Showing papers by "Maastricht University published in 2002"
TL;DR: In this paper, the authors explore 40 years of data on R&D partnerships and present an analysis of some basic historical trends and sectoral patterns in R&DM partnering since 1960, and also provide an overview of some major international (sectoral) patterns in the forming of RDR partnerships within the Triad (North America, Europe and Asia).
1,811 citations
TL;DR: Long-term exposure to traffic-related air pollution may shorten life expectancy, and the association between exposure to air pollution and (cause specific) mortality was assessed with Cox's proportional hazards models.
1,557 citations
TL;DR: Both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate, and the role of structural remodeling in the progression of AF is still unclear.
Abstract: The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided a possible explanation for the progressive nature of this arrhythmia. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to an increase in stability of AF. However, 'domestication of AF' must also depend on a 'second factor' since the persistence of AF continues to increase after electrical remodeling has been completed. Atrial contractile remodeling (loss of contractility) leads to a reduced atrial transport function after cardioversion of AF. An important clinical consequence is that during several days after restoration of sinus rhythm, the risk of atrial thrombus formation is still high. In addition, the reduction of atrial contractility during AF may enhance atrial dilatation which may add to the persistence of AF. Tachycardia-induced structural remodeling takes place in a different time domain (weeks to months). Myolysis probably contributes to the loss of atrial contractile force. Although it might explain the loss of efficacy of pharmacological cardioversion and the development of permanent AF, the role of structural remodeling in the progression of AF is still unclear. Atrial structural remodeling also occurs as a result of heart failure and other underlying cardiovascular diseases. The associated atrial fibrosis might explain intra-atrial conduction disturbances and the susceptibility for AF. Thus, both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate. New strategies for prevention and termination of AF should be build on our knowledge of the mechanisms and time course of AF-induced atrial remodeling.
1,339 citations
TL;DR: This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis as well as the pathogenic potential of antibodies alone.
Abstract: Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo(-/-)) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2-deficient (Rag2(-/-)) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 x 10(8) or 5 x 10(7) anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2(-/-) mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis.
1,063 citations
TL;DR: The objective of this study was to report on the incidence of and factors related to the occurrence of central nervous system metastases in a cohort of patients who were diagnosed with colorectal, lung, breast, or kidney carcinoma or melanoma.
Abstract: Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands ljschouten@epidunimaasnl BACKGROUND: The objective of this study was to report on the incidence of and factors related to the occurrence of central nervous system metastases in a cohort of patients who were diagnosed with colorectal, lung, breast, or kidney carcinoma or melanoma METHODS: Using the population-based Maastricht Cancer Registry (MCR), a cohort was created of patients with colorectal carcinoma (n = 720 patients), lung carcinoma (n = 938 patients), breast carcinoma (n = 802 patients), renal carcinoma (n = 114 patients), and melanoma (n = 150 patients) The patients had to live in the catchment area of the University Hospital Maastricht (UHM) and had to have been diagnosed at the UHM during the period 1986-1995 Patients with brain metastases were searched for by linking the MCR to the Neuro-Oncology Registry of the UHM Radiology files were checked as well Follow-up lasted until December 31, 1998 RESULTS: Brain metastases were diagnosed in 232 patients (85%) in the cohort (n = 2724 patients) Of these patients, 84 patients were diagnosed with brain metastases within 1 month after their primary diagnosis, 82 patients were diagnosed with brain metastases within 1 year of their primary diagnosis, and 66 patients were diagnosed with brain metastases more than 1 year after their primary diagnosis The cumulative incidence after 5 years was estimated at 163% in patients with lung carcinoma, 98% in patients with renal carcinoma, 74% in patients with melanoma, 50% in patients with breast carcinoma, and 12% in patients with colorectal carcinoma The incidence was lower in patients age > or = 70 years compared with younger patients (breast and lung carcinoma), lower in patients who were diagnosed before 1991 compared with patients who were diagnosed after 1991 (breast and lung carcinoma), and lower in patients who had nonsmall cell lung carcinoma compared with patients who had small cell lung carcinoma CONCLUSIONS: The frequency of brain metastases in this cohort was highest in patients with lung carcinoma, followed by patients with renal carcinoma There was no evidence of an increasing incidence of brain metastasis in patients with carcinoma of the breast or lung
935 citations
TL;DR: Development of guidelines based on a systematic review of the evidence in reports of systematic searches of the literature for diagnostic research, of methodological criteria to evaluate diagnosticResearch, of methods for statistical pooling of data on diagnostic accuracy, and of ways for exploring heterogeneity are developed.
