La revue "Bulletin et Mémoires de l'Académie royale de Médecine de Belgique" (ISSN 0377-8231) est publiée mensuellement depuis 1841, sous la responsabilité éditoriale du Secrétaire perpétuel.
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- p. 670: Rapport de la Commission à laquelle a été renvoyé l'examen du travail manuscrit soumis par M. le Dr A. Ballenghien à Roubaix, intitulé: Tumeur polykystique de l'ovaire gauche entièrement développé du côté droit; rupture du pédicule pendant l'opération - M. Van Cauwenberghe, Rapporteur
- pp. 671-704: Rapport de la Commission chargé de l'examen de l'ouvrage publié par MM. les Dr Van Campenhout et Dryepont: Sur les travaux du laboratoire médical de Léopoldville en 1899-1900 - M. Barella, Rapporteur
- pp. 750-760: A. Broden: La maladie du sommeil. Communication préliminaire
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- 2017 : Numéro 42, Numéro 41, Numéro 40
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- 2006 : Numéro 3 (La musique contemporaine), Numéro 2, Numéro 1
Les Proceedings of the Belgian Royal Academies of Medecine est une initiative conjointe de l'Académie avec sa consoeur néerlandophone, la Koninklijke Academie voor Geneeskunde van België.
C'est une revue en ligne couvrant tous les domaines intéressant la médecine humaine et animale.
Tous les articles soumis à la revue sont évalués en double aveugle par au moins deux référents.
Thanks to chemo- and radiotherapy the life expectancy for children with cancer has increased considerably. However, these cancer treatments may have serious side effects, sterility being an important one. Adult men have the possibility to circumvent this side effect by banking their semen. Prepubertal boys, however, can not benefit from this option, because spermatogenesis has not been initiated yet. A possible solution to preserve their fertility is banking and transplanting the precursor cells of spermatogenesis, i.e. the spermatogonial stem cells or SSCs. Since the first report of this model in 1994, a lot of progress has been made. However, before SSC transplantation (SSCT) can be offered in a clinical setting, both the efficiency and safety of the technique has to be guaranteed. This review overviews the studies that have been carried out in this regard.
Epigenetic mechanisms in development, inheritance and disease PDF
Mathieu Bollen, Nikki Minnebo, Aleyde Van Eynde 19-40
Epigenetics is a relatively new and exciting field of the (bio)medical sciences. It confers an additional layer of information that controls gene expression by mechanisms involving DNA methylation, histone modifications, chromatin compaction and non-coding RNAs. As most epigenetic marks are mitotically transferable and sometimes even stable during meiosis, these modifications can potentially be passed on to future generations. Proper epigenetic signaling is essential for normal proliferation and differentiation, and epigenetic misregulation is a key feature of many common diseases including cancer, diabetes and cardiovascular disease. As most epigenetic marks are reversible, understanding the underlying disease mechanisms reveals the therapeutic potential for interference with aberrant epigenetic signatures. These therapies hold great promises for a wide range of applications. However, the creation of both potent and specific epigenetic therapies requires a detailed insight into the patients’ epigenomic landscape. Here, we provide an overview of the major epigenetic signaling pathways and their contribution to development and disease.
Intracellular Ca2+-release channels like the inositol 1,4,5-trisphosphate receptor (IP3R) play a pivotal role in a plethora of cell biological and physiological processes. IP3R-mediated Ca2+ flux from the endoplasmic reticulum, the main intracellular Ca2+ store, ought to be tightly regulated. This is achieved by a complex network of associated proteins. Recently, IP3Rs have been identified as targets for the anti-apoptotic Bcl-2-family members, Bcl-2 and Bcl-Xl, which control the Ca2+-flux properties of the channel. In collaboration with the Distelhorst lab, our lab has focused on the identification of the molecular determinants responsible for IP3R/Bcl-2-complex formation. These studies revealed a novel role for Bcl-2 as an endogenous inhibitor of IP3R-mediated Ca2+ flux, thereby suppressing pro-apoptotic Ca2+ signals. In addition, novel peptide tools were developed that disturb IP3R/Bcl-2 complexes. These tools are particularly useful in Bcl-2-dependent cancers, like chronic lymphocytic leukemia to alleviate Bcl-2’s inhibitory role on IP3Rs and to provoke pro-apoptotic Ca2+ signals. Furthermore, molecular studies revealed important differences between Bcl-2 and Bcl-Xl at the level of the BH4 domain, underlying differences in the regulation of IP3R-channel activity between Bcl-2 and Bcl-Xl. This also opens the avenue to selectively target Bcl-2 in cancer cells, while maintaining essential Bcl-Xl pro-survival functions in healthy cells.
