Showing papers by "Katholieke Universiteit Leuven published in 2003"

Angiogenesis in health and disease.

Abstract: Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.

Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia

Abstract: Background Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. Methods We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. Results After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 perce...

The one number you need to grow.

Abstract: Companies spend lots of time and money on complex tools to assess customer satisfaction. But they're measuring the wrong thing. The best predictor of top-line growth can usually be captured in a single survey question: Would you recommend this company to a friend? This finding is based on two years of research in which a variety of survey questions were tested by linking the responses with actual customer behavior--purchasing patterns and referrals--and ultimately with company growth. Surprisingly, the most effective question wasn't about customer satisfaction or even loyalty per se. In most of the industries studied, the percentage of customers enthusiastic enough about a company to refer it to a friend or colleague directly correlated with growth rates among competitors. Willingness to talk up a company or product to friends, family, and colleagues is one of the best indicators of loyalty because of the customer's sacrifice in making the recommendation. When customers act as references, they do more than indicate they've received good economic value from a company; they put their own reputations on the line. And they will risk their reputations only if they feel intense loyalty. The findings point to a new, simpler approach to customer research, one directly linked to a company's results. By substituting a single question--blunt tool though it may appear to be--for the complex black box of the customer satisfaction survey, companies can actually put consumer survey results to use and focus employees on the task of stimulating growth.

Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.

Abstract: Background Treatment with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, can result in the formation of antibodies against infliximab. We evaluated the clinical significance of these antibodies in patients with Crohn's disease. Methods In a cohort of 125 consecutive patients with Crohn's disease who were treated with infliximab infusions, we evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, side effects (including infusion reactions), and the use of concomitant medications before and 4, 8, and 12 weeks after each infusion. Results A mean of 3.9 infusions (range, 1 to 17) per patient were administered over a mean period of 10 months. Antibodies against infliximab were detected in 61 percent of patients. The presence of concentrations of 8.0 μg per milliliter or greater before an infusion predicted a shorter duration of response (35 days, as compared with 71 days among patients with concentrations of less than 8.0 μg per millilite...

Buonocore memorial lecture, adhesion to enamel and dentin: current status and future challenges

Abstract: Bonding to tooth tissue can be achieved through an "etch&rinse," "self-etch" or "glass-ionomer" approach. In this paper, the basic bonding mechanism to enamel and dentin of these three approaches is demonstrated by means of ultramorphological and chemical characterization of tooth-biomaterial interfacial interactions. Furthermore, bond-strength testing and measurement of marginal-sealing effectiveness (the two most commonly employed methodologies to determine "bonding effectiveness" in the laboratory) are evaluated upon their value and relevance in predicting clinical performance. A new dynamic methodology to test biomaterial-tooth bonds in a fatigue mode is introduced with a recently developed micro-rotary fatigue-testing device. Eventually, today's adhesives will be critically weighted upon their performance in diverse laboratory studies and clinical trials. Special attention has been given to the benefits/drawbacks of an etch&rinse versus a self-etch approach and the long-term performance of these adhesives. Correlating data gathered in the laboratory with clinical results clearly showed that laboratory research CAN predict clinical effectiveness. Although there is a tendency to simplify bonding procedures, the data presented confirm that conventional three-step etch&rinse adhesives still perform most favorably and are most reliable in the long-term. Nevertheless, a self-etch approach may have the best future perspective. Clinically, when adhesives no longer require an "etch&rinse" step, the application time, and probably more importantly, the technique-sensitivity are substantially reduced. Especially "mild," two-step self-etch adhesives that bond through a combined micromechanical and chemical interaction with tooth tissue closely approach conventional three-step systems in bonding performance.

A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome

Abstract: Background Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. Methods We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. Results Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRα (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRα is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 perce...

European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement.

Abstract: IntroductionOver the past 20 years or so, the accuracy of the conventional Riva-Rocci/Korotkoff technique of blood pressure measurement has been questioned and efforts have been made to improve the technique with automated devices. In the same period, recognition of the phenomenon of white-coat hype

Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program

Abstract: Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytc leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35-45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n = 278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

