Showing papers by "Erasmus University Medical Center published in 2006"

The Dutch tariff: results and arguments for an effective design for national EQ-5D valuation studies

Abstract: The objective of this study was to estimate a Dutch EQ-5D tariff and to determine in a simulation study using the dataset of the original UK valuation study, the number of health states and respondents needed to estimate a reliable tariff. In all, 300 Dutch respondents directly valued 17 states compared to 3000 respondents and 42 states in the original MVH protocol. The results reaffirmed differences in health-related preferences between countries, justifying the estimation of national tariffs. The mean absolute error was 0.030. The design of this study is recommended for national EQ-5D valuation studies.

An antibody-deficiency syndrome due to mutations in the CD19 gene

Abstract: BACKGROUND: The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen. METHODS: We evaluated four patients from two unrelated families who had increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of mature B cells in blood. We found a mutation in the CD19 gene in all four patients. The CD19 gene in the patients and their first-degree relatives was sequenced, and flow-cytometric immunophenotyping of B cells, immunohistochemical staining of lymphoid tissues, and DNA and messenger RNA analysis were performed. B-cell responses on the triggering of the B-cell receptor were investigated by in vitro stimulation; the antibody response after vaccination with rabies vaccine was also studied. RESULTS: All four patients had homozygous mutations in the CD19 gene. Levels of CD19 were undetectable in one patient and substantially decreased in the other three. Levels of CD21 were decreased, whereas levels of CD81 and CD225 were normal, in all four patients. The composition of the precursor B-cell compartment in bone marrow and the total numbers of B cells in blood were normal. However, the numbers of CD27+ memory B cells and CD5+ B cells were decreased. Secondary follicles in lymphoid tissues were small to normal in size and had a normal cellular composition. The few B cells that showed molecular signs of switching from one immunoglobulin class to another contained V H-C α and V H-C γ transcripts with somatic mutations. The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired, and in all four patients, the antibody response to rabies vaccination was poor. CONCLUSIONS: Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective. Copyright

Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4

Abstract: DNA double-strand break (DSB) repair by nonhomologous end joining (NHEJ) requires the assembly of several proteins on DNA ends. Although biochemical studies have elucidated several aspects of the NHEJ reaction mechanism, much less is known about NHEJ in living cells, mainly because of the inability to visualize NHEJ repair proteins at DNA damage. Here we provide evidence that a pulsed near IR laser can produce DSBs without any visible alterations in the nucleus, and we show that NHEJ proteins accumulate in the irradiated areas. The levels of DSBs and Ku accumulation diminished in time, showing that this approach allows us to study DNA repair kinetics in vivo. Remarkably, the Ku heterodimers on DNA ends were in dynamic equilibrium with Ku70/80 in solution, showing that NHEJ complex assembly is reversible. Accumulation of XRCC4/ligase IV on DSBs depended on the presence of Ku70/80, but not DNA-PKCS. We detected a direct interaction between Ku70 and XRCC4 that could explain these requirements. Our results suggest that this assembly constitutes the core of the NHEJ reaction and that XRCC4 may serve as a flexible tether between Ku70/80 and ligase IV.

Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome

Abstract: Arterial tortuosity syndrome (ATS) is an autosomal recessive disorder characterized by tortuosity, elongation, stenosis and aneurysm formation in the major arteries owing to disruption of elastic fibers in the medial layer of the arterial wall1. Previously, we used homozygosity mapping to map a candidate locus in a 4.1-Mb region on chromosome 20q13.1 (ref. 2). Here, we narrowed the candidate region to 1.2 Mb containing seven genes. Mutations in one of these genes, SLC2A10, encoding the facilitative glucose transporter GLUT10, were identified in six ATS families. GLUT10 deficiency is associated with upregulation of the TGFβ pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome, in which aortic aneurysms associate with arterial tortuosity3. The identification of a glucose transporter gene responsible for altered arterial morphogenesis is notable in light of the previously suggested link between GLUT10 and type 2 diabetes4,5. Our data could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggest that therapeutic compounds intervening with TGFβ signaling represent a new treatment strategy.