Cognitive and motor disorders in schizophrenia PDF
Bernard Sabbe 77-88
Schizophrenia still remains a serious chronic psychiatric disorder with a lifetime prevalence in the general population of 0.8-1.0%. This disease causes great human suffering for the patient himself and his family and forms a major challenge in terms of functional outcome and quality of life, and of societal costs. The schizophrenic syndrome encompasses positive, negative, cognitive and depressive symptoms. Delusions, hallucinations and formal thought disorder are classified as positive symptoms, while affective blunting, poverty of thought and speech, and apathy are listed as negative symptoms. The cognitive cluster refers to alterations in processing speed, attention, working memory, verbal and visual learning and memory, executive functions and social cognition. Psychomotor symptoms comprise disturbances in the planning, the programming, the execution and the monitoring of movements; at the clinical level these psychomotor changes are expressed in psychomotor poverty, catatonic symptoms, neurological soft signs and extrapyramidal symptoms.
Whereas since the development of neuroleptic medications in the fifties and sixties of the past century the positive symptoms have been a major focus of clinical and scientific attention, interest in the cognitive and motor symptoms has highly increased in the past 15 years. It has been established that these symptoms have a much stronger relationship with the functional outcome of the patients than positive symptoms, in terms of the level of daily activities, the vocational capacities, and the interpersonal and social functioning.
By a joint initiative of the National Institute of Mental Health, the Food and Drug Administration, the academic research centers and the pharmaceutical industry, called MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) a consensus test battery was developed in order to measure systematically the different types of cognitive disturbances. In each cognitive domain animal models and tests were developed for translational purpose. New molecular targets for treating these cognitive deficits were defined, such as: the nicotine receptor in the hippocampus, the dopamine receptor (D1) in the prefrontal cortex, the 5HT2A-receptor and the noradrenergic receptor in the prefrontal and the anterior cingulate cortex (ACC), and the histamine receptor (H3); research further focusses on glutamate enhancers, muscarinic agonists and GABA-A partial agonists. The effects of these numerous compounds are investigated in normal healthy volunteers and schizophrenic patients using cognitive psychological tasks, electrophysiological methods, neuro-imaging and genetics. An example of studies in our research group are the effects of antipsychotics on the amplitude of the Error Related Negativity (ERN), an event related potential generated in the ACC immediately after making an error. Finally the massive increase into social cognitive research in schizophrenia is summarized. This fast expanding scientific domain involves emotional processing, social perception and knowledge, attribution bias, and Theory of Mind (ToM) or mentalizing.
It is concluded that the actual research into cognitive and motor processes in schizophrenia aims at increasing the specificity of the dysfunctions in different cognitive domains, basal processes and underlying neural networks, and the sensitivity for the effects of new compounds. This knowledge favours our insight in the fysiopathogenesis of schizophrenia as a neurodevelopmental disorder.
Challenges and possible clinical applications of human embryonic stem cell research PDF
Björn Heindryckx, Margot Van der Jeught, Thomas O'Leary, Petra De Sutter 89-111
Human embryonic stem cells (hESC) are harvested from the inner cell mass of the pre-implantation embryo and possess several unique characteristics. First, they are self-renewing, meaning they can grow indefinitely in an appropriate culture environment and secondly, they are pluripotent, which means they have the potential to become nearly every cell of the human body. Consequently, hESC offer a unique insight into basic human development in vitro, allow better understanding of the genetic and molecular controls of these processes, and are of pharmaceutical interest to test or develop new drugs. The most exciting and high-profile potential application of hESC research is the possibility that such cells can be used for regenerative medicine. Still, several obstacles have to be overcome before clinical applications can be considered: (i) xeno-free derivation and culture of hESC is necessary; (ii) hESC should be safe after transplantation and (iii) their identity and behaviour should be well-known.