Abstract: Although guidelines for critical appraisal of diagnostic research and meta-analyses have already been published, these may be difficult to understand for clinical researchers or do not provide enough detailed information. Development of guidelines based on a systematic review of the evidence in reports of systematic searches of the literature for diagnostic research, of methodological criteria to evaluate diagnostic research, of methods for statistical pooling of data on diagnostic accuracy, and of methods for exploring heterogeneity. Guidelines for conducting diagnostic systematic reviews are presented in a stepwise fashion and are followed by comments providing further information. Examples are given using the results of two systematic reviews on the accuracy of the urine dipstick in the diagnosis of urinary tract infections, and on the accuracy of the straight-leg-raising test in the diagnosis of intervertebral disc hernia.
899 citations
TL;DR: Using cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer shows that this approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone.
Abstract: Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position.We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.
879 citations
TL;DR: In this paper, the authors present instructional techniques for increasing germane cognitive load in studying worked examples, effects of example elaboration training on decreasing cognitive interference and overload (Stark, Mandl, Gruber, & Renkl), CLT-based instructional design when dealing with very high element interactivity material (Pollock, Chandler, & Sweller), effects of worked examples on older learners (Van Gerven, Paas, & Schmidt), a cognitive theory of multimedia learning (Mayer & Moreno), and the use of external representations to help manage CL in Computer Supported
728 citations
TL;DR: It was concluded that rats with partial lesions of the ventrolateral CPu are the most appropriate models to study early and late stages of PD.
719 citations
TL;DR: In this paper, the authors explore the preferences that companies have as they use alternative (quasi) external sources of innovative competencies such as strategic technology alliances, mergers and acquisitions, or a mix of these.
Abstract: This paper explores the preferences that companies have as they use alternative (quasi) external sources of innovative competencies such as strategic technology alliances, mergers and acquisitions, or a mix of these. These alternatives are studied in the context of distinct industrial, technological and international settings during the first half of the 1990s. Different strategies followed by companies and the role played by routinized sets of preferences are also taken into consideration. The analysis demonstrates that these options are influenced by both different environmental conditions and firm specific circumstances, such as those related to protecting core businesses.
681 citations
TL;DR: Results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2α and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.
Abstract: Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2alpha on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2alpha, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2alpha attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2alpha kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2alpha. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2alpha and reduced inhibition of protein synthesis in response to hypoxia. PERK(-/-) mouse embryo fibroblasts failed to phosphorylate eIF2alpha and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2alpha and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.
TL;DR: In vivo arterial stiffness is a dynamic property based on vascular function and structure that is influenced by confounding factors like blood pressure, age, gender, body mass index, heart rate, and treatment, so standardization of the measurement conditions is imperative.
TL;DR: The thrombogram in PPP appears to be a broad function test of the haemostatic-thrombotic mechanism of the blood.
Abstract: Summary By using a “slow” fluorogenic thrombin substrate and continuous comparison to a simultaneously run calibrator, thrombin generation can be monitored automatically, on line, in clotting PPP or PRP at a throughput of up to 100 samples per hour The resulting “Thrombogram” in PPP measures hypocoagulability (haemophilias, oral anticoagulants, heparins (-likes), direct inhibitors) and hypercoagulabilities (AT deficiency, prothrombin hyperexpression, protC and S deficiency, factor V Leiden, oral contraceptives) In PRP it is diminished in thrombopathies, in von Willebrand disease, by antibodies blocking GPIIb-IIIa or GPIb, or by antiplatelet drugs like aspirin and clopidogrel Lupus anticoagulant both retards and increases thrombin generationThe thrombogram thus appears to be a broad function test of the haemostatic- thrombotic mechanism of the blood
TL;DR: Platelet activation and blood coagulation are complementary, mutually dependent processes in haemostasis and thrombosis and platelets take over the initiating role of tissue factor and factor VIIa in coagulations activation.