C-Reactive Protein Levels, Variation in the C-Reactive Protein Gene, and Cancer Risk: The Rotterdam Study

Abstract: Purpose It remains unclear if inflammation itself may induce cancer, if inflammation is a result of tumor growth, or a combination of both exists. The aim of this study was to examine whether C-reactive protein (CRP) levels and CRP gene variations were associated with an altered risk of colorectal, lung, breast, or prostate cancer. Patients and Methods A total of 7,017 participants age ≥ 55 years from the Rotterdam Study were eligible for analyses. Mean follow-up time was 10.2 years. High-sensitivity CRP measurements were performed to identify additional values of 0.2 to 1.0 mg/L compared with standard procedures. Genotypes of the CRP gene were determined with an allelic discrimination assay. Results High levels (> 3 mg/L) of CRP were associated with an increased risk of incident cancer (hazard ratio, 1.4; 95% CI, 1.1 to 1.7) compared with persons with low levels (< 1 mg/L), even after a potential latent period of 5 years was introduced. Although CRP seems to affect several cancer sites, the association w...

Neural crest–derived cells with stem cell features can be traced back to multiple lineages in the adult skin

Abstract: Given their accessibility, multipotent skin-derived cells might be useful for future cell replacement therapies. We describe the isolation of multipotent stem cell-like cells from the adult trunk skin of mice and humans that express the neural crest stem cell markers p75 and Sox10 and display extensive self-renewal capacity in sphere cultures. To determine the origin of these cells, we genetically mapped the fate of neural crest cells in face and trunk skin of mouse. In whisker follicles of the face, many mesenchymal structures are neural crest derived and appear to contain cells with sphere-forming potential. In the trunk skin, however, sphere-forming neural crest-derived cells are restricted to the glial and melanocyte lineages. Thus, self-renewing cells in the adult skin can be obtained from several neural crest derivatives, and these are of distinct nature in face and trunk skin. These findings are relevant for the design of therapeutic strategies because the potential of stem and progenitor cells in vivo likely depends on their nature and origin.

Outcome of non-invasive treatment modalities on back pain: an evidence-based review.

Abstract: At present, there is an increasing international trend towards evidence-based health care. The field of low back pain (LBP) research in primary care is an excellent example of evidence-based health care because there is a huge body of evidence from randomized trials. These trials have been summarized in a large number of systematic reviews. This paper summarizes the best available evidence from systematic reviews conducted within the framework of the Cochrane Back Review Group on non-invasive treatments for non-specific LBP. Data were gathered from the latest Cochrane Database of Systematic Reviews 2005, Issue 2. The Cochrane reviews were updated with additional trials, if available. Traditional NSAIDs, muscle relaxants, and advice to stay active are effective for short-term pain relief in acute LBP. Advice to stay active is also effective for long-term improvement of function in acute LBP. In chronic LBP, various interventions are effective for short-term pain relief, i.e. antidepressants, COX2 inhibitors, back schools, progressive relaxation, cognitive–respondent treatment, exercise therapy, and intensive multidisciplinary treatment. Several treatments are also effective for short-term improvement of function in chronic LBP, namely COX2 inhibitors, back schools, progressive relaxation, exercise therapy, and multidisciplinary treatment. There is no evidence that any of these interventions provides long-term effects on pain and function. Also, many trials showed methodological weaknesses, effects are compared to placebo, no treatment or waiting list controls, and effect sizes are small. Future trials should meet current quality standards and have adequate sample size.

A Randomized, Blinded, Multicenter Trial of Lipid-Associated Amphotericin B Alone versus in Combination with an Antibody-Based Inhibitor of Heat Shock Protein 90 in Patients with Invasive Candidiasis

Abstract: BACKGROUND: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.

Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function

Abstract: Airway DCs play a crucial role in the pathogenesis of allergic asthma, and interfering with their function could constitute a novel form of therapy. The sphingosine 1-phosphate receptor agonist FTY720 is an oral immunosuppressant that retains lymphocytes in lymph nodes and spleen, thus preventing lymphocyte migration to inflammatory sites. The accompanying lymphopenia could be a serious side effect that would preclude the use of FTY720 as an antiasthmatic drug. Here we show in a murine asthma model that local application of FTY720 via inhalation prior to or during ongoing allergen challenge suppresses Th2-dependent eosinophilic airway inflammation and bronchial hyperresponsiveness without causing lymphopenia and T cell retention in the lymph nodes. Effectiveness of local treatment was achieved by inhibition of the migration of lung DCs to the mediastinal lymph nodes, which in turn inhibited the formation of allergen-specific Th2 cells in lymph nodes. Also, FTY720-treated DCs were intrinsically less potent in activating naive and effector Th2 cells due to a reduced capacity to form stable interactions with T cells and thus to form an immunological synapse. These data support the concept that targeting the function of airway DCs with locally acting drugs is a powerful new strategy in the treatment of asthma.

