALK-1, can cause HHT. Both genes encode putative receptors for the transforming growth factor-beta superfamily of ligands. Many mutations in each gene have been identified in HHT kindreds from around the world, and with few exceptions mutations are unique and family specific. The prevalence of HHT in the Leeward Islands of the Netherlands Antilles is possibly the highest of any geographical location. We wished to establish whether this high prevalence is due to a genetic founder effect or to multiple mutational events. HHT kindreds from the Netherlands Antilles and The Netherlands were screened for mutations in the two genes associated with HHT. Haplotype analysis of a 5-cM region on chromosome 9 flanking the endoglin gene revealed three distinct disease haplotypes in the ten Antillean families studied. Seven of these families share a splice-site mutation in exon 1 of endoglin. Two other Antillean families share a missense mutation in exon 9a of endoglin. This mutation was also found in a Dutch family that shares the same disease haplotype as the Antillean families with this mutation. Thus it appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colonist. The limited scope of mutations suggests that a presymptomatic screening program for HHT would be feasible in this population.

Alleles↗

PubMed1999

Neutrophil activation in sickle cell disease.

Vascular occlusion is the main cause of the morbidity and mortality observed in patients with sickle cell disease (SCD). Increasing evidence indicates that (activated) neutrophils could play an important role in the initiation and propagation of vaso-occlusive processes in SCD. In this study, the activation state of neutrophils in sickle cell patients was analyzed by determining the level of expression of neutrophil antigens such as CD62L, CD11b, CD66b, CD63, and Fcgamma receptors. We also analyzed plasma levels of lactoferrin, elastase, soluble (s)CD16 (sFcgammaRIII), and serum levels of soluble (s)CD62L (sL-selectin) as neutrophil activation markers in these patients. Significant differences were observed in the activation state of neutrophils in non-symptomatic sickle cell patients compared to healthy HbAA controls as exemplified by significant decrease in L-selectin expression, enhanced expression of CD64, and increased levels of soluble markers like sL-selectin, elastase, and sCD16. During vaso-occlusive crisis the differences were even more pronounced. These results show neutrophils to be activated in sickle cell patients, suggesting a role of importance in the pathophysiology of sickle cell disease.

Abdomen, Acute↗

PubMed1999

Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia.

OBJECTIVE: To compare serum levels of angiogenic growth factors vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and angiogenin in pre-eclamptic women and matched controls. DESIGN: Retrospective analysis of -70 degrees C stored serum of women who developed pre-eclampsia and matched controls. SETTING: Department of Gynaecology and Obstetrics, St Elisabeth Hospital, Curaçao, Netherlands Antilles. SAMPLE: Thirty women with pre-eclampsia and 30 normotensive controls matched for age and gestation. RESULTS: VEGF and PIGF serum levels were significantly lower in pre-eclamptic pregnancies, compared with controls (VEGF 0.31 +/- 1.20 vs 18.30 +/- 24.97 pg/mL, P = 0.0004; PlGF 54.19 +/- 32.05 vs 497.95 +/- 340.51 pg/mL, P < 0.0001). Matched couple analysis showed VEGF serum concentrations to be lower in the majority of pre-eclamptic women and PlGF concentrations to be lower in all pre-eclamptic women. Angiogenin serum levels showed no statistical significant difference between pre-eclamptic pregnancies and controls (523.68 +/- 367.55 vs 670.41 +/- 251.54 ng/mL, P = 0.058), with matched couple analysis showing no clear pattern. CONCLUSIONS: Decreased serum levels of VEGF and PIGF characterise, and therefore seem to be of importance during (the development of), pre-eclampsia. This selective deficit of angiogenic growth factors might in part explain the shallow placentation found in this pregnancy complication.

Angiogenesis Inducing Agents↗

PubMed1999

Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy.

It has been shown that the clinical course of sickle cell (SS) patients can be ameliorated by administration of hydroxyurea (HU). Induction of hemoglobin F (HbF) is thought to be the mechanism responsible for clinical improvement in some patients. However, HU has a variable effect on HbF production and there exists no good correlation between the extent of HbF increase and clinical response. On the other hand, the degree of adherence of SS to vascular endothelium and neutrophil counts correlate well with clinical severity. Being a cytotoxic drug, used in myeloproliferative diseases, HU may alter proliferation among various cell lines. Moreover, HU has been reported to reduce red blood cell (RBC) adhesion receptor expression in young SS individuals and induces changes in endothelial cells in vitro. It should be conceived that in addition to its effects on HbF production, HU may change the clinical symptoms of SS patients by affecting the degree of adherence of different blood cells, by influencing the activity of endothelium as well as the activity of white blood cells (WBC) and platelets. To analyze whether several of the determinants of adhesion are modulated by HU treatment we studied the levels of endothelial activity (soluble vascular adhesion molecule-1, (sVCAM-1), interleukin-8 (IL-8), fibronectin, neutrophil activity (sL-selectin, sIL-6 receptor-alpha, myeloperoxidase) and platelet activity (von Willebrand factor) in relation to clinical symptoms, hematological data and HbF levels in 8 SS patients before and during 5 months of HU therapy. Steady state sVCAM-1 levels are increased compared to normal controls and a significant decrease is noted during HU treatment, suggesting a decrease in the interactions between RBC and vascular endothelium. The IL-8 levels are comparable to those in normal controls and remain unaffected by HU therapy. Intercurrent infection and crises reveal striking increases in IL-8 which are accompanied by leukocytosis, but otherwise the IL-8 levels do not correlate with hematological data. HU has no demonstrable effect on fibronectin or soluble neutrophil adhesion molecules, but the levels of myeloperoxidase decrease significantly while WBC counts do not, implying a reduction in neutrophil activity which may help attenuate the propagation phase of a vasoocclusive crisis.

