In the years following WW II, all 'Western' countries were struck by recurrent epidemics of infantile paralysis (poliomyelitis). In the early 1950s, a vaccine developed by Jonas Salk in Pittsburgh, became available in the U.S. and Canada. In 1953-54 central virology laboratories in Sweden, Denmark and France were already well advanced in setting up local production lines of the vaccine. At that point in time, the Catholic University of Leuven, on the initiative of the young microbiology professor, Piet De Somer, and in collaboration with the pharmaceutical concern R.I.T. (Recherches et Industries Thérapeutiques, Genval, Belgium), erected a new, multidisciplinary medical research institute, the Rega Institute. One of the research units to be headed by De Somer was destined to introduce the relatively new discipline of virology. As a test case, De Somer decided to venture on developing a production line of the Salk vaccine. In less than one year's time, the project was successful, such that Belgium became one of the first European countries to be self-supporting for its vaccine supply and to be able to initiate a large-scale vaccination campaign. The planning, preparation and execution of the project was accompanied by an extensive correspondence of De Somer with experts and other concerned parties in Belgium and abroad. This correspondence has been preserved and allows for a detailed reconstruction of the remarkable achievement.
Despite the progress in medicine, infectious endocarditis is often diagnosed late, as its symptomatology is subject to a high variability. The clinical features are usually atypical. Since the introduction of the Duke criteria, clinical, bacteriological and echocardiographical findings are being integrated, allowing an earlier definitive diagnosis. The incidence remains practically stable. The decrease in post-rheumatic valvular heart disease at population level is compensated by an increase in degenerative valvular heart disease as predisposing factor. Moreover, the share of patients with intravascular foreign material is increasing. Endocarditis is usually characterized by a complicated development. About half of the patients develop heart failure as a consequence of the destruction of the affected valve with serious valvular insufficiency. One third of the patients present cerebral or peripheral embolization. Embolization predominantly occurs at the beginning, until the first two weeks of antibiotic treatment. Abscess formation occurs more frequently than is suspected based on echographical examinations. Particularly a Staphylococcus aureus infection in the presence of an artificial valve leads to extravalvular extension with abscess formation around the artificial valve. Treatment should be initiated promptly. High doses of antibiotics, tailored to the microorganism and the valve type (native or artificial valve), are administered intravenously during four, or more frequently, six weeks. In more than half of the patients cardiac surgery is also required. As soon as an indication for cardiac surgery is present, the operation should not be postponed. Experience learns that a smaller risk is associated with an early intervention. The operation is performed in a technically easier way. Eventually, also the total duration of hospitalization is shorter. Despite the available antibiotics and the technical progress in cardiac surgery, mortality remains high. This is the consequence of an increasing share of aggressive hospital germs, on the one hand, and an older population, characterized by a higher comorbidity, on the other hand.
Structural biologists focus on the structure of biomolecules. Several techniques are available to study the structure adopted by a biomolecule and unravel how this structure is related to its constitution and function. For their biological role in a functioning cell or organism, biomolecules interact with each other and/or rather small molecules in their environment. Drugs can exploit interaction with biomolecules to manipulate their biological function to obtain a therapeutic effect. Structure determination of biomolecules that (could) serve as therapeutic target is an important starting point in rational drug design. Once the structure of a biological target is known, a potential binding site for drugs and possible interactions at this site have to be identified. In the stage of drug design this information is a valuable input for modeling experiments. They can virtually scan libraries of compounds by docking them into the binding site. This strategy ranks potential ligands that can be chemically modified to optimize their interaction at the binding site ('lead optimization') in order to improve affinity and selectivity for the biomolecular target. Modeling can also be used to virtually 'build' new molecules starting from possible interactions and shape of the target binding site ('de novo design'). Structural biology can contribute in different stages of drug development to direct the process or optimize existing compounds.