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force

Abstract: Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system An overview of the management of classical PNS, ie paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given Myasthenia gravis and paraproteinemic neuropathies are not included in this report No evidence-based recommendations were possible, but good practice points were agreed by consensus Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search PDG-PET is useful if the initial radiological tumour screen is negative Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction Symptomatic therapy should be offered to all patients with PNS

CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease.

Abstract: Objectives: To analyze the diagnostic sensitivity and specificity of various brain-derived proteins (14-3-3, Tau, neuron specific enolase [NSE], and S100b) in the CSF of patients with Creutzfeldt-Jakob disease (CJD) and to analyze biologic factors that modify these parameters. Methods: CSF was tested for 14-3-3, Tau, NSE, and S100b in 1,859 patients with sporadic, genetic, iatrogenic, and variant CJD, and in 1,117 controls. Results: The highest sensitivity was achieved for 14-3-3 and Tau in sporadic CJD (85% and 86%), and a combined determination of 14-3-3 and Tau, S100b, or NSE increased the sensitivity to over 93%. A multivariate analysis showed that the sensitivity of all tests was highest in patients with the shortest disease duration, age at onset >40 years, and homozygosity at codon 129 of the prion protein gene. In a group of patients with repeated lumbar punctures, a second test also increased the diagnostic sensitivity. Conclusions: The detection of elevated levels of brain-derived proteins in the CSF in patients with suspected Creutzfeldt-Jakob disease is a valuable diagnostic test. A second lumbar puncture may be of value in patients with atypical clinical course in whom the first test was negative.

BRCA1 Mutation Analysis of 41 Human Breast Cancer Cell Lines Reveals Three New Deleterious Mutants

Abstract: Germ line mutations of the BRCA1 gene confer a high risk of breast cancer and ovarian cancer to female mutation carriers. The BRCA1 protein is involved in the regulation of DNA repair. How specific tumor-associated mutations affect the molecular function of BRCA1, however, awaits further elucidation. Cell lines that harbor BRCA1 gene mutations are invaluable tools for such functional studies. Up to now, the HCC1937 cell line was the only human breast cancer cell line with an identified BRCA1 mutation. In this study, we identified three other BRCA1 mutants from among 41 human breast cancer cell lines by sequencing of the complete coding sequence of BRCA1. Cell line MDA-MB-436 had the 5396 + 1G>A mutation in the splice donor site of exon 20. Cell line SUM149PT carried the 2288delT mutation and SUM1315MO2 carried the 185delAG mutation. All three mutations were accompanied by loss of the other BRCA1 allele. The 185delAG and 5396 + 1G>A mutations are both classified as pathogenic mutations. In contrast with wild-type cell lines, none of the BRCA1 mutants expressed nuclear BRCA1 proteins as detected with Ab-1 and Ab-2 anti-BRCA1 monoclonal antibodies. These three new human BRCA1 mutant cell lines thus seem to be representative breast cancer models that could aid in further unraveling of the function of BRCA1.

Perceived parenting style and practices and the consumption of sugar-sweetened beverages by adolescents

Abstract: The purpose of this study was to investigate whether perceived parenting practices and parenting style dimensions (strictness and involvement) are associated with adolescents' consumption of sugar-sweetened beverages. In this cross-sectional study, secondary school students (n = 383, mean age 13.5 years) completed a self-administered questionnaire on their consumption of sugar-sweetened beverages, attitude, social influences, self-efficacy, habit strength, food-related parenting practices and the general parenting style dimensions of 'strictness' and 'involvement'. Data were analyzed using multiple linear regression analyses. More restrictive parenting practices were associated with lower consumption of sugar-sweetened beverages (β = -38.0 ml; 95% CI = -48.1, -28.0). This association was highly mediated (∼55%) by attitude, self-efficacy and modeling from parents. Nevertheless, a significant direct effect remained (β = -17.1 ml; 95% CI = -27.2, -6.90). Interactions between perceived parenting style and parenting practices showed that the association between parenting practices and sugar-sweetened beverage consumption was stronger among adolescents who perceived their parents as being moderately strict and highly involved. Parents influence their children's sugar-sweetened beverage consumption and should therefore be involved in interventions aimed at changing dietary behaviors. Interventions aimed at the promotion of healthy parenting practices will improve when they are tailored to the general parenting style of the participants.