Abstract: Platelet activation and blood coagulation are complementary, mutually dependent processes in haemostasis and thrombosis. Platelets interact with several coagulation factors, while the coagulation product thrombin is a potent platelet-activating agonist. Activated platelets come in a procoagulant state after a prolonged elevation in cytosolic [Ca2+]i. Such platelets, e. g. when adhering to collagen via glycoprotein VI, expose phosphatidylserine (PS) at their outer surface and produce (PS-exposing) membrane blebs and microvesicles. Inhibition of aminophospholipid translocase and activation of phospholipid scramblase mediate the exposure of PS, whereas calpain-mediated protein cleavage leads to membrane blebbing and vesiculation. Surface-exposed PS strongly propagates the coagulation process by facilitating the assembly and activation of tenase and prothrombinase complexes. Factor IXa and platelet-bound factor Va support these activities. In addition, platelets can support the initiation phase of coagulation by providing binding sites for prothrombin and factor XI. They thereby take over the initiating role of tissue factor and factor VIIa in coagulation activation.
TL;DR: In this article, the authors briefly review the distribution of psychotic symptoms in non-clinical populations, the developmental aspects of psychosis proneness, and the outcome characteristics of psychosis-prone subjects.
TL;DR: The findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used.
TL;DR: In this article, the authors examined the relationship between self-efficacy and symptoms of affective disorders in a large sample of normal adolescents (n =596) and found that low levels of selfefficacy generally were accompanied by high levels of trait anxiety/neuroticism, anxiety disorders symptoms, and depressive symptoms.
TL;DR: A fall risk model converted to a "desk model," consisting of the predictors postural sway, fall history, hand dynamometry, and depression, provides added value in the identification of community-dwelling elderly at risk for recurrent falling and facilitates the prediction of recurrent falls.
TL;DR: Time series analysis of the daily measures showed that improvements in pain-related fear and pain catastrophizing occurred only during the exposure in vivo and not during the graded activity, irrespective of the treatment order.
Abstract: Background and objective: Several cognitive–behavioral factors contribute to the persistence of pain disability in patients with chronic back pain. Fear-avoidance beliefs and fear of movement/(re)injury in particular have been shown to be strong predictors of physical performance and pain disability. Patients reporting substantial pain-related fear might benefit from exposure in vivo to a set of individually tailored, fear-eliciting, and hierarchically ordered physical movements rather than more general graded activity. Patients and interventions: Six consecutive patients with chronic low back pain who reported substantial fear of movement/(re)injury were included in the study. After a no-treatment baseline measurement period, the patients were randomly assigned to one of two interventions. In the first intervention, patients received exposure in vivo first, followed by graded activity. In the second intervention, the sequence of treatment modules was reversed. Before each treatment module, treatment credibility was assessed. Daily measures of pain-related fear, pain catastrophizing, and pain intensity were completed using visual analog scales. In addition, standardized measures of pain disability, pain-related fear, and pain vigilance were taken before and after each treatment module and at the 1-year follow-up. To obtain more objective data on actual activity levels, an ambulatory activity monitor was carried by the patients during 1 week before and after each treatment module. Results: Time series analysis of the daily measures showed that improvements in pain-related fear and pain catastrophizing occurred only during the exposure in vivo and not during the graded activity, irrespective of the treatment order. Analysis of the pretreatment to post-treatment differences also revealed that decreases in pain-related fear also concurred with decreases in pain disability and pain vigilance and an increase in physical activity levels. All improvements remained at the 1-year follow-up.