The main purpose for human assisted reproductive technologies (ART) is clearly to bypass reproductive failures. This purpose is totally different from the aims in animal ART, being genetic improvement and more recently conservation of endangered species. Apoptosis or programmed cell death has been detected before implantation in in vivo as well as in vitro embryos and might contribute to lower developmental competence and embryonic losses of in vitro embryos. In vitro embryo quality is clearly jeopardized by quality of the gametes (oocytes and spermatozoa) and suboptimal culture condition, but there is no consensus on which factor is most important in the incidence of apoptosis during early embryo development. The objective of the present study was to unravel the contribution of both male and female gamete quality to the incidence of apoptosis of bovine embryos produced in vitro. In vivo bull fertility expressed a very low correlation with cleavage rate and blastocyst yield. In contrast, developmental kinetics and oocyte diameter are important markers of embryo developmental potential and embryo quality in terms of the appearance of apoptosis, indicating a significant maternal effect on embryo quality.
Based on an estimated incidence of of 1 cancer case per 1000-1500 pregnancies, 3000-5000 new patients can be expected in Europe annually. The treatment of cancer in pregnant women is a challenge since both the maternal and the fetal well-being need to be considered. This study was initiated to gain more insight into the problems associated with cancer and chemotherapy during pregnancy.A multicentric registration study was set up to evaluate the currently applied treatment modalities for cancer during pregnancy, and the consequences of their use for pregnancy. Secondly, a preclinical and clinical pharmacological study addressing pharmacokinetics of chemotherapy in pregnant women and transplacental passage of chemotherapy was performed. Thirdly, we investigated the effects of prenatal exposure to chemotherapy on fetal neurological development. We observed an equal distribution of tumour types between pregnant and age-matched nonpregnant women. Data on neonatal outcome suggest that exposure to chemotherapy in the 2nd or 3rd trimester of pregnancy does not worsen outcome. This finding is explained by the fact that chemotherapy is not administered during the period of organogenesis and by the fetal protection offered by the placental barrier-function. Physiological changes of pregnancy resulted in a decreased plasma drug exposure of chemotherapeutic agents.Before major conclusions can be drawn with regard to the long term fetal outcome and the efficacy of chemotherapy during pregnancy, more patients and a longer follow up period is required. Therefore, this research project is continued and expanded nationally and internationally.
The use of devices for cosmetic treatment and esthetic skin treatments has increased in recent years. Some of these treatments, especially those that pass the dermo-epidermal barrier, can cause complications and secondary effects. In Belgium, there is almost no legislation concerning this type of treatment. Therefore, the Belgian Health Council has advised in a recent publication of January 2011, that there is an urgent need for adequate regulation concerning the use of devices for cosmetic treatment and esthetic skin treatment. The Council suggests to start up an evaluation commission, and also to have strict guidelines about the training needed for professionals who do this kind of treatments. Inspections by a competent authority should control the adherence to the forthcoming legislation.
During the last decades a new in vitro technique has entered the field of allergy diagnosis, that is, component-resolved allergy diagnosis (CRD). In contrast to traditional specific IgE (sIgE) assays, CRD does not rely upon whole extract preparations from native allergens but on quantification of sIgE antibodies to single protein components, purified from natural sources or obtained by recombinant techniques. At present, it emerges that CRD can improve management of the allergic patient as it allows (to some extent) to discriminate between clinically significant and irrelevant sIgE result and to establish sensitization patterns with particular prognostic outcomes. Nevertheless, further clinical validation is mandatory before the technique can enter mainstream application. By no means can CRD currently be considered as a substitute to traditional sIgE assays.
Translational research and biobanking are "in", also in Flanders and in Belgium. In Flanders the Advice report 120 from the Flemish Council for Science and innovation, entitled "Extension of translational research in Flanders" paved the way for the Center for Medical Innovation. The Center for Medical Innovation aims at promoting collaboration between Flemish Universities, university hospitals, pharma and biotech industry and the Flemish Government specifically in the domain of translational research. The Initiative # 27 of the Cancer plan from the Federal Government aims at financing a virtual interuniversity tumor bank in order to promote "cancer" translational research in a collaborative network between academic structures, general hospitals en different industrial partners (pharmacy, biotechnology, diagnostics, ...) active in research in Belgium. However, the scientific interest in the human tissues is not new, at all. This text aims at giving an overview of the development and evolutions of "biobanking" initiatives.