Biochemical pathways and their clinical applications in acute ischemic stroke PDF
Raf Brouns, Ann De Smedt, Robbert-Jan Van Hooff, Maarten Moens, Jacques De Keyser 112-126
Tissue damage following acute focal cerebral ischemia results from multiple pathophysiological mechanisms called the ischemic cascade. This is a complex series of neurochemical processes involving cellular bioenergetic failure, excitotoxicity, oxidative stress, blood–brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells. These key biochemical pathways are targets for the development of improved stroke treatments and novel diagnostic tools.
Human embryonic stem cell research has generated much hope, but also fear and repulsion. National legislators, as well as the European Parliament, the European Patent Office and the European Court of Justice have had to make decisions relating to what is or is not allowed in the field of hESC research and patenting, and their decisions are often difficult to reconcile. In order to understand this divergence and the specific restrictions that different regulators impose, insight is needed into the different opinions regarding the moral status of the pre-implantation embryo (blastocyst), into the moral distinction between using spare embryos versus research embryos, and into the moral distinction between producing hESC lines and using them for non-commercial research and allowing such production and research in a commercial or industrial setting. While one need not agree that all of these perceived differences are in fact morally relevant, knowing that many people perceive them as being relevant is in itself valuable for understanding the debate and the decisions that different regulators make.
Exploring the relation between the intracellular fate and biological activity of oligodeoxynucleotide containing nanoparticles PDF
Katrien Remaut, Stefaan C De Smedt, Joseph Demeester 140-156
Antisense deoxyoligonucleotides (ODNs) show potential in the treatment of genetic disorders, cancer and viral infections. Antisense ODNs need to reach the target tissue in an intact way, since their sequence is crucial for obtaining the desired antisense effect. Naked ODNs only poorly cross cellular membranes. Also, naked phospodiester ODNs (PO-ODNs) are very sensitive for degradation. Therefore, in non-viral gene therapy, the ODNs are delivered as complexes with either cationic liposomes or cationic polymers. This increases the protection of PO-ODNs against enzymatic degradation and their cellular uptake and intracellular trafficking. We developed an easy method, based on Fluorescence Correlation Spectroscopy (FCS) and Fluorescence Resonance Energy Transfer (FRET) to follow the degadation of both naked and complexed PO-ODNs in buffer and in living cells. By using FRET-FCS, a clear correlation can be found between the protection of PO-ODNs against enzymatic degradation and their obtained biological effect. In this review we will give an overview of the potential of FRET-FCS and the different non-viral gene delivery systems that we studied so far using this technique.
Multimodal evaluation of gait and stride dynamics in relapsing and progressive forms of multiple sclerosis. PDF
Shibeshih Belachew, Sébastien Piérard, Rémy Phan-Ba, Marc Van Droogenbroeck 66-69
Ambulation measures are being increasingly recognized as highly relevant to the quantification of multiple sclerosis (MS) severity and response to treatment. Feet paths are highly informative for gait analysis and we have recently designed a new system, which captures the position of the feet in real time. We use several range laser scanners (RLS) to analyze a horizontal slice of the scene in which each foot is considered as a point, and the vertical movements are ignored. Neat ambulation measures may be easily extracted such as walking speed, distance between feet over time, swing phase duration, and gait asymmetry in specific settings of walking recommendations. Our RLS platform is much cheaper than existing sensor-based and motion capture systems and may be more convenient for the development of multicentric clinical trials settings since patients can be easily and rapidly assessed without tags or sensors in the hallway of an outpatient clinic. We use 4 BEA LZR-i100 RLS arranged in a corridor of at least 10m long and 4m width, devoid of obstacle. The scanned plane is chosen to be located at 15 cm above the floor, which is right above the tibio-tarsal joint of the ankle in a barefoot configuration for adult individuals in stance phase.
