Biomedical subjects

Paul van der Valk

Publications and source records attributed to Paul van der Valk.

At least 19 recordsLinked to original sources

PubMed2007

Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis.

BACKGROUND: Histopathologic studies have shown that subpial cortical demyelination is extensive in chronic multiple sclerosis (MS). OBJECTIVE: To study whether subpial cortical demyelination in MS is associated with focal or diffuse white matter (WM) pathologic features on magnetic resonance imaging (MR imaging). DESIGN: Comparison of postmortem MR imaging findings with histopathologic findings. SETTING: Brain donations from a general community. PATIENTS: Three patients with MS with extensive cortical demyelination and 3 patients with minor cortical demyelination were selected from an MS autopsy data set. The postmortem MR imaging and histopathologic data of the patients were compared. MAIN OUTCOME MEASURES: Two observers blinded to the results of each other assessed the presence, extent, and distribution of focal and diffuse pathologic changes in WM by MR imaging and by histopathology. RESULTS: Extensive subpial demyelination was not associated with a significant increase in the area of focal and diffuse WM pathologic changes as assessed by Luxol fast blue histochemistry or by MR imaging or with the presence or extent of juxtacortical abnormalities on MR imaging. CONCLUSIONS: The lack of association of MS gray matter demyelination with diffuse or focal WM changes indicates that gray matter demyelination in MS occurs largely independent of WM pathologic changes. The extent or distribution of WM abnormalities cannot be used to identify extensive cortical demyelination in the clinical setting.

Aged↗

PubMed2006

Prognostic factors in adult soft tissue sarcomas of the head and neck: a single-centre experience.

Adult soft tissue sarcomas of the head and neck are rare and consist of a variety of histopathological subtypes and sites. The purpose of this study was to review patients treated for adult soft tissue sarcomas of the head and neck at our institute. The medical records of 41 adult patients treated for head and neck soft tissue sarcomas between 1983 and 2004 were reviewed. Thirty-six tumours were histologically reviewed. Histopathological revision showed that 7% of the original sarcomas were found not to be sarcomas and 39% of the sarcoma subtypes changed. Multivariate analysis showed that surgical margin status and lymph node metastases are the most important prognostic factors. Review of histopathological examination of tumours showed a change in subtype in a substantial number of head and neck sarcomas. Negative surgical margins are an important prognostic factor, but are difficult to obtain in head and neck sarcomas.

Adolescent↗

PubMed2006

Simvastatin affects cell motility and actin cytoskeleton distribution of microglia.

Statin treatment is proposed to be a new potential therapy for multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. The effects of statin treatment on brain cells, however, are hardly understood. We therefore evaluated the effects of simvastatin treatment on the migratory capacity of brain microglial cells, key elements in the pathogenesis of MS. It is shown that exposure of human and murine microglial cells to simvastatin reduced cell surface expression of the chemokine receptors CCR5 and CXCR3. In addition, simvastatin treatment specifically abolished chemokine-induced microglial cell motility, altered actin cytoskeleton distribution, and led to changes in intracellular vesicles. These data clearly show that simvastatin inhibits several immunological properties of microglia, which may provide a rationale for statin treatment in MS.

Actins↗

PubMed2006

Systemic treatment of malignant thymoma: a decade experience at a single institution.

OBJECTIVES: Thymic malignancies are rare tumors on the superior anterior mediastinum. Treatment of advanced stages includes chemotherapy. The objective of this analysis was to review the treatment of this disease in the past decade. METHODS: This is a retrospective analysis of the results obtained in a total of 29 patients with advanced malignant thymomas who underwent systemic chemotherapy in the past 10 years at our institution. Sixteen received neoadjuvant chemotherapy in the attempt to shrink the tumor and then perform a radical operation. The others received chemotherapy as palliation. Platinum based chemotherapy was mainly used. RESULTS: The response rate to first-line chemotherapy was 50% in the neoadjuvant setting and 31% in the advanced setting. A better survival was observed in patients who underwent chemotherapy as part of their combined modality treatment, in patients with thymomas, and in patients without visceral metastases. Some patients responded to targeted therapies at relapse. CONCLUSIONS: A better understanding of the biology of this rare tumor may allow in the future the development of better therapies for the more aggressive tumor types (WHO type C), which appear to be increasing in frequency.