Clinical pharmacokinetics of docetaxel : recent developments.

Abstract: Docetaxel belongs to the class of taxane antineoplastic agents that act by inducing microtubular stability and disrupting the dynamics of the microtubular network. The drug has shown a broad spectrum of antitumour activity in preclinical models as well as clinically, with responses observed in various disease types, including advanced breast cancer and non-small cell lung cancer. The pharmacokinetics and metabolism of docetaxel are extremely complex and have been the subject of intensive investigation in recent years. Docetaxel is subject to extensive metabolic conversion by the cytochrome P450 (CYP) 3A isoenzymes, which results in several pharmacologically inactive oxidation products. Elimination routes of docetaxel are also dependent on the presence of drug-transporting proteins, notably P-glycoprotein, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, impact substantially on interindividual variability in drug handling. Strategies to individualise docetaxel administration schedules based on phenotypic or genotype-dependent differences in CYP3A expression are underway and may ultimately lead to more selective chemotherapeutic use of this agent.

TMPRSS2:ERG Fusion by Translocation or Interstitial Deletion Is Highly Relevant in Androgen-Dependent Prostate Cancer, But Is Bypassed in Late-Stage Androgen Receptor–Negative Prostate Cancer

Abstract: Recently, a unique fusion between the prostate-specific, androgen-regulated TMPRSS2 gene and the ETS genes ERG, ETV1, or ETV4 has been described in clinical prostate cancer. We investigated mechanisms of expression of four ETS genes, ERG, ETV1, ETV4, and FLI1, in 11 xenografts representing different stages of prostate cancer. All five androgen-dependent xenografts showed as major transcript overexpression of two splice variants of TMPRSS2:ERG, linking TMPRSS2 exon 1 or 2 sequences to ERG exon 4. In one of two androgen-sensitive xenografts, fusion transcripts of TMPRSS2 and ETV1 were detected. Array-based comparative genomic hybridization and interphase fluorescence in situ hybridization indicated both interstitial deletions and translocations as mechanisms of TMPRSS2:ERG gene fusion. Importantly, TMPRSS2 to ERG fusions were also observed in three of four androgen-independent, androgen receptor (AR)-negative xenografts and in two AR-negative clinical prostate cancer specimens; however, the fusion gene was not expressed. In almost all AR-negative tumor samples, overexpression of wild-type ETV4 or FLI1 was detected. Combined, our observations indicate a key role of fusion of TMPRSS2 and ETS genes in most androgen-regulated prostate cancers, which might be bypassed by androgen-independent expression of wild-type ETS factors in late-stage disease.

High von Willebrand Factor Levels Increase the Risk of First Ischemic Stroke Influence of ADAMTS13, Inflammation, and Genetic Variability

Abstract: Background and Purpose— Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism. Methods— In a case-control study of 124 first-ever ischemic stroke patients and 125 age- and sex-matched controls, we studied vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), ADAMTS13 activity, the −1793C/G polymorphism in the vWF gene, and C-reactive protein. Results— vWF antigen and activity levels were significantly higher in cases than in controls. The relative risk of ischemic stroke was highest in individuals in the upper quartile of vWF:Ag (odds ratio, 3.2; ...

Impaired genome maintenance suppresses the growth hormone-insulin-like growth factor 1 axis in mice with cockayne syndrome

Abstract: Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

C-reactive protein in atherosclerosis: A causal factor?

Abstract: Atherosclerosis is considered a to be multifactorial disease driven by inflammatory reactions. The process of inflammation also contributes to the pathogenesis of acute atherothrombotic events. C-reactive protein (CRP) is an acute phase protein and its concentration in serum reflects the inflammatory condition of the patient. Levels of CRP are consistently associated with cardiovascular disease (CVD) and predict myocardial infarctions and stroke. Since CRP is present in the atherosclerotic lesion, it may actively contribute to the progression and/or instability of the atherosclerotic plaque. The role of CRP in inflammation and its causality in atherosclerosis are the subject of many investigations but are not yet fully elucidated. This review focuses on recently identified mechanisms by which CRP may modulate and evolve the process of atherosclerosis. We discuss the function of CRP and review the most recent evidence for an independent role of CRP in the development of atherosclerosis. Many studies suggest such a role, but a number of the described effects may be the result of contamination of the CRP preparations.