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Biomedical subjects

Jan Stolk

Publications and source records attributed to Jan Stolk.

18 recordsLinked to original sources
PubMed2007

Finite element-based preclinical testing of cemented total hip implants.

We developed a finite element model to preclinically test cemented hip implants for damage accumulation, including cement crack formation, creep, and stem migration. Using this model, we simulated the mechanical failure processes of four cemented total hip arthroplasty implants (Lubinus SPII, Mueller Curved, Exeter and Charnley, all with known clinical results) during cyclic normal walking and stair-climbing loads. These four implants were selected to ascertain whether the simulation predicted greater damage development around clinically inferior stems, whether clinically inferior designs could be identified by an initial stress analysis without the prediction of cement damage, and whether the simulation could predict high implant subsidence rates in combination with minimal cement damage. Based on the predicted cement crack patterns and crack formation rates, the simulation correctly identified the clinically inferior implant designs. Based only on the initial stress analysis under a stair-climbing load, it was not possible to identify clinically inferior designs. High subsidence values and minimal cement damage were predicted for the Exeter implant, similar to clinical findings. Our findings suggest the simulation may be effective in differentiating between a range of implants and design features.

Bone Cements↗
PubMed2006

A disintegrin and metalloprotease 33 and chronic obstructive pulmonary disease pathophysiology.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality. It is associated with airway obstruction, increased airway hyper-responsiveness (AHR), and ongoing airway and lung inflammation dominated by CD8 lymphocytes and neutrophils. Single-nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene have been associated with AHR and COPD. OBJECTIVE: To assess whether SNPs in ADAM33 are associated with the severity of AHR and airway inflammation in COPD. METHODS: Eight SNPs in ADAM33 (F+1, Q-1, S_1, S_2, ST+5, T_1, T_2, V_4) were genotyped in 111 patients with COPD (96 males, 69 current smokers, mean (standard deviation (SD)), aged 62 (8) years, median pack-years 42 (IQR 31-55), mean postbronchodilator forced expiratory volume in 1 s (FEV(1))% predicted 63 (9). Provocative concentration of methacholine causing a decrease in FEV(1) of 20% (PC(20) methacholine), sputum and bronchial biopsies were collected. RESULTS: Patients with the ST+5 AA genotype had more severe AHR, higher numbers of sputum inflammatory cells and CD8 cells in bronchial biopsies than patients with the GG genotype (p = 0.03, 0.05 and 0.01, respectively). CD8 cell numbers were lower in patients carrying the minor allele of SNP T_1 and T_2, and homozygotic minor variants of SNP S_2 compared with the wild type (p = 0.02, 0.01 and 0.02, respectively). CONCLUSIONS: This is the first study revealing that SNPs in a gene that confers susceptibility to COPD in the general population-that is, ADAM33-are associated with AHR and airway inflammation in COPD. These findings constitute an important step forward in linking gene polymorphisms with COPD pathophysiology, thereby possibly contributing to better treatments for this progressive and disabling disease in the future.

ADAM Proteins↗
PubMed2006

Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1, although it has been suggested that SERPINA3 may also play a role. To detect cryptic genetic variants that might contribute to disease, we identified 15 SNP haplotype tags from high-density SNP maps of the two genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted so far. For SERPINA1, six newly identified haplotypes with a common backbone of five SNPs were found to increase the risk of disease by six- to 50-fold, the highest risk of COPD reported to date. In contrast, no haplotype associations for SERPINA3 were identified.

Aged↗
PubMed2006

Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease.

Smoking may affect epithelial repair and differentiation differentially in smokers with and without chronic obstructive pulmonary disease (COPD). We hypothesized that epithelial repair is disturbed in patients with COPD owing to higher expression of epidermal growth factor (EGF)-like factors and/or receptors. We studied epithelial expression of EGF, transforming growth factor a, amphiregulin, heregulin (HRG), betacellulin (BTC), and their receptors, EGFR, HER-2, and HER-3, by immunohistochemical analysis in resected bronchial tissue from 20 subjects with (forced expiratory volume in 1 second [FEV(1)] <75% of predicted value) and 18 without (FEV(1) >85% predicted value) COPD. All subjects underwent surgery for lung cancer. The proportion of intact, damaged, goblet, or squamous metaplastic epithelium was similar in subjects with and without COPD. Regardless of smoking status, HRG expression was higher in intact epithelium of patients with COPD than in those without. Subgroup analysis showed higher EGFR expression in intact epithelium (1.4 times; P pound .04) and higher EGF, BTC, and HRG expression in damaged epithelium (1.4-1.8 times; P<or=.05) of ex-smokers with COPD compared with ex-smokers without COPD. These data support our hypothesis and suggest that current smoking obscures intrinsically higher expression in COPD.