Adolescent↗

PubMed1998

New concepts in assessing sickle cell disease severity.

Vasoocclusion leads to pain, chronic organ damage, and a decreased life expectancy in patients with sickle cell disease. Therapeutic options for sickle cell disease have usually been evaluated according to their capacity for reducing the frequency of vasoocclusive crises requiring clinical attention. However, the frequency of vasoocclusive crises is not representative for the rate of accumulating organ damage in most sickle cell patients. This implies that the frequency of vasoocclusive crises needn't correlate with disease severity and, although being of importance, cannot solely serve as a parameter of treatment efficacy. Therefore, additional new objective parameters are needed to effectively study the vasoocclusive process in sickle cell disease. Several studies show that intricate adhesive interactions between (red) blood cells, plasma components, and endothelium play a crucial role in the pathophysiology of sickle cell vasoocclusion, offering new potential parameters to effectively assess disease severity as well as new therapeutical targets in the near future. Whether these adhesive mechanisms involve the causes or the effects of vasoocclusion will be determined if their inhibition, by interventive measures, results in therapeutic benefits.

Anemia, Sickle Cell↗

PubMed1998

Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients.

We investigated whether pediatric patients with sickle cell disease (SCD) (9 +/- 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be improved by folate supplementation. The patients were supplemented with vitamins B6 and B12 during one week and with folate during the following week. Circulating folate, homocysteine, vitamin B6 and vitamin B12 levels were measured at baseline (patients and controls), after one week and after two weeks (patients). The patients had similar folate, vitamin B6, and vitamin B12, but higher homocysteine levels compared with HbAA controls (12.7 +/- 4.5 vs. 10.9 +/- 3.5 micromol/l; P = 0.04). Vitamin B6 and B12 supplementation did not change their homocysteine levels, but folate supplementation caused a 53% reduction (to 5.7 +/- 1.6). We conclude that patients with SCD have adequate vitamin B6 and B12 status, but suboptimal folate status, leading to elevated plasma homocysteine levels. They may therefore benefit from folate supplementation to reduce their high risk for endothelial damage.

Adolescent↗

PubMed1998

Elevated IL-8 levels during sickle cell crisis.

The vaso-occlusive process (VOC) in sickle cell disease is of a complex nature. It involves intricate interactions between sickle red blood cells, endothelium and probably also leukocytes. As these interactions are regulated by cytokines, we analyzed the role of the potent neutrophil chemokine IL-8 by measuring serum levels in sickle cell patients during sickle cell crisis. These results were compared to nonsymptomatics and healthy controls. In patients having a vaso-occlusive crisis both HbSS and HbSC patients showed significantly enhanced serum IL-8 levels compared to healthy controls. Several of these patients showed extremely elevated serum IL-8 levels which were independent of the crisis inducing factor. Furthermore, a sickle cell patient with VOC as a complication of rhGM-CSF treatment similarly showed high IL-8 serum levels at crisis onset. Nonsymptomatic sickle cell patients serum IL-8 levels were comparable to healthy controls. These results implicate a role for IL-8 at or during (the initiation of) sickle cell crisis.

Anemia, Sickle Cell↗

PubMed1998

Cytokines and soluble adhesion molecules in sickle cell anemia patients during hydroxyurea therapy.

Hydroxyurea (HU) induces HbF production and can reduce painful crises in some patients with sickle cell anemia (SS). However, HbF induction alone cannot explain the beneficial effect of HU treatment as some patients experience clinical improvement while showing only minor increases in HbF. Other actions of HU, in particular its effects on vascular endothelium, adhesion molecule expression and cytokine production may also play a role in the final therapeutic outcome. In order to analyze these effects we studied the levels of interleukin-3 (IL-3), interleukin-6, granulocyte-macrophage colony-stimulating factor, erythropoietin, stem cell factor, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1, soluble E-selectin and soluble P-selectin in 7 SS patients before and during 5 months of HU treatment. Use of HU seems to have no detectable effect on soluble adhesion molecules, but the steady state levels of soluble vascular adhesion molecule-1 are enhanced in SS patients compared to normal controls. Of the cytokines studied, only IL-3 showed an increase during therapy, suggesting HU may induce early erythroid progenitors capable of producing HbF by a direct or indirect effect on IL-3 production. Remarkably, the steady state stem cell factor levels in sickle cell patients seemed to be decreased compared to healthy controls.

Adult↗

PubMed1996

Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific increment during vasoocclusive crisis.

Adhesion of sickle erythrocytes to vascular endothelium plays a central role in sickle cell disease complications. Cytokines and adhesion molecules are critically involved in the regulation of these adhesive processes. To analyze their role, IL-6, GM-CSF, sVCAM-1, sICAM-1, sE-Selectin, and sP-Selectin serum levels were determined in sickle cell patients under basic conditions and during vasoocclusive crisis. In nonsymptomatic patients a high serum level of sVCAM-1 was observed compared to controls. In patients having vasoocclusive crisis sVCAM-1 levels increased even more and seemed to correlate with crisis evolution.

Adolescent↗