Adult↗

PubMed2005

Expression and localization of inhibitor of apoptosis proteins in normal human tissues.

The family of inhibitor of apoptosis (IAP) proteins can suppress apoptosis induced by a variety of triggers. Among the IAPs, cIAP1, cIAP2, and XIAP have been characterized as inhibitors of specific caspases, and their expression, together with that of survivin, has been shown in several studies to play a role as tumor marker and prognostic factor for the survival of patients with cancer. Although survivin is usually not expressed in normal adult tissues, cIAP1, cIAP2, and XIAP have been found broadly expressed at messenger RNA level within normal cells. Here, we report an immunohistochemical study in a comprehensive panel of normal human tissues, and we confirm at the protein level the wide expression of IAPs. These results are consistent with a physiological role of IAPs in normal cells. Moreover, we show that IAPs' expression levels and localization patterns differ depending on the cell lineage. The variable subcellular localization of the IAPs within different cell types suggests that compartmentalization may contribute to regulate their function. The physiological role of these proteins should be further investigated to help tailor IAP-targeted therapeutic strategies for patients with cancer and circumvent possible side effects.

Apoptosis Regulatory Proteins↗

PubMed2005

Effects of irradiation and cisplatin on human glioma spheroids: inhibition of cell proliferation and cell migration.

PURPOSE: Investigation of cell migration and proliferation of human glioma cell line spheroids (CLS) and evaluation of morphology, apoptosis, and immunohistochemical expression of MIB-1, p53, and p21 of organotypic muticellular spheroids (OMS) following cisplatin (CDDP) and irradiation (RT). MATERIAL AND METHODS: Spheroids of the GaMg glioma cell line and OMS prepared from biopsy tissue of six glioblastoma patients were used. Radiochemosensitvity (5 microg/ml CDDP followed by RT) was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. RESULTS: Combination treatment led to a migration inhibition of 38% (CDDP 13%; RT 27%) and specific growth delay of 2.6 (CDDP 1.3; RT 2.1) in CLS. Cell cycle analysis after combination treatment showed an accumulation of cells in the G2/M phase. In OMS, apoptosis increased, cell proliferation decreased, and p53/p21 expression increased more pronounced following CDDP+RT. No morphological damage was observed. CONCLUSION: CDDP can lead to enhancement of the RT effect in spheroids of both human glioma cell line spheroids and biopsy spheroids from glioblastoma specimens. The exerted effect is additive rather than synergistic.

Antineoplastic Agents↗

PubMed2005

Expression of cyclooxygenase-2 and epidermal growth factor receptor in primary and recurrent glioblastoma multiforme.

PURPOSE: To investigate the pattern and level of cyclooxygenase-2 (COX-2) expression in a series of high grade primary and recurrent glioblastoma multiforme (GBM) and correlation with time to recurrence and patients' survival following therapy. The relationship between COX-2 and epidermal growth factor receptor (EGFR) immunoreactivities was evaluated. MATERIALS AND METHODS: Specimens of 14 primary and 14 recurrent GBMs (eight pairs) following surgery and full course radiation therapy were processed for immunostaining on COX-2 and EGFR. Tumor cell positivity was semi-quantitatively scored. COX-2 scores of the primary tumor and recurrence were correlated with the time to radiological tumor progression and patients' survival. RESULTS: COX-2 positive tumor cells were disseminated throughout the tumor parenchyma. The intensity and pattern of COX-2 expression were heterogeneous, with predominant expression in areas surrounding tumor necrosis. Scoring of COX-2 positivity revealed values between 1 and 80% of the cells. Primary GBMs with COX-2 expression levels between 25% and 70% of the tumor cells showed a shorter time to radiological recurrence than GBMs with <10% COX-2 positive tumor cells (respectively, 219 +/- 50 and 382 +/- 77 days). No correlation was found between the COX-2 expression in the primary tumor and patients' survival (r (s) = -0.073) following therapy. No correlation was found either between COX-2 and EGFR immunoreactivity. CONCLUSIONS: Immunohistochemical expression of COX-2 in GBM showed large variation. Hence, determination of COX-2 expression in tumor specimen for each individual might be relevant for selection of those patients, who could benefit from adjuvant therapy with selective COX-2 inhibitors.