Adult↗
PubMed2005

Short-term variability of biomarkers of proteinase activity in patients with emphysema associated with type Z alpha-1-antitrypsin deficiency.

BACKGROUND: The burden of proteinases from inflammatory cells in the lung of subjects with type Pi ZZ of alpha-1-antitrypsin deficiency is higher than in those without the deficiency. Cross-sectional studies have shown increased levels of biomarkers of extracellular matrix degradation in vivo. Longitudinal variability of these biomarkers is unknown but desirable for clinical studies with proteinase inhibitors. METHODS: We measured three different types of biomarkers, including desmosines, elastase-formed fibrinogen fragments and heparan sulfate epitope JM403, in plasma and urine for a period of 7 weeks in a group of 12 patients who participated in a placebo-controlled study to assess the safety of a single inhalation of hyaluronic acid. RESULTS: Effect of study medication on any of the biomarkers was not seen. Baseline desmosines in plasma and urine correlated with baseline CO diffusion capacity (R = 0.81, p = 0.01 and R = 0.65, p = 0.05). Mean coefficient of variation within patients (CVi) for plasma and urine desmosines was 18.7 to 13.5%, respectively. Change in urinary desmosine levels correlated significantly with change in plasma desmosine levels (R = 0.84, p < 0.01). Mean CVi for fibrinogen fragments in plasma was 20.5% and for JM403 in urine was 27.8%. No correlations were found between fibrinogen fragments or JM403 epitope and desmosines. CONCLUSION: We found acceptable variability in our study parameters, indicating the feasibility of their use in an evaluation of biochemical efficacy of alpha-1-antitrypsin augmentation therapy in Pi Z subjects.

Adult↗
PubMed2005

The contradictory effects of pores on fatigue cracking of bone cement.

The beneficial effect of porosity reduction on the fatigue life of bone cement has been demonstrated in numerous experimental studies. Clinically, however, it seems that the beneficial effect of porosity reduction of cement around total hip replacement components can only be found in large follow-up studies. Little is known about the actual mechanical effect of a pore on fatigue crack formation in cement mantles. We studied the effect of pores on the crack formation process in a finite element model of a transverse slice of a total hip reconstruction. We created models with a single large pore and models with multiple pores at levels of 2, 4, and 9%. The models were cyclically torque-loaded, causing macrocracks to appear in the cement mantle. In all models, we found that pores acted as microcrack initiators. However, pores could have both a detrimental and a beneficial effect on the macrocrack propagation in the cement mantle. Both effects were seen in the models with a single large pore and in the models with multiple pores. Pores would either accelerate, deviate, or decelerate the macrocrack propagation in the cement mantle. The effect of the pores depended on the location of the pores with respect to the stress intensities in the model, but was independent of the pore size or the level of porosity. The results may explain why the beneficial effect of vacuum mixing is difficult to demonstrate clinically. Stress intensities that are present in a cement mantle in an in vivo situation may overshadow the detrimental effect of a pore, while the beneficial effect may become more pronounced.

Bone Cements↗
PubMed2005

Expression of the anaphylatoxin receptors C3aR and C5aR is increased in fatal asthma.