Gully erosion and environmental change: importance and research needs

Abstract: Assessing the impacts of climatic and, in particular, land use changes on rates of soil erosion by water is the objective of many national and international research projects. However, over the last decades, most research dealing with soil erosion by water has concentrated on sheet (interrill) and rill erosion processes operating at the (runoff) plot scale. Relatively few studies have been conducted on gully erosion operating at larger spatial scales. Recent studies indicate that (1) gully erosion represents an important sediment source in a range of environments and (2) gullies are effective links for transferring runoff and sediment from uplands to valley bottoms and permanent channels where they aggravate off site effects of water erosion. In other words, once gullies develop, they increase the connectivity in the landscape. Many cases of damage (sediment and chemical) to watercourses and properties by runoff from agricultural land relate to (ephemeral) gullying. Consequently, there is a need for monitoring, experimental and modelling studies of gully erosion as a basis for predicting the effects of environmental change (climatic and land use changes) on gully erosion rates. In this respect, various research questions can be identified. The most important ones are: (1) What is the contribution of gully erosion to overall soil loss and sediment production at various temporal and spatial scales and under different climatic and land use conditions? (2) What are appropriate measuring techniques for monitoring and experimental studies of the initiation and development of various gully types at various temporal and spatial scales? (3) Can we identify critical thresholds for the initiation, development and infilling of gullies in different environments in terms of flow hydraulics, rain, topography, soils and land use? (4) How does gully erosion interact with hydrological processes as well as with other soil degradation processes? (5) What are appropriate models of gully erosion, capable of predicting (a) erosion rates at various temporal and spatial scales and (b) the impact of gully development on hydrology, sediment yield and landscape evolution? (6) What are efficient gully prevention and gully control measures? What can be learned from failures and successes of gully erosion control programmes? These questions need to be answered first if we want to improve our insights into the impacts of environmental change on gully erosion. This paper highlights some of these issues by reviewing recent examples taken from various environments.

Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology.

Abstract: The management of acute myocardial infarction continues to undergo major changes. Good practice should be based on sound evidence derived from well-conducted clinical trials. Because of the great number of trials on new treatments performed in recent years and because of new diagnostic tests, the European Society of Cardiology decided that it was opportune to upgrade the 1996 guidelines and appointed a Task …

Lévy Processes in Finance: Pricing Financial Derivatives

Abstract: Preface. Acknowledgements. Introduction. Financial Mathematics in Continuous Time. The Black-Scholes Model. Imperfections of the Black-Scholes Model. Levy Processes and OU Processes. Stock Price Models Driven by Levy Processes. Levy Models with Stochastic Volatility. Simulation Techniques. Exotic Option Pricing. Interest-Rate Models. Appendix A: Special Functions. Appendix B: Levy Processes. Appendix C: S&P 500 Call Option Prices. References. Index.

Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.

Abstract: ObjectivesMaintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin dose vs. blood glucose control on the observed outcome benefits.DesignA prospective, randomized, contr

Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension

Abstract: background It is uncertain whether ambulatory blood-pressure measurements recorded for 24 hours in patients with treated hypertension predict cardiovascular events independently of blood-pressure measurements obtained in the physician’s office and other cardiovascular risk factors. methods We assessed the association between base-line ambulatory blood pressures in treated patients and subsequent cardiovascular events among 1963 patients with a median follow-up of 5 years (range, 1 to 66 months). results We documented new cardiovascular events in 157 patients. In a Cox proportional-hazards model with adjustment for age, sex, smoking status, presence or absence of diabetes mellitus, serum cholesterol concentration, body-mass index, use or nonuse of lipidlowering drugs, and presence or absence of a history of cardiovascular events, as well as blood pressure measured at the physician’s office, higher mean values for 24-hour ambulatory systolic and diastolic blood pressure were independent risk factors for new cardiovascular events. The adjusted relative risk of cardiovascular events associated with a 1-SD increment in blood pressure was 1.34 (95 percent confidence interval, 1.11 to 1.62) for 24-hour ambulatory systolic blood pressure, 1.30 (95 percent confidence interval, 1.08 to 1.58) for ambulatory systolic blood pressure during the daytime, and 1.27 (95 percent confidence interval, 1.07 to 1.57) for ambulatory systolic blood pressure during the nighttime. For ambulatory diastolic blood pressure, the corresponding relative risks of cardiovascular events associated with a 1-SD increment were 1.21 (95 percent confidence interval, 1.01 to 1.46), 1.24 (95 percent confidence interval, 1.03 to 1.49), and 1.18 (95 percent confidence interval, 0.98 to 1.40). conclusions In patients with treated hypertension, a higher ambulatory systolic or diastolic blood pressure predicts cardiovascular events even after adjustment for classic risk factors including office measurements of blood pressure.

Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

Abstract: TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat) and the synthetic ligand 4alphaPDD. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5',6'-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone.