TL;DR: Investigation of psychometrics of three traditional and new childhood anxiety scales in a large sample of normal adolescents found them to be reliable in terms of internal consistency and evidence was obtained for the convergent and divergent validity of the various anxiety questionnaires.
TL;DR: Assessment of the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depression symptoms in cancer patients undergoing cytokine therapy indicates that the development of depressive symptoms in patients undergoing chemotherapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophile.
Abstract: Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood-brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.
TL;DR: A potential mechanism of increased immunosurveillance during inflammation at the site in which ascending bacteria enter the kidney tissue, i.e., the collecting ducts and the distal part of the nephron is indicated.
Abstract: The reported requirement of functional Toll-like receptor (TLR)4 for resistance to Gram-negative pyelonephritis prompted us to localize the expression of TLR2 and TLR4 mRNA in the kidney at the cellular level by in situ hybridization The majority of the constitutive TLR2 and TLR4 mRNA expression was found to be strategically located in the renal epithelial cells Assuming that the TLR mRNA expression is representative of apical protein expression, this suggests that these cells are able to detect and react with bacteria present in the lumen of the tubules To gain insight in the regulation of TLR expression during inflammation, we used a model for renal inflammation Renal inflammation evoked by ischemia markedly enhanced synthesis of TLR2 and TLR4 mRNA in the distal tubular epithelium, the thin limb of Henle’s loop, and collecting ducts The increased renal TLR4 mRNA expression was associated with significant elevation of renal TLR4 protein expression as evaluated by Western blotting Using RT-PCR, the enhanced TLR2 and TLR4 mRNA expression was shown to be completely dependent on the action of IFN-γ and TNF-α These results indicate a potential mechanism of increased immunosurveillance during inflammation at the site in which ascending bacteria enter the kidney tissue, ie, the collecting ducts and the distal part of the nephron
TL;DR: The results demonstrate that the matrix influences the efficacy of an antioxidant, and components in green and black tea, which show the highest masking in combination with beta-casein, are epigallocatechin gallate and gallic acid.
Abstract: Flavonoids are potent antioxidants. It is also known that flavonoids bind to proteins. The effect of the interaction between tea flavonoids and proteins on the antioxidant capacity was examined. Their separate and combined antioxidant capacities were measured with the Trolox equivalent antioxidant capacity (TEAC) assay. It was observed that the antioxidant capacity of several components of green and black tea with α-, β-, and κ-casein or albumin is not additive; that is, a part of the total antioxidant capacity is masked by the interaction. This masking depends on both the protein and the flavonoid used. Components in green and black tea, which show the highest masking in combination with β-casein, are epigallocatechin gallate and gallic acid. The results demonstrate that the matrix influences the efficacy of an antioxidant. Keywords: Antioxidant capacity; tea; flavonoids; casein; albumin; catechin
TL;DR: In this paper, an accounting framework for innovation is proposed, in which changes in output between periods (years, decades) or differences between spatial units (firms, industries, countries) are attributed to changes or differences in the inputs and in a residual that is known as total factor or multifactor productivity (TFP or MFP) or simply productivity.