BACKGROUND: The mechanisms leading to death from asthma are not completely understood. Recent studies suggest the involvement of the anaphylatoxins C3a and C5a, generated during complement activation, and their receptors C3aR and C5aR in the pathogenesis of asthma. OBJECTIVE: The aim of our study was to investigate the expression of C3aR and C5aR in fatal asthma. METHODS: We analyzed lung tissue from 14 subjects who died of asthma (fatal asthma; FA) and 14 subjects who died of nonpulmonary causes (controls) and bronchial biopsy specimens from 16 subjects with mild intermittent asthma (MIA). C3aR and C5aR expression was evaluated by immunohistochemistry, and a semiquantitative analysis of the intensity of staining was performed according to a visual analogue scale (score, 0-3). RESULTS: C3aR was expressed on airway epithelium, smooth muscle, submucosal, and parenchymal vessels. C5aR was expressed on myeloid cells infiltrating the submucosa and on airway epithelium. Statistical analysis demonstrated higher expression of C3aR on submucosal vessels in FA compared with controls and MIA (median [minimum-maximum], controls, 0.24 [0-1.48]; MIA, 0.0 [0-1.00]; FA, 1.56 [0.13-3]; P = .002). C3aR was also increased on parenchymal vessels in FA (controls, 0.56 [0-2.00]; FA, 1.81 [0.5-3]; P = .0004). C5aR expression on airway epithelium was increased in FA compared with controls and MIA (controls, 1.25 [0.25-3]; MIA, 1.00 [0-2.00]; FA, 3.00 [1.13-3.00]; P = .001). CONCLUSION: The results of our study suggest a role of complement in FA.

Adult↗
PubMed2005

Variability in densitometric assessment of pulmonary emphysema with computed tomography.

OBJECTIVES: The objectives of this study were to investigate whether computed tomography (CT) densitometry can be applied consistently in different centers; and to evaluate the reproducibility of densitometric quantification of emphysema by assessment of different sources of variation, ie, intersite, interscan and inter- and intraobserver variability, in comparison with intersubject variability. MATERIALS AND METHODS: In 5 different hospitals, 119 patients with emphysema were scanned using standardized protocols. In each site, an observer performed a quantitative densitometric analysis (including blood recalibration) on the corresponding patient group (n=23-25) and one observer analyzed the entire group of 119 patients. After several months, the latter observer analyzed all data for a second time. Subsequently, different sources of variation were assessed by variance component analysis with and without volume correction of the data. RESULTS: Inter- and intraobserver variability marginally contributes to the total variability (<0.001%). The interscan variability was 0.02% of the total variation after application of volume correction. The intersite variability was 48% as a result of one deviating CT scanner. Air recalibration normalized deviating air densities in CT scanners. Within sites, the intersubject variability ranged between 93% and 99% based on the analysis of 2 subsequent CT scans of the patients. CONCLUSIONS: Almost all variability in the density measurement of emphysema originates from differences between scanners and from differences in severity of emphysema between patients. Lung densitometry with multislice CT scanners is a highly reproducible measurement, especially if corrected for lung volume, because this reduces interscan variability.

Absorptiometry, Photon↗
PubMed2004

Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment.

FEV(1) is fundamental to the diagnosis and staging of chronic obstructive pulmonary disease. In emphysema, airflow obstruction usually coexists with impairment of gas exchange, but discordance is not infrequent. We hypothesized that variations in the distribution of emphysema would be associated with functional differences and therefore account for discordant physiology. We used quantitative computed tomography to assess emphysema severity and distribution in 119 subjects with alpha1-antitrypsin deficiency (PiZ phenotype) and grouped them according to distribution pattern. In the 102 subjects with emphysema, 65 had a predominantly basal pattern ("basal"), but 37 (36%) had greater involvement of the upper regions ("apical"). Subjects from each group were matched for total volume of emphysema and age, and matched pairs analysis was used to relate emphysema distribution to clinical phenotype. Basal distribution was associated with greater impairment of FEV(1) (mean difference, 9.9% predicted; 95% confidence interval, 3.8 to 16.0; p = 0.002) but less impairment of gas exchange (Pa(O(2)) mean difference, 0.5 kPa, 0.03 to 0.1; p = 0.016) and alveolar-arterial oxygen gradient (mean difference, 0.7 kPa; 0.2 to 1.2; p = 0.007) than the apical distribution. Emphysema distribution correlated with physiologic discordance (r = -0.409, p < 0.001). The use of single physiologic parameters as a surrogate measure of emphysema severity may introduce systematic bias in the staging of subjects with emphysema.

Adult↗
PubMed2004

Influence of calibration on densitometric studies of emphysema progression using computed tomography.