Two-dimensional supramolecular self-assembly probed by scanning tunneling microscopy

Abstract: Supramolecular chemistry has a very large impact on chemistry of current interest and the use of non-covalent but directional forces is appealing for the construction of 'supramolecular architectures'. The invention of scanning probe microscopy techniques has opened new doorways to study these concepts on surfaces. This review deals with recent progress in the study of two-dimensional supramolecular self-assembly on surfaces probed by scanning tunneling microscopy, with a special emphasis on structure, dynamics and reactivity of hydrogen bonded systems.

Consumer Perceptions of Price (Un)Fairness

Abstract: A series of studies demonstrates that consumers are inclined to believe that the selling price of a good or service is substantially higher than its fair price. Consumers appear sensitive to several reference points—including past prices, competitor prices, and cost of goods sold—but underestimate the effects of inflation, overattribute price differences to profit, and fail to take into account the full range of vendor costs. Potential corrective interventions—such as providing historical price information, explaining price differences, and cueing costs—were only modestly effective. These results are considered in the context of a four‐dimensional transaction space that illustrates sources of perceived unfairness for both individual and multiple transactions.

Benchmarking state-of-the-art classification algorithms for credit scoring

Abstract: In this paper, we study the performance of various state-of-the-art classification algorithms applied to eight real-life credit scoring data sets. Some of the data sets originate from major Benelux and UK financial institutions. Different types of classifiers are evaluated and compared. Besides the well-known classification algorithms (eg logistic regression, discriminant analysis, k-nearest neighbour, neural networks and decision trees), this study also investigates the suitability and performance of some recently proposed, advanced kernel-based classification algorithms such as support vector machines and least-squares support vector machines (LS-SVMs). The performance is assessed using the classification accuracy and the area under the receiver operating characteristic curve. Statistically significant performance differences are identified using the appropriate test statistics. It is found that both the LS-SVM and neural network classifiers yield a very good performance, but also simple classifiers such as logistic regression and linear discriminant analysis perform very well for credit scoring.

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

Abstract: Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

Effect of 6-Month Whole Body Vibration Training on Hip Density, Muscle Strength, and Postural Control in Postmenopausal Women: A Randomized Controlled Pilot Study

Abstract: High-frequency mechanical strain seems to stimulate bone strength in animals. In this randomized controlled trial, hip BMD was measured in postmenopausal women after a 24-week whole body vibration (WBV) training program. Vibration training significantly increased BMD of the hip. These findings suggest that WBV training might be useful in the prevention of osteoporosis. Introduction: High-frequency mechanical strain has been shown to stimulate bone strength in different animal models. However, the effects of vibration exercise on the human skeleton have rarely been studied. Particularly in postmenopausal women—who are most at risk of developing osteoporosis—randomized controlled data on the safety and efficacy of vibration loading are lacking. The aim of this randomized controlled trial was to assess the musculoskeletal effects of high-frequency loading by means of whole body vibration (WBV) in postmenopausal women. Materials and Methods: Seventy volunteers (age, 58–74 years) were randomly assigned to a whole body vibration training group (WBV, n = 25), a resistance training group (RES, n = 22), or a control group (CON, n = 23). The WBV group and the RES group trained three times weekly for 24 weeks. The WBV group performed static and dynamic knee-extensor exercises on a vibration platform (35–40 Hz, 2.28–5.09g), which mechanically loaded the bone and evoked reflexive muscle contractions. The RES group trained knee extensors by dynamic leg press and leg extension exercises, increasing from low (20 RM) to high (8 RM) resistance. The CON group did not participate in any training. Hip bone density was measured using DXA at baseline and after the 6-month intervention. Isometric and dynamic strength were measured by means of a motor-driven dynamometer. Data were analyzed by means of repeated measures ANOVA. Results: No vibration-related side effects were observed. Vibration training improved isometric and dynamic muscle strength (+15% and + 16%, respectively; p < 0.01) and also significantly increased BMD of the hip (+0.93%, p < 0.05). No changes in hip BMD were observed in women participating in resistance training or age-matched controls (−0.60% and −0.62%, respectively; not significant). Serum markers of bone turnover did not change in any of the groups. Conclusion: These findings suggest that WBV training may be a feasible and effective way to modify well-recognized risk factors for falls and fractures in older women and support the need for further human studies.