Malaria is a global tropical disease causing more than 1 million deaths and 300 million clinical cases every year. It is caused by parasites from the genus Plasmodium and is transmitted by Anopheles mosquitoes. Approximately 3 billion people live in malaria-endemic regions and a majority of them are infected. In this review, we discuss the life cycle of the parasite, the complex interactions with the human host and the ensuing immune reactions and complications. The immune system plays a dual role in malaria, by providing life-saving immunity against the parasite, but also by causing often lethal complications in a number of patients. Cytokines, chemokines and proteases are key players in the immunopathological complications, and we propose immunomodulation with dexamethasone as a promising strategy for the therapy of malaria-associated acute respiratory distress syndrome.
Lung transplantation is a life-saving treatment option in carefully selected patients with end-stage lung disease. Life expectancy after this form of treatment has progressively increased with a current survival of 90% after 1 year, 70% after 5 years, and 50% after 10 years in experienced centers. Apart from a survival benefit, this treatment aims to improve the quality of life. Bilateral lung transplantation is the type of operation that is performed most frequently because of superior survival results, especially when chronic rejection develops. Single lung transplantation is now reserved for older patients with pulmonary fibrosis. Heart-lung transplantation is rarely done, only in patients with Eisenmenger's syndrome or complex congenital heart disease. Belgium is one of the world leaders in terms of number of deceased organ donors with a lung recovery rate of about 35%. With a total of 8.3 lung transplants per million population, Belgium is currently the number 1 in the world. The procedure nowadays is performed in 4 University Hospitals (UA-KUL-ULB-UCL) in the country. Between 1983 and 2009, nearly 1000 proedures were performed. The most common indication was emphysema, followed by cystic fibrosis, pulmonary fibrosis, pulmonary arterial hypertension, and Eisenmenger's syndrome. Further application of this treatment option is hampered by several problems such as donor organ shortage, primary graft dysfunction, chronic rejection presenting as bronchiolitis obliterans syndrome, and side effect of chronic immunosuppression. In the Laboratory for Experimental Thoracic Surgery and the Laboratory for Pneumology at the Katholieke Universiteit Leuven, intensive research is done by our group looking for new methods to increase the lung donor pool and to prevent and to treat chronic rejection.
Important derences in all-causes mortality and in cardiovascular mortality exist between populations and they cannot be explained by differences in the level of medical care. During the last 20 years important changes have occurred in the level of cardiovascular mortality with an increase in Hungary anda decrease in Japan. These rapid changes in mortality cannot be explained by genetic factors. The epidemiological evidence strongly points towards nutrition and especially to the intake of saturated fat and salt as the major determinant of the existing differences in mortality. Saturated fat also appears to be related to total cancer mortality. A major effort should be directed towards a decrease in the dietary intake of saturated fat by Western populations.
While genetic factors play a role in the development of obesity, its dramatic increase in prevalence over the past few years strongly suggests an important environmental role. The results of a review on environmental opportunities and barriers for physical activity and dietary intake influencing the obesity epidemic among children and adolescents are presented. Although evidence clearly shows the impact of the environment on obesity-related lifestyle factors among children, evidence for effective strategies combating this obesogenic environment is scarce. Interventions aiming to change environmental factors to reduce childhood obesity may include providing extra sporting facilities and healthy foods/meals at school (e.g., provision of fruit), efforts to improve safety and accessibility of walking, cycling, and play areas, while at the same time attempting to influence social values attached to weight, food, or physical activity. Some level of institutionalization of systems that support the desired changes is required to sustain long-term environmental changes (e.g., ban of softdrinks at school). Better-designed and -conducted research on the true importance of environmental factors for obesogenic behavioral change is needed to achieve success of large-scale environmental change interventions.