The fundamental importance of calibration for any measuring device is indisputable, but computed tomography (CT) calibration in longitudinal lung densitometry studies is largely unexplored. Although the validity of CT as a measure of emphysema has been confirmed in cross-sectional studies, there are limited data on long-term reproducibility, and this is critically important for validating its use as an outcome measure in therapeutic trials. A general understanding of the strengths and pitfalls of CT densitometry is critical for physicians reviewing the published literature using this methodology. In our study of 57 patients with alpha-1 antitrypsin deficiency (phenotype PiZ), progression of voxel index determined from three successive annual scans acquired with a fully calibrated scanner was intimately associated with changes in CT air densitometry, sampled from patient images. Images were therefore reanalyzed, using a correction technique validated in phantom studies that adjusted for changes in measured air density, and the reliability of the voxel index as a measure of emphysema progression was improved. Comparison of adjusted voxel index thresholds indicated the optimum threshold was -950 Hounsfield units. Internal air calibration is therefore critical in longitudinal and multicenter lung densitometry studies of emphysema and incorporation of a correction factor is essential for quantitative image analysis.

Absorptiometry, Photon↗
PubMed2004

Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is defined by progressive, irreversible airflow limitation and an inflammatory response of the lungs, usually to cigarette smoke. However, COPD is a heterogeneous disease in terms of clinical, physiologic, and pathologic presentation. We aimed to evaluate whether airflow limitation, airway responsiveness, and airway inflammation are separate entities underlying the pathophysiology of COPD by using factor analysis. A total of 114 patients (99 males/15 females, age 62 +/- 8 years, 42 pack-years smoking, no inhaled or oral steroids > 6 months) with irreversible airflow limitation (postbronchodilator FEV(1) 63 +/- 9% predicted, FEV(1)/inspiratory vital capacity [IVC] 48 +/- 9%) and symptoms of chronic bronchitis or dyspnea were studied in a cross-sectional design. Postbronchodilator FEV(1) and FEV(1)/IVC, reversibility to inhaled beta(2)-agonists, diffusing capacity, provocative concentration of methacholine required to produce a 20% drop in FEV(1), total serum IgE, exhaled nitric oxide, and induced sputum cell counts (% eosinophils, % neutrophils) were collected. Factor analysis yielded 4 separate factors that accounted for 63.6% of the total variance. Factor 1 was comprised of FEV(1), FEV(1)/IVC, and residual volume/total lung capacity. Factor 2 included reversibility, IgE, provocative concentration of methacholine required to produce a 20% drop in FEV(1,) and diffusing capacity. Factor 3 contained exhaled nitric oxide and factor 4 included sputum % neutrophils and % eosinophils. We conclude that airflow limitation, airway inflammation, and features commonly associated with asthma are separate and largely independent factors in the pathophysiology of COPD.

Aged↗
PubMed2004

Optimization and standardization of lung densitometry in the assessment of pulmonary emphysema.

Currently, lung densitometry for the assessment of pulmonary emphysema has been fully validated against pathology, pulmonary function, and health status, and it is therefore being applied in pharmacotherapeutic trials. Nevertheless, its application for the early detection of emphysema has not yet been introduced in daily clinical practice. The main reason for this is the fact that it is not yet regarded a fully optimized and standardized technique. In this work, an overview is given on the current status of different standardization aspects that play an important role in this, ie, image acquisition, choice of densitometric parameter and image processing. To address these issues, solutions have been sought from the literature and from original data from previous studies. Standardization and optimization of lung densitometry has reached a more advanced stage than has been reported so far. If normal values will become available, this technique will be feasible for clinical practice. As a result, standardization for the detection and assessment of other density-related lung diseases can be achieved in a shorter period of time.

Absorptiometry, Photon↗
PubMed2004

Comparison of the sensitivities of 5 different computed tomography scanners for the assessment of the progression of pulmonary emphysema: a phantom study.

RATIONALE AND OBJECTIVES: To compare the sensitivities of 5 different computed tomography scanners (4 multislice CT [MSCT] and 1 single-slice CT) in the assessment of the progression of pulmonary emphysema. METHODS: A Perspex cylinder phantom was constructed containing small pieces of polythene foam with densities representative of lung. Changing the cylinder's volume simulated subtle lung density changes. The sensitivity to density changes was defined by the variation in the residual errors from the linear regression line between time and density. RESULTS: The single-slice CT scanner was significantly less sensitive to density changes than MSCT scanners. Also, among MSCT scanners, small but significant differences were found when the standardized acquisition protocol was used. CONCLUSIONS: Considering the large sensitivity differences between single- and multislice CT scanners, we would recommended using MSCT scanners in clinical multicenter trials in emphysema. The protocol standardization of MSCT scanners can still be further improved.