Adult↗

PubMed2005

Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis.

Postmortem MRI-guided tissue sampling significantly enhances the yield of MS lesions in autopsy material, but so far it is unknown whether abnormalities concur with blood-brain barrier alterations. Here we sampled MS lesions with focal and diffuse abnormalities (diffusely abnormal white matter; DAWM) on MRI; both were coupled to the presence of MS lesions upon neuropathological examination. Extravascular distribution of fibrinogen, indicating BBB disturbance, was observed in so-called (p)reactive lesions that reflect discrete areas of microglial activation without demyelination within an otherwise normal appearing white matter. Leakage became more extensive in active demyelinating MS lesions to chronic inactive lesions. An enlargement of the perivascular (Virchow-Robin) space containing infiltrated leukocytes was associated with both DAWM and focal abnormalities on postmortem MRI. This study shows for the first time that in MS brain changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI.

Aged↗

PubMed2005

Retinoblastoma: MR imaging parameters in detection of tumor extent.

PURPOSE: To assess diagnostic accuracy of preoperatively performed magnetic resonance (MR) imaging for detection of tumor extent in a large patient population with histopathologically proved retinoblastoma. MATERIALS AND METHODS: Local ethics committee approval and informed consent were not required for retrospective review of patients' images and records. Fifty-eight eyes in 28 girls (mean age, 21 months; range, 2-59 months) and 28 boys (mean age, 24 months; range, 2-76 months) with retinoblastoma were retrospectively reviewed by one radiologist on unenhanced T1-weighted, dual-echo T2-weighted, and gadolinium-enhanced T1-weighted MR images. MR imaging parameters such as growth pattern, anterior chamber hyperintensity, and involvement of choroid, ciliary body, optic nerve, sclera, orbital fat, and pineal gland were determined. Tumor volume was measured and correlated to metastatic risk factors. Imaging and pathologic findings were compared. Statistical analysis was performed by using logistic regression with log likelihood ratio chi(2) test or Fisher exact test. RESULTS: Choroidal invasion was suspected with MR imaging in 21 eyes; findings were false-positive in 13 eyes and false-negative in three (73% sensitivity, 72% specificity, 72% accuracy). Anterior chamber hyperintensity on T1-weighted MR images obtained after contrast agent administration correlated well with clinical presence of reactive neovascular processes. MR imaging findings were true-positive in 21 of 32 eyes with proved prelaminar optic nerve invasion (66% sensitivity) and false-positive in one (96% specificity, 79% accuracy). Postlaminar optic nerve invasion was correctly detected in two eyes; in two other eyes, this metastatic risk factor was missed (50% sensitivity, 100% specificity, 97% accuracy). Scleral and extrascleral tumor invasion were correctly excluded in all eyes. Tumor volume was statistically associated with prelaminar optic nerve invasion (P = .001) and choroidal invasion (P = .031). CONCLUSION: MR imaging is accurate for tumor staging and detection of metastatic risk factors; detection of intraocular tumor infiltration remains difficult. Tumor volume, measured with MR imaging, was associated with prelaminar optic nerve and choroidal involvement.

Child↗

PubMed2005

The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions.