Intimate partner violence (IPV) is an important public health problem, which has been extensively studied all over the world, yet Belgian data are limited. IPV remains a taboo resulting in denial and underreporting. For an obstetrician-gynaecologist (OB/GYN), IPV, committed by a male partner to a woman, is of particular interest, because of its negative impact on women's and children's health. In Belgium there are few data on IPV and guidelines for OB/GYN are -missing. In a multi-centered survey surveillance study which was carried out among pregnant women attending 5 large hospitals in the province of East Flanders, the lifetime prevalence of IPV was estimated to be 10.1% and the period prevalence during pregnancy and/or in the year preceding pregnancy 3.4%. In our highly medicalised society, only 19.2% and 6.6% of the victims of physical and sexual abuse respectively sought medical care. Routine screening for IPV by a general practitioner or OB/GYN was found to be largely acceptable. In a questionnaire-based Knowledge, Attitude, and Practice survey among OB/GYN in Flanders, OB/GYN prove -unfamiliar with IPV and largely underestimate the extent of the problem. Merely 6.8% of the respondents ever received any education on IPV. They refute the incentive of universal screening, even during pregnancy and one of the major barriers is fear of offending patients. Physician education was found to be the strongest predictor of a positive attitude towards screening and of current screening practices. Hence, there is a definite need to improve women's awareness regarding abuse and to endorse physician training on IPV.
Anti-angiogenic therapy and therapeutic angiogenesis have been proposed as opposite strategy for the treatment of cancer and ischemic diseases, respectively. However, both approaches do not provide long term solutions of these pathological conditions and have failed in clinical trials. Therefore, novel strategies are needed. In the current work we describe: 1) how vessels sense and re-adapt oxygen supply and, hence, perfusion in case of oxygen shortage, therefore identifying PHD2 oxygen sensor as a novel target to normalize the tumor vasculature, reduce cancer hypoxia and prevent cancer cell extravasations and dissemination; 2) anti-P1GF as a efficient and safe tool in cancer therapy that does not prune excessively pathological vessels and does not affect the normal vasculature; 3) hypoxia tolerance via inhibition of the oxygen sensor PHD1 as alternative strategy to therapeutic angiogenesis. Altogether, our findings provide new alternatives in the treatment of ischemic disorders and cancer, largely unmet medical problems to date.
Research conducted in my group in the period 2006-2009 has led to a better understanding of the oncogenic mechanisms of the FIP1L1-PDGFRA and NUP214-ABL1 oncogenes. Insights into these mechanisms may help us to design novel strategies to treat leukemia. In addition, we have identified the small molecule inhibitor sorafenib as a potent inhibitor of the FIP1L1-PDGFRA and its T674I imatinib resistant mutant. Sorafenib was originally developed as a BRAF inhibitor, but our work demonstrates that sorafenib can also be used to treat FIP1L1-PDGFRA positive leukemia, demonstrating that new therapies to treat rare leukemias may be simply found by testing drugs that are already in use for the treatment of other diseases. Finally, using genome-wide screening approaches, we have identified the MYB gene as a novel oncogene implicated in the pathogenesis of T-ALL, and we suggest that MYB may represent a novel target for therapy in T-ALL as well as in other cancers.
Type 1 diabetes is characterized by a selective destruction of the insulin producing beta-cells leading to frank hyperglycemia. Daily insulin injections are lifesaving but can often not avoid suboptimal glycemic control, an increased risk for hypoglycemia and the development of chronic diabetic complications. Therapies replacing the destroyed beta-cells aim to prevent or delay these detrimental complications while avoiding hypoglycemic episodes. The main objective of our multicenter study was to define conditions under which a beta-cell implant safely induces and maintains long-term metabolic control in type 1 diabetic recipients. We demonstrated that cultured beta-cell preparations, fully morphologically characterized by their cell number and cellular composition, and functionally correlated with beta-cell mass can be used to prepare grafts with reproducible clinical metabolic outcome. At least 2 million beta-cells per kg bodyweight were needed to achieve signs of functioning grafts, reduced glycemic variability and a reduced risk for hypoglycemic events. We demonstrated that the hyperglycemic clamp can be used to measure the in vivo functional beta-cell mass after transplantation. In insulin independent recipients of a beta-cell and pancreas-kidney graft, the functional beta-cell mass represents respectively 25 and 63% of that in healthy controls. We showed that ATG-sirolimus monotherapy resulted in a worse outcome of beta-cell transplantation compared to ATG-sirolimus-tacrolimus combination therapy. Moreover, use of sirolimus was accompanied with unacceptable side effects. In conclusion, we showed that characterizing the beta-cell graft in vitro, measuring the functional beta-cell mass in vivo and defining a save and efficient immunosuppressive regimen are important steps to a cure for diabetes.