A review of pressure‐driven membrane processes in wastewater treatment and drinking water production

Abstract: In pressure-driven membrane processes (reverse osmosis, nanofiltration, ultrafiltration, and microfiltration) a pressure exerted on the solution at one side of the membrane serves as a driving force to separate it into a permeate and a retentate. The permeate is usually pure water, whereas the retentate is a concentrated solution that must be disposed of or treated by other methods. Membranes may be polymeric, organo-mineral, ceramic, or metallic, and filtration techniques differ in pore size, from dense (no pores) to porous membranes. Depending on the type of technique, salts, small organic molecules, macromolecules, or particles can be retained, and the applied pressure will differ. This paper reviews the principles behind the different techniques, the types of membranes used, rejection mechanisms, and process modeling. Applications of pressure-driven membrane processes are also considered, including reverse osmosis and nanofiltration for the treatment of wastewater from landfills and composting plants, nanofiltration in the textile industry, and ultrafiltration and microfiltration in drinking water production and wastewater treatment. Lastly, the paper discusses recent developments, including techniques to prevent membrane fouling by modifications affecting surface roughness or hydrophilicity/hydrophobicity, or by cleaning the membranes, and methods for treating or disposing of the retentate.

Optimal training design for MIMO OFDM systems in mobile wireless channels

Abstract: This paper describes a least squares (LS) channel estimation scheme for multiple-input multiple-output (MIMO) orthogonal frequency division multiplexing (OFDM) systems based on pilot tones. We first compute the mean square error (MSE) of the LS channel estimate. We then derive optimal pilot sequences and optimal placement of the pilot tones with respect to this MSE. It is shown that the optimal pilot sequences are equipowered, equispaced, and phase shift orthogonal. To reduce the training overhead, an LS channel estimation scheme over multiple OFDM symbols is also discussed. Moreover, to enhance channel estimation, a recursive LS (RLS) algorithm is proposed, for which we derive the optimal forgetting or tracking factor. This factor is found to be a function of both the noise variance and the channel Doppler spread. Through simulations, it is shown that the optimal pilot sequences derived in this paper outperform both the orthogonal and random pilot sequences. It is also shown that a considerable gain in signal-to-noise ratio (SNR) can be obtained by using the RLS algorithm, especially in slowly time-varying channels.

Heart rate variability in athletes.

Abstract: This review examines the influence on heart rate variability (HRV) indices in athletes from training status, different types of exercise training, sex and ageing, presented from both cross-sectional and longitudinal studies. The predictability of HRV in over-training, athletic condition and athletic performance is also included. Finally, some recommendations concerning the application of HRV methods in athletes are made.The cardiovascular system is mostly controlled by autonomic regulation through the activity of sympathetic and parasympathetic pathways of the autonomic nervous system. Analysis of HRV permits insight in this control mechanism. It can easily be determined from ECG recordings, resulting in time series (RR-intervals) that are usually analysed in time and frequency domains. As a first approach, it can be assumed that power in different frequency bands corresponds to activity of sympathetic (0.04-0.15 Hz) and parasympathetic (0.15-0.4 Hz) nerves. However, other mechanisms (and feedback loops) are also at work, especially in the low frequency band. During dynamic exercise, it is generally assumed that heart rate increases due to both a parasympathetic withdrawal and an augmented sympathetic activity. However, because some authors disagree with the former statement and the fact that during exercise there is also a technical problem related to the non-stationary signals, a critical look at interpretation of results is needed. It is strongly suggested that, when presenting reports on HRV studies related to exercise physiology in general or concerned with athletes, a detailed description should be provided on analysis methods, as well as concerning population, and training schedule, intensity and duration. Most studies concern relatively small numbers of study participants, diminishing the power of statistics. Therefore, multicentre studies would be preferable. In order to further develop this fascinating research field, we advocate prospective, randomised, controlled, long-term studies using validated measurement methods. Finally, there is a strong need for basic research on the nature of the control and regulating mechanism exerted by the autonomic nervous system on cardiovascular function in athletes, preferably with a multidisciplinary approach between cardiologists, exercise physiologists, pulmonary physiologists, coaches and biomedical engineers.

Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1

Abstract: Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PlGF) regulates inter- and intramolecular cross talk between the VEGF RTKs Flt1 and Flk1. Activation of Flt1 by PGF resulted in intermolecular transphosphorylation of Flk1, thereby amplifying VEGF-driven angiogenesis through Flk1. Even though VEGF and PGF both bind Flt1, PGF uniquely stimulated the phosphorylation of specific Flt1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross talk through formation of Flk1/Flt1 heterodimers. The inter- and intramolecular VEGF receptor cross talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.