Humans↗
PubMed2003

Can finite element models detect clinically inferior cemented hip implants?

Rigorous preclinical testing of cemented hip prostheses against the damage accumulation failure scenario will reduce the incidence of aseptic loosening. For that purpose, a finite element simulation is proposed that predicts damage accumulation in the cement mantle and prosthetic migration. If the simulation is to become a convincing preclinical test, it should be able to distinguish between implants in a clinically relevant way, based on accurate predictions of long-term failure mechanisms of cemented hip prostheses. The algorithm was used to simulate long-term fatigue experiments on femoral reconstructions with Mueller Curved and Lubinus SPII stems. Clinically, the Mueller Curved system performs inferior to the Lubinus SPII system. The finite element simulation predicted much more cement damage around the Mueller Curved stem and showed that the entire cement mantle was involved in the failure process, which was not the case around the Lubinus SPII stem. In addition, the Mueller Curved stem was predicted to migrate more than the Lubinus SPII. The predictions showed excellent agreement with the experimental findings: similar damage locations in the cement, more damage for the Mueller Curved, similar prosthetic migration directions, and more migration for the Mueller Curved stem. This is the first time that a finite element simulation is able to differentiate between a clinically superior and an inferior implant, based on accurate simulation of the long-term failure mechanisms in a cemented reconstruction. Its use for preclinical testing purposes is corroborated.

Cementation↗
PubMed2002

4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease.

Cigarette smoking results in oxidative stress and inflammation in the lungs, which are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). 4-Hydroxy-2-nonenal (4-HNE), a highly reactive diffusible product of lipid peroxidation, is a key mediator of oxidant-induced cell signaling and apoptosis. 4-HNE has a high affinity toward cysteine, histidine, and lysine groups and forms direct protein adducts. We investigated the presence of 4-HNE-modified proteins in lung tissue obtained from subjects with and without COPD. We studied 23 current or ex-smokers with similar smoking histories with COPD (n = 11; FEV(1) < 70% predicted) or without COPD (n = 12; FEV(1) > 84% predicted) who had undergone lung resection. As 4-HNE and transforming growth factor-beta(1) (TGF-beta(1)) can modulate gamma-glutamylcysteine synthetase (gamma-GCS) mRNA levels in lung cells, we assessed the relations between 4-HNE-modified protein levels, FEV(1), gamma-GCS, and TGF-beta(1). 4-HNE-modified protein levels were elevated in airway and alveolar epithelial cells, endothelial cells, and neutrophils in subjects with COPD, compared with the levels in subjects without COPD (p < 0.01). We also observed a significant inverse correlation between the levels of 4-HNE adducts in alveolar epithelium, airway endothelium, and neutrophils and FEV(1) (p < 0.05) and a positive correlation between 4-HNE adducts and TGF-beta(1) protein and mRNA as well as gamma-GCS mRNA levels in airway and alveolar epithelium (p < 0.01). The elevated levels of 4-HNE may play a role in the signaling events in lung inflammation leading to the imbalance of the expression of both proinflammatory mediators and protective antioxidant genes in COPD.

Aldehydes↗
PubMed2002

Stair climbing is more detrimental to the cement in hip replacement than walking.

Stair climbing may be detrimental to cemented total hip arthroplasties, because it subjects the reconstruction to high torsional loads. The current study investigated how stair climbing contributes to damage accumulation in the cement around a femoral stem compared with walking, taking into account the different frequencies of these activities during patient functioning. In finite element analyses, the damage accumulation process in the cement mantle around a Lubinus SPII stem was simulated for three different loading histories: (1) isolated walking, representative for patients who climb no stairs; (2) isolated stair climbing; (3) alternating walking and stair climbing in a ratio of nine to one cycles, representative for patients who climb many stairs. Relative to isolated walking, isolated stair climbing increased the amount of cement damage by a factor of 6. Inclusion of 10% stair climbing cycles in the loading history increased the amount of damage by 47% relative to isolated walking. Stair climbing produced damage along the entire stem, whereas isolated walking produced damage proximomedially and around the tip only. This study confirmed that stair climbing is more risky for failure of cemented femoral stems than walking. A few stair climbing cycles during daily patient functioning increases the amount of cement damage dramatically.

Biomechanical Phenomena↗