Abstract: The purpose of this paper is to propose and illustrate an accounting framework for innovation. We characterize the intensity of innovation by a sales-weighted measure of innovation: the share of sales in innovative products, but other output indicators of innovation could be considered as well. Comparing statistics on the share of innovative sales across countries, industries, or firms measures but does not explain the intercountry, interindustry, or interfirm differences in innovation intensity. To have a more meaningful basis of comparison we need a model. If an exact model of innovation in its various dimensions existed and if we knew it, we would be able to understand fully why innovation differs among countries, industries, or firms. Of course, such a model does not exist. Nevertheless it is worth trying to account for innovation differences, if only very roughly. In such an endeavor, what remains to be explained is as important to consider as what can be explained, because it reflects the extent of innovative ability or capacity, or “innovativeness.” To motivate our approach better and make it more explicit, we find it appealing to draw a comparison with the standard framework for growth accounting and the underlying model of a production function. Production output is viewed as resulting from a process of transformation of inputs into output that can be represented and analyzed in terms of a production function. Based on the production function, an accounting framework can be constructed in which changes in output between periods (years, decades) or differences between spatial units (firms, industries, countries) are ascribed to changes or differences in the inputs and in a residual that is known as total factor or multifactor productivity (TFP or MFP) or simply productivity. Likewise, innovation output can be viewed as resulting from innovation inputs, such as R&D efforts, and other contextual determinants, such as the pressure of competition. This linkage can be represented in terms of an innovation function and an innovation accounting framework, on the basis of which changes in innovation output between periods or differences between spatial units can be ascribed to changes or differences in the factors of innovation and in a residual that we call innovativeness, or the unexplained ability to turn innovation inputs into innovation output. Innovativeness is thus to innovation what TFP is to production. Innovativeness is conditional on a model of an innovation function and a set of factors of innovation, just as TFP is conditional on an assumed specification of the production function and measured factors of production. Both correspond to omitted factors of performance such as technological, organizational, cultural, or environmental factors (and to other sources of misspecification errors), although TFP is commonly interpreted as being mainly an indicator of technology. The produc-
TL;DR: Levels of sTNF-R55, sT NF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with CopD after smoking cessation.
Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by significant chronic inflammation in the pulmonary compartment as well as in the circulation. This study aimed to elucidate the relationship between local and systemic inflammation in smoking-induced COPD by assessing levels of soluble (s) tumor necrosis factor (TNF) receptors, TNF-alpha, and interleukin-8 (IL-8) in induced sputum and in plasma. Sputum induction was performed in 18 subjects with COPD (FEV(1) 56% predicted) and 17 healthy smokers (FEV(1) 99% predicted). Patients with COPD showed significantly higher percentages of neutrophils and levels of sTNF-R55 and IL-8 in sputum as compared with control subjects, whereas sputum sTNF-R75 levels tended to be higher in COPD. Sputum TNF-alpha levels were similar in both groups. When comparing sTNF receptors in sputum and plasma, no direct correlations were found despite elevation of circulating sTNF-R75 levels in patients with COPD. In addition, sputum sTNF receptors were inversely related to the FEV(1) in patients with COPD, whereas circulating sTNF receptors were not, suggesting different regulation of inflammation in the pulmonary and systemic compartment. When subjects were divided according to their current smoking status, levels of sTNF-R55, sTNF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with COPD after smoking cessation.
TL;DR: This work examined the relation between severity of white matter lesions and cognitive decline over a nearly 10‐year period in 563 elderly subjects sampled from the general nondemented Dutch population.
Abstract: The prospect of declining cognitive functions is a major fear for many elderly persons. Cerebral white matter lesions, as commonly found with magnetic resonance imaging, have been associated with cognitive dysfunction in cross-sectional studies. Only a few longitudinal studies using small cohorts confirmed these findings. We examined the relation between severity of white matter lesions and cognitive decline over a nearly 10-year period in 563 elderly subjects sampled from the general nondemented Dutch population. Severity of white matter lesions was scored for periventricular and subcortical regions separately using an extensive semiquantitative scale. Cognitive function was measured by the Mini-Mental State Examination at regular time intervals during 1990 to 2000, and magnetic resonance imaging scans were made in 1995 to 1996. More severe white matter lesions were associated with more rapid cognitive decline over a mean follow-up period of 7.3 years (standard deviation, 1.5). After adjusting for age, gender, educational level, measures of depression, and brain atrophy and infarcts, subjects with severe periventricular white matter lesions experienced cognitive decline nearly three times as fast (0.28 Mini-Mental State Examination points/year [95% confidence interval, 0.20-0.36]) as the average (0.10 points/year [95% confidence interval, 0.09-0.11]). There was no independent relationship between severity of subcortical white matter lesions and rate of cognitive decline.