We expect further studies to validate and empower the meaning of non-intrusive RLS-derived gait measures that should pave the ground for major improvements in the way we will assess the efficacy of disease-modifying treatments (DMTs), physical therapy and symptomatic interventions on walking impairment, ataxia and fatigability in MS. RLS-derived gait measures may also reveal to be crucial in the near future for the development of treatments that would specifically target progressive forms of MS.
Using genome-wide association studies to better understand multiple sclerosis PDF
Benedicte Dubois 70-76
Neurological diseases have a substantial and growing impact in our society. Multiple Sclerosis is one of the most common neurological disorders. Life-time risk of developing the disease is 1/500 in north-western Europe. Approximately 1.3 million individuals worldwide and 10,000 individuals in Belgium suffer from the disease. Onset of the disease typically occurs in early adulthood, between 20 and 40 years of age, at the start of building out a family and a professional career. The disease leads to significant physical and cognitive disability and hence has an important impact on the personal, social and professional life of patients and their relatives. The currently available treatments are only partially effective. The pathogenesis of the disease has not been unravelled yet, but the past years have seen exciting progress in the field. A large number of genetic risk factors have been identified, and patients differ in which combination of genetic risk factors they carry. We now are facing the challenge of translating this list of genes into an improved understanding of disease mechanisms and hopefully to better treatments.
Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million subjects worldwide and causes Adult T-cell leukemia-lymphoma (ATLL) or HAM/TSP (HTLV-induced myelopathy - tropical spastic paraparesis). BLV is the etiological agent of enzootic bovine leukemia. HTLV-1 and BLV have developed strategies to subvert hosts' immune surveillance. Understanding these mechanisms has allowed development of novel therapeutic approaches.
Epigenetics and the periconception environment in ruminants PDF
Ann Van Soom 1-23
Particularly in ruminant species, conclusive evidence has been accrued that environmental influences to which gametes or embryos are exposed to before, during and after conception (i.e. the periconception period) can induce epigenetic changes in the genome. Such epigenetic changes may adversely affect the future health, development, productivity and fertility of those offspring, in some cases even leading to the so-called “Large Offspring Syndrome”. Epigenetics are adjustments in gene expression which are established "on top" (i.e. “epi” in Greek) of the genes. Earlier data obtained in ruminants have demonstrated changes in DNA-methylation of imprinted genes in the placenta and in the organs of calves or lambs born after cloning or in vitro culture, but more recently dietary changes have also been implicated in changes in the phenotype of resulting offspring, causing insulin resistance and hypertension. In this review paper we will first explain how epigenetics can influence gene expression and why gametes and embryos are especially vulnerable to epigenetic changes caused by environmental influences at periconception, next we will describe how placental function is affected by epigenetic changes in “Large Offspring Syndrome” and finally we will discuss how maternal nutrition can affect in an epigenetic way ruminant embryonic and fetal development.
There is lack of international uniformity in the approach to screening and diagnosis of gestational diabetes (GDM) . The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has reached a consensus on a new screening strategy for pregestational diabetes in pregnancy and screening for GDM. However, there still is a lot of controversy on the IADPSG recommendation for screening for GDM. After analysis of the evidence, the Flemish Association of Diabetes (VDV) , The Flemish Association of Obstetricians (VVOG) and the Association of General Physicians (Domus Medica) have reached a new Flemish consensus. This new consensus recommends an universal screening for pregestational diabetes in pregnancy, at the latest at first prenatal contact, preferentially by measuring the fasting plasma glucose by using the same diagnostic criteria as in the non-pregnant state. The consensus decided, at this time, not to recommend the new IADPSG screening strategy for GDM but instead recommends the use of the two-step screening strategy with a 50g glucose challenge test and 3-hour 100g (or 2 hour 75g) oral glucose tolerance test with the Carpenter & Coustan criteria for diagnosis of GDM. This consensus will be reevaluated within the next three years based on the new available evidence.
Medical models represent portions of human anatomy obtained from three-dimensional (3D) medical imaging. The aim was to provide a current overview of clinical applications of rapid prototyping (RP) technologies in cranio-maxillofacial (CMF) surgery. We also presented new RP applications in reconstructive, orthognathic, and malformative CMF surgery.