Complement activation is known to occur in white matter multiple sclerosis (MS) lesions. It is thought to mediate oligodendrocyte/myelin damage and to be a marker of pathologic heterogeneity among individuals. Less is known about complement deposition in the gray matter in MS. The aim of this study was to characterize the presence and distribution of complement activation products in cortical MS lesions. Immunohistochemical staining was performed on cryostat sections from the brains of 22 MS patients and 5 nonneurologic control patients obtained at autopsy. Deposition of the complement activation products C1q, C3d, and C5b-9 (membrane attack complex) was detected on and within macrophages/microglia and astrocytes and in blood vessel walls in white matter MS lesions. C3d and C4d were detected along myelin sheaths at the edge of the lesions. In the gray matter part of combined gray matter/white matter lesions complement activation was less frequent, but increased immunopositivity was detected for C3d on blood vessels, and for C3d and C4d on myelin at the border of lesions, when compared with control areas. In contrast, in the purely cortical lesions, the extent of complement deposition in general was low. In conclusion, the role of complement in MS pathogenesis seems lesion location-dependent.

Adult↗

PubMed2005

Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain.

PURPOSE: Breast cancer resistance protein (BCRP) is a half adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed on cellular membranes and included in the group of multidrug resistant (MDR)-related proteins. Recently, upregulation of different MDR proteins has been shown in human epilepsy-associated conditions. This study investigated the expression and cellular distribution of BCRP in human control and epileptic brain, including a large number of both neoplastic and nonneoplastic specimens from patients with chronic pharmacoresistant epilepsy. METHODS: Several epileptogenic pathologies, such as hippocampal sclerosis (HS), focal cortical dysplasia (FCD), dysembryoplastic neuroepithelial tumor, oligodendroglioma astrocytoma, and glioblastoma multiforme were studied by using Western blot and immunocytochemistry. RESULTS: With Western blot, we could demonstrate the presence of BCRP in both normal and epileptic human brain tissue. In contrast to P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2, BCRP expression levels did not change in tissue from patients with HS, compared with control hippocampus. No BCRP immunoreactivity was observed in glial or neuronal cells, including reactive astrocytes and dysplastic neurons in FCD. BCRP expression was, however, increased in tumor brain tissue. Immunocytochemistry demonstrated that BCRP was exclusively located in blood vessels and was highly expressed at the luminal cell surface and in newly formed tumor capillaries. This localization closely resembles that of P-gp. The higher expression observed in astrocytomas by Western blot analysis was related to the higher vascular density within the tumor tissue. CONCLUSIONS: These results indicate a constitutive expression of BCRP in human endothelial cells, representing an important barrier against drug access to the brain. In particular, the strong BCRP expression in the microvasculature of epileptogenic brain tumors could critically influence the bioavailability of drugs within the tumor and contribute to pharmacoresistance.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Oncolytic virotherapy of meningiomas in vitro with replication-competent adenovirus.

OBJECTIVE: To evaluate the efficacy of the conditionally replicating adenovirus (Ad) Ad.d24 for oncolysis of benign and malignant meningiomas. METHODS: Primary meningioma cells and organotypic spheroids were cultured from tumor biopsies of 12 consecutive unselected patients. Four different Ads were constructed and tested on meningioma cells and spheroids: a replication-deficient Ad encoding the luciferase marker gene (Ad.Luc), a replication-competent Ad with complete E1 region (Ad.E1+), a replication-competent Ad encoding the luciferase gene in the E3 region (Ad.E1Luc), and a conditionally replicating Ad with an E1ACR2 deletion (Ad.d24). Replication of the latter is restricted to cells with a defective retinoblastoma pathway, whereas Ad.E1+ and Ad.E1Luc can replicate in all human cells like a wild-type Ad. Their oncolytic activity was compared in primary meningioma cells and spheroids by use of viability and outgrowth assays. RESULTS: Adenoviral penetration into organotypic meningioma spheroids was detected with the replication-competent Ad.E1Luc, whereas infection with the replication-deficient Ad.Luc was limited to the outer layer of the spheroid. Replication of the Ads and oncolysis was demonstrated in primary cell cultures of meningioma cells at high dose, i.e., greater than 50 plaque-forming units per cell. At a lower dose of 5 plaque-forming units per cell, Ad.d24 kills meningioma cells more efficiently than Ad.E1+. Infection of organotypic meningioma spheroids with Ad.d24 resulted in decreased viability and suppression of outgrowth as compared with untreated control spheroids. CONCLUSION: Infection of meningioma cells and spheroids with replication-competent Ads results in efficient oncolysis. The Ad modified to replicate selectively in retinoblast-mutant cells, Ad.d24, seemed to be an efficient oncolytic agent in benign, atypical, and malignant meningiomas.