TL;DR: Overall, it was concluded that although semiautomated and voxel-based methods can provide a reasonable estimate of regional brain volume, they cannot serve as a substitute for manual volumetry.
TL;DR: It is suggested that theIFN-α–induced changes in the serotonergic turnover could play a role in the development of IFN- α–induced depressive symptoms.
Abstract: There is now evidence that repeated administration of interferon-alpha (IFN-alpha) to patients with chronic active hepatitis and cancers induces depressive symptoms. There is also evidence that induction of the cytokine network modulates the serotonergic system and that major depression is related to activation of the cytokine network and disturbances in the serotonergic metabolism. The aims of this study were to examine the effects of IFN-alpha-based immunotherapy on the development of depressive symptoms in relation to its effects on plasma tryptophan and kynurenine and serum serotonin (5-HT). Eighteen patients affected by chronic active hepatitis C were treated with IFN-alpha (3-6 million units subcutaneously three to six times a week for 6 months) and had measurements of the previous parameters before starting immunotherapy and 2, 4, 16, and 24 weeks later. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) scale, respectively. Immunochemotherapy with IFN-alpha (1) significantly increased the MADRS and HAM-A scores and serum kynurenine concentrations and (2) significantly reduced plasma tryptophan and serum 5-HT concentrations. IFN-alpha-based immunotherapy significantly increased the kynurenine per tryptophan quotient, which estimates the activity of indoleamine 2,3-dioxygenase, the major tryptophan-catabolizing enzyme, which is induced by IFNs. There are significant relationships between the IFN-alpha-induced changes in the MADRS score and serum kynurenine (positive) and 5-HT (negative) concentrations. Immunotherapy with IFN-alpha significantly increases the severity of depressive symptoms. The latter is related to changes in the serotonergic system, such as depletion of serum 5-HT and induction of the catabolism of tryptophan to kynurenine. It is suggested that the IFN-alpha-induced changes in the serotonergic turnover could play a role in the development of IFN-alpha-induced depressive symptoms.
TL;DR: Current views of the relationship between competence and performance are described and some of the implications of the distinctions between the two areas are delineated for the purpose of assessing doctors in practice.
Abstract: Objective This paper aims to describe current views of the relationship between competence and performance and to delineate some of the implications of the distinctions between the two areas for the purpose of assessing doctors in practice.
Methods During a 2-day closed session, the authors, using their wide experiences in this domain, defined the problem and the context, discussed the content and set up a new model. This was developed further by e-mail correspondence over a 6-month period.
Results Competency-based assessments were defined as measures of what doctors do in testing situations, while performance-based assessments were defined as measures of what doctors do in practice. The distinction between competency-based and performance-based methods leads to a three-stage model for assessing doctors in practice. The first component of the model proposed is a screening test that would identify doctors at risk. Practitioners who ‘pass’ the screen would move on to a continuous quality improvement process aimed at raising the general level of performance. Practitioners deemed to be at risk would undergo a more detailed assessment process focused on rigorous testing, with poor performers targeted for remediation or removal from practice.
Conclusion We propose a new model, designated the Cambridge Model, which extends and refines Miller's pyramid. It inverts his pyramid, focuses exclusively on the top two tiers, and identifies performance as a product of competence, the influences of the individual (e.g. health, relationships), and the influences of the system (e.g. facilities, practice time). The model provides a basis for understanding and designing assessments of practice performance.
TL;DR: In this article, the aim of an interdisciplinary working group at the International Centre for Integrative Studies (ICIS) was to list participatory methods from the scholarly literature scattered over various disciplines.
Abstract: Participatory methods are increasingly used in Integrated Assessment (IA). The aim of an interdisciplinary working group at the International Centre for Integrative Studies (ICIS) was to list participatory methods from the scholarly literature scattered over various disciplines. In this paper, we summarise our findings. Recent experiences with participation in IA are discussed from a methodological perspective. It is argued that it is of crucial importance that principles, considerations, arguments, design choices, the process itself and lessons learned are reported to provide a basis for the IA community to reflect on experiences and to stimulate theory development.