Material and methods:
A systematic review of the literature was conducted on PubMed, and based on title-abstract sifting by one observer. Inclusion criteria consisted of medical rapid prototyping, 3D models, stereolithography, selective laser sintering, fused deposition modelling, 3D printing, polyjet, maxillofacial, craniofacial, cranioplasty, and implantology. In total we found 534 articles and 99 were retained for this review.
Four principal sources of 3D models for clinical applications in CMF surgery are stereolithography (majority of applications), selective laser sintering, 3D printing, and fused deposition modeling (one application). 3D models were used in most of domains of CMF surgery such as: reconstructive (oncologic, trauma), orthognathic, and temporo-mandibular surgery, in craniofacial malformations, cranioplasty, and implantology.
There exist still problems with costs of models and machines, with toxicity of material used to build up the model, with need of a specific expertise (multidisciplinary team work), which still limits the use of 3D RP models to complex cases and to university hospitals teams.
Further research should be directed toward development of ecological low-cost 3D RP techniques still providing an accuracy acceptable with its clinical use.
Prostate cancer: what is next for the radiation oncologist? PDF
Sofie Isebaert, Karin Maria Haustermans 111-126
External beam radiotherapy is one of the standard radical treatment options for men with prostate cancer, being still the most common non-skin malignancy in men in developed countries. Despite technical advances in the field of treatment planning and radiation delivery, the rate of biochemical failure for these patients is still significant. New strategies to improve radiocurability for prostate cancer are therefore urgently warranted. The implementation of both functional imaging techniques as well as molecular biology in the radiation treatment process of PCa has the potential to improve prognostication and therefore also to improve the triage of patients for a particular primary and/or adjuvant treatment modality. Moreover, these techniques could guide the targeting of an ablative radiation dose only to the intra-prostatic, macroscopic tumor or even only to radioresistant sub-volumes within the tumor, thereby limiting the risk of normal tissue toxicity that is associated with whole-gland radiation dose-escalation. Hopefully, this more individualized treatment approach will lead to a better local tumor control after radiotherapy and eventually to a better overall survival.
Developmental programming in maternal diabetes and obesity PDF
André Van Assche 127-131
Influences in utero and in early neonatal life induce a permanent response in the fetus and the newborn, leading to enhanced susceptibility to later diseases. These effects are transgenerational and are probably due to an epigenetic transmission mediated by the mother.
Diabetes and obesity during pregnancy show a marked increased prevalence and induce obesity and diabetes in the next generations. The most important causal factor is fetal hyperinsulinism. It is necessary to detect and control diabetes during pregnancy and to avoid obesitas at preference at adolescent age.
Duchenne Muscular Dystrophy: recent perspectives on pathophysiology PDF
Nicolas Deconinck, Bernard Dan 132-144
Duchenne Muscular Dystrophy (DMD) affects young boys and is characterized by the absence of dystrophin, a large cytoskeletal protein present in skeletal and cardiac muscle cells and neurons. Although the gene sequence and the protein structure of dystrophin are well characterized, comprehensive understanding of the mechanism leading from the absence of dystrophin to the muscular degeneration is still debated.
Dystrophin is considered a key structural element in the muscle fiber, and the primary function of the dystrophin-associated protein complex is to stabilize plasma membrane, although a role of signaling is still possible. Mechanically induced damage through eccentric contractions puts a high stress on fragile membranes and provokes micro-lesions that could eventually lead to loss of calcium homeostasis. Altered regeneration, inflammation, impaired vascular adaptation, and fibrosis form downstream events that are controled by epigenic factors. A variety of pharmacological and genetic strategies are currently under investigation to restore dystrophin expression in the dystrophin deficient mdx mouse and in DMD patients. Because no etiologic therapy is available for Duchenne muscular dystrophy, a better understanding of the primary and downstream mechanisms could prove useful for producing new adjuvant treatments. All pathophysiological mechanisms are reviewed together with perspectives on management.