Adenoviridae↗

PubMed2004

Clinical predictors of bacterial involvement in exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: The wide use of antibiotics for treatment of exacerbations of chronic obstructive pulmonary disease (COPD) lacks evidence. The efficacy is debatable, and bacterial involvement in exacerbation is difficult to verify. The aim of this prospective study was to identify factors that can help to estimate the probability that a microorganism is involved in exacerbation of COPD and, therefore, predict the success of antibiotic treatment. METHODS: Clinical data and sputum samples were obtained from 116 patients during exacerbation of COPD. Bacterial infection was defined by the abundant presence of >or=1 potential pathological microorganism in relation to the normal flora in sputum. RESULTS: Of 116 exacerbations, 22 (19%) had bacterial involvement. The combination of a negative result of a sputum Gram stain, a relevant nonclinical decrease in lung function (compared with baseline measurements), and occurrence of <2 exacerbations in the previous year were 100% predictive of a nonbacterial origin of the exacerbation. The presence of all 3 of these clinical characteristics yielded a positive predictive value of 67% for a bacterial exacerbation. CONCLUSIONS: Patients presenting with an exacerbation who have a negative result of sputum Gram stain, do not have a clinically relevant decrease in lung function, and have experienced <2 exacerbations of COPD in the previous year do not require antibiotic treatment [corrected]. A treatment protocol taking into account these variables might lead to a 5%-24% reduction in unnecessary treatment with antibiotics, depending on actual prescription rates.

Administration, Inhalation↗

PubMed2004

Cutting edge: activity of human adult microglia in response to CC chemokine ligand 21.

The approximately 50 known chemokines are classified in distinct subfamilies: CXC, CC, CX3C, and C. Although the signaling of chemokines often is promiscuous, signaling events between members of these distinct chemokine classes are hardly observed. The only known exception so far is the murine CC chemokine ligand (CCL)21 (secondary lymphoid tissue chemokine, Exodus-2, 6Ckine), which binds and activates the murine CXC chemokine receptor CXCR3. However, this exception has not been found in humans. In this study, we provide evidence that human CCL21 is a functional ligand for endogenously expressed CXCR3 in human adult microglia. In absence of CCR7 expression, CCL21 induced chemotaxis of human microglia with efficiency similar to the CXCR3 ligands CXC chemokine ligand 9 (monokine induced by IFN-gamma) and CXC chemokine ligand 10 (IFN-gamma-inducible protein-10). Because human CCL21 did not show any effects in CXCR3-transfected HEK293 cells, it is indicated that CXCR3 signaling depends on the cellular background in which the CXCR3 is expressed.

Adult↗

PubMed2004

A qualitative evaluation of a comprehensive self-management programme for COPD patients: effectiveness from the patients' perspective.