Regenerative Medicine: from enhancing Endogenous Repair to Tissue Engineering PDF
Frank P. Luyten, Katleen Vandamme 145-163
Regenerative medicine aims to restore the structure and function of damaged tissues or organs. This process of postnatal tissue healing mimics developmental processes of tissue formation, and major progress in the understanding of the cellular and molecular basis of tissue formation and remodelling has now provided the knowledge platform to make significant advances in the field of regenerative medicine. Endogenous (intrinsic) repair may be guided and enhanced in different phases of wound healing including inflammation, debris removal and cell recruitment, followed by stimulation of cell proliferation, differentiation and tissue formation. When the stimulation of intrinsic repair is insufficient or inappropriate, leading to scar tissue formation and loss of function, extrinsic repair needs to be considered, i.e. (stem) cell therapies and tissue engineering approaches with growth factor formulations, smart biomaterials, cell populations or combination products that can contribute locally to the tissue repair processes. Here, we provide an overview of the strategies seeking to repair damaged tissues and more in particular in the repair of the locomotoric apparatus and maxillofacial tissue healing.
Update on nutritional management of the premature infants. PDF
Thibault Senterre, Jacques Rigo 164-178
Premature infants frequently suffer from insufficient postnatal nutritional support due to their immaturity as well as their hemodynamic and metabolic instability, leading to cumulative nutritional deficits during the first weeks of life. Thus, most premature infants develop a postnatal growth restriction. About 40-95% of very low birth weight (VLBW, <1500g) infants fall into the category of small for gestational age by the time of discharge. These phenomena have been associated with both short and long-term adverse outcomes and, therefore, represent a major challenge for neonatologists. This article discusses a recent practical approach to optimize nutritional support in premature infants from birth onwards. The approach incorporates the most recent policy related to nutritional recommendations and the article will demonstrate that adequate nutritional support is feasible in VLBW infants significantly improving postnatal growth and biological homeostasis, even in extremely premature infants <28 weeks. This policy is characterized by the immediate use of standardized parenteral nutrition solutions after birth and afterwards, and by the rapid introduction of an enriched feeding regimen as tolerated. Recently, this policy has been reproduced by the industry that has developed the first industrial parenteral nutrition solution for premature infants. Therefore, these initiatives represent a great opportunity to improve neonatal intensive care and premature infants’ development and long-term outcomes.
Lessons learned from the intersection of two frequent monogenic disorders: the Marfan syndrome and autosomal dominant polycystic kidney disease PDF
Dorien Schepers, Stéphanie Dautricourt, Lauranne De Decker, Ann Raes, Lut Van Laer, Bart L Loeys 179-197
Aortic aneurysms, which lead to aortic dissections and ruptures if left untreated, are among the most life threatening forms of cardiovascular disease. Thoracic aortic aneurysm is a prominent clinical feature of several hereditary connective tissue disorders, including Marfan syndrome (MFS). MFS is caused by mutations in FBN1, which encodes fibrillin-1, an important extracellular matrix protein. Through the study of MFS mouse models and diseases related to MFS, it became clear that dysregulated TGF-β signaling contributes significantly to the pathogenesis of thoracic aortic aneurysms.
Thoracic aortic and other aneurysms do also occur in autosomal dominant polycystic kidney disease (ADPKD). Mutations in PKD1 or PKD2 are responsible for ADPKD. The function of the polycystins, the proteins encoded by these two genes, is not clear yet, but an upregulation of TGF-β signaling has also been suggested as a pathogenetic mechanism. Although the main manifestation of ADPKD consists of renal cysts, a clear cardiovascular involvement with aneurysm formation has been demonstrated. Vice versa, kidney cysts have been observed in MFS. This clinical overlap suggests a mechanistic link between ADPKD and MFS. This link provides interesting opportunities for investigations on the pathogenic mechanisms of both diseases, more in particular the mechanisms leading to formation of thoracic aortic aneurysms.
Model of cyst formation in autosomal dominant polycystic liver disease PDF
Manoe Jacoba Janssen 208-217
Autosomal dominant polycystic liver disease (PCLD) is a genetic disorder that leads to the development of multiple fluid filled hepatic cysts. Somatic second hit mutations play an important role in the development of liver cysts, indicating that cyst formation is recessive at the cellular level. Here, we describe in detail the disease model that emerged from experimental studies and how these results have affected the field of polycystic liver disease.
Synthetic cannabinoids: general considerations PDF
Nik De Brabanter 218-234
Around 2008 synthetic cannabinoids were found to be present in and responsible for the psychoactive effects of herbal mixtures with names like ‘Spice’ or ‘K2’. In response to the increased popularity of these products, (inter)national organizations and governments started banning these cannabimimetics gradually. However, the lack of an uniform and international regulation makes it hard to control this issue.
For the different types of synthetic cannabinoids the scientific knowledge in terms of pharmacokinetics and pharmacodynamics is limited. This also means that little is known on the health of users, both on short and long term.
In the last years effort has been made to make detection of these products possible in different biological matrices. However, since the number of cannabimimetic compounds on the market appears to grow every month, both scientist and legislators run after a moving target.
Measuring renal function in older patients PDF
Gijs Van Pottelbergh, pierre Wallemacq, nathalie Demoulin, liesbeth hoste, benoit Bolon, Hans Pottel, Michel Jadoul, Jean-Marie Degryse 78-87
The glomerular filtration rate (GFR) is a well-accepted marker of renal function. However, the use of gold-standard tests to measure the GFR is difficult in clinical practice. As an alternative, creatinine or cystatin C plasma concentrations are often used to estimate the GFR. However, the GFR estimations are not well validated in older patients.
Older (>65 year) participants were recruited by their physician. All participants received an injection of 2, 5 ml iohexol, and eight timed blood samples were collected 20 to 600 min. after the injection to calculate the true GFR. The creatinine and cystatin C serum concentrations were measured and were used to estimate the GFR using the Cockcroft–Gault (CG), MDRD and CKD-EPI equations and a serum cystatin C-based equation (Cyst C). The eGFR values were compared with the true GFR.
The study included 36 participants (14 males, mean age 83 years and mean true GFR 49 ml/min/1.73 m²). On average, the MDRD, CKD-EPI and Cyst C equations overestimated the mGFR by 7.8, 3,6 and 8.0 ml/min/1.73 m², respectively, and the CG equation underestimated the mGFR by 13.6 ml/min/1.73 m². The CKD-EPI equation provided the most accurate GFR estimation, but its results differed by more than 30% compared with the true GFR in 19 out of 36 participants.
There is an urgent need for a more accurate GFR estimation equation in elderly and very elderly patients.
Anaphylaxis during general anaesthesia: a 10-year survey at the University Hospital of Antwerp PDF
Julie Leysen, Liene De Witte, Chris H Bridts, Didier G Ebo 88-100
Anaesthesia-related allergy is a rare but potentially life-threatening condition with serious consequences of diagnostic error. The authors report their experience of a 10-year survey in a Flemish referral centre.
Between January 2001 and December 2011, a total of 344 patients who experienced perioperative anaphylaxis were referred to our allergy centre. Allergy was documented on the basis of clinical history, skin tests, measurement of specific immunoglobulin E (sIgE) antibodies and/or basophil activation tests.
A total of 344 patients were studied (111 male, 233 female; age ranging from 21 months to 86 years (median 47 years)). Mild reactions, mostly cutaneous, were reported in 110 patients and severe potentially life-threatening reactions in 176 patients. In the remainder 58 patients severity of the reaction was not reported. An IgE-mediated pathomechanism was documented in 246 cases (72%). Importantly, an IgE-mediated mechanism was not restricted to the severe reactions but also observed in 57% of the mild reactions. The most common offenders were neuromuscular blocking agents (NMBA) (40%), latex (25%), β-lactam antibiotics (12%) and chlorhexidine (9%). In 18 patients (7%) with an IgE-mediated allergy more than 1 causative agent was identified. In 7 patients, an indolent mastocytosis was diagnosed.
In our region, the most frequent causes of anaphylaxis during general anaesthesia are NMBA, particularly rocuronium, latex, antibiotics and chlorhexidine. Given the prevalence of double sensitization it is advocated to test all potential causative agents. Indolent mastocytosis should not be overlooked. Confirmatory testing should not be restricted to patients with severe anaesthesia-related anaphylaxis but also offered to patients with mild (cutaneous) reactions.
Primary prevention of breast cancer: state of the art in 2012 PDF
Fabienne Liebens 101-110
Breast cancer is the most frequent cancer in women and the first cause of mortality linked to malignancies. In Belgium the mortality rate is 1 on 4 being amongst the highest across EU countries. Despite huge progress in screening and treatment, cancer remains a plague in the developed world. As a consequence urgent efforts are needed to foster primary prevention. All women should be encouraged to decrease alcohol consumption, to control body weight, to exercise, to avoid uncontrolled hormone treatments and to follow healthy lifestyle also reducing cardiovascular risk and diabetes. They should also be informed on the benefits of long lasting breastfeeding and early pregnancy. More accurate primary prevention allows defining for each woman her personal risk profile. Indeed undisputed progress has been made nowadays in identifying properly high risk women likely to benefit from tailored preventive intervention.
Selective inhibition of the p53–MDM2 interaction by nutlin drugs: a new therapeutic perspective for neuroblastoma PDF
Tom Van Maerken, Ali Rihani, Alan Van Goethem, Anne De Paepe, Frank Speleman, Jo Vandesompele 198-207
Neuroblastoma is one of the most common and most deadly childhood tumors. There is an unmet need to develop new therapeutic modalities for this malignancy that preferentially should be guided by our increasing knowledge of the biology of neuroblastoma. Proliferation and survival of neuroblastoma cells is critically dependent on suppression of the activity of the tumor suppressor protein p53, which is often mediated by increased activity of the MDM2 oncoprotein. Accordingly, small-molecule inhibitors of the interaction between MDM2 and p53 may provide a useful therapeutic option for the treatment of neuroblastoma by restoring the potent antitumor activity of wild-type p53. One of the most promising classes of selective inhibitors of the p53–MDM2 interaction are the nutlins, which have been extensively studied over the last years in several tumor types, including neuroblastoma. We discuss here preclinical data that support the notion that nutlin drugs may offer therapeutic benefit for children with neuroblastoma, on condition that wild-type p53 is present.
The increasing complexity of glucocorticoid receptor signaling and regulation PDF
Sofie Johanna Desmet, Ilse Beck, Nadia Bougarne, Dorien Clarisse, Julie Deckers, Dariusz Ratman, Jan Tavernier, Karolien De Bosscher 33-52
Glucocorticoids, although being one of the eldest drugs in the clinic and despite their widespread usage for the treatment of inflammatory and immune disorders and cancer, have not yet come of age when it comes to a full understanding of how they work. The majority of the biological actions of glucocorticoid hormones are explained by a wide diversity in the cellular action mechanism of the hormone-activated Glucocorticoid Receptor (GR). All molecular mechanisms described in the current overview are not only complex, exhibiting an astonishing degree of gene- and tissue-specificity, but on top of this they are also non-exclusive. This layering of mechanisms makes it extremely difficult for researchers to extract the crucial pieces of information that would assist in a rational design of drugs with an improved therapeutic profile, i.e. a satisfying and maintained therapeutic response in the absence of the many incapacitating glucocorticoid-associated side effects, such as diabetes, osteoporosis, muscle wasting, depression etc. In direct correlation with increased glucocorticoid usage as observed in the clinic, the impetus and desire to reveal all of these mechanisms -and most importantly, to try to integrate them in a sensible manner for the sake of finding better alternatives- has never been stronger.
Growth of tumors can accelerate during the peri-operative period. Understanding the complex role of inflammation and its consequences, positive and deleterious could lead to identify inflammatory-related biomarkers and therapeutic opportunities. In the works described here, we show how the neutrophil:lymphocyte ratio can be used as a prognostic factor before breast, lung and kidney cancer surgery, and how and why the intraoperative use of non-steroidal anti-inflammatorydrugs has been identified as a promising way to prevent, at least some, postoperative cancer relapses.
Locoregional cancer therapy including intraperitoneal (IP) drug therapy offers the potential to increase the therapeutic index by enhanced local drug exposure while at the same time limiting systemic absorption and toxicity. The efficacy of IP drug therapy depends on the extent of drug penetration in tumour tissue, which is driven by diffusion and convection. Obstacles to drug transport include elevated interstitial fluid pressure and the density of the interstitial matrix which