The COPE self-management programme, including a self-management education course, self-treatment of exacerbations and a fitness programme, appeared to have no significant effect on health related quality of life (HRQoL) as measured by the St. George's Respiratory Questionnaire (SGRQ). This is in contrast to our hypothesis and despite expressions of satisfaction of patients to healthcare workers. To understand this discrepancy, a qualitative study was performed. A purposive sample of 20 participants of the COPE self-management programme were interviewed at home using in-depth, semi-structured interviews. Interviews were audio taped and transcribed verbatim and analysed according grounded theory. The fitness programme was most positively evaluated by patients due to the perceived increase of exercise capacity and the social aspect of the group training. Major effects gained by the self-management education course reported by patients were the skills to evenly distribute their energy and to listen to their body signals. Most patients thought favourable about self-treatment of exacerbations. The possibility to start early, not having to call a doctor and autonomy were raised as important advantages. Furthermore, several patients reported increased self-confidence and coping behaviour as important effects of the COPE programme. Finally, many patients reported feeling safe due to the frequent follow-up visits and 24h access to the hospital, and this aspect elicited to be very important. In this study, the qualitative interviews suggest that the SGRQ and possibly other existing HRQoL instruments might fail to capture the full experience of patients in self-management studies. The need for more elaborate qualitative research on this subject is indicated.

Adaptation, Psychological↗

PubMed2004

Managing COPD: no more nihilism!

This special issue of Patient Education and Counseling is long overdue. During most of the last two decades asthma, and notably asthma self-management has been in the spotlight, while COPD has had to endure a nihilistic approach. The first sign that interest was shifting to the treatment of COPD came from a few large randomized trials on the use of inhaled corticosteroids (ICS) in COPD. Although these studies demonstrated a moderate effect of ICS in COPD, it has become clear that true improvements in the management of this chronic disease will have to come from behavioral interventions. This special issue of Patient Education and Counseling is dedicated solely to the non-pharmaceutical management of COPD. It addresses many issues related to behavioral therapy, such as smoking cessation, exercise training, nutritional aspects, and self-management programs, including action plans to self-treat exacerbations. With the availability of all the treatment and management options, described in this special issue, a nihilistic attitude toward the patient with COPD is no longer justified.

Adrenal Cortex Hormones↗

PubMed2004

Management of stable COPD.

Chronic obstructive pulmonary disease (COPD) is a systemic disease with major impact worldwide. In the treatment of COPD a holistic approach should be taken. In order to reach this, an individual treatment plan should be made which includes at least elements of smoking cessation, optimisation of pulmonary status by pharmacotherapy and exercise embedded in a new lifestyle. Furthermore, more research on nutritional and metabolic intervention strategies for COPD patients is needed. With the availability of all these treatment options, a nihilistic attitude toward the patient with COPD is no longer justified.

Adrenal Cortex Hormones↗

PubMed2004

The effect of a minimal contact smoking cessation programme in out-patients with chronic obstructive pulmonary disease: a pre-post-test study.

This study assessed the efficacy of an individual, minimal contact, smoking cessation programme in chronic obstructive pulmonary disease (COPD) patients, using a pre-post-test design. The study was part of a large ongoing investigation into the efficacy of self-management in patients with COPD (the COPE-study). In total, the participants received three 15-30 min home-based counselling sessions. Additionally, patients were provided with a written self-help manual. On the patient's request, the chest physician prescribed bupropion or nicotine replacement therapy (NRT). Cessation rates after nine months were based on self-report, and afterwards confirmed by salivary cotinine analysis. Patients were biochemically classified as smoker if their cotinine levels exceeded 20 ng/ml. At baseline, one third of the 269 patients in the COPE-study were active smokers (according to self-report). Almost 70% (n=64) of these patients were willing to participate in the smoking cessation program. After nine months follow-up, 23 (36.5%) patients self-reported abstinence. However, the cotinine validated abstinence rate was much lower: 12.7% (n=8), implying that the actual abstinence rate is severely overestimated by self-report in this study. The results suggest that the (validated) effectiveness of this intervention is probably in line with that of comparable programmes for "healthy" persons. However, considering the urgent need for quitting in COPD patients, a more intensive programme resulting in higher quit rates, seems to be required for this high-risk population.

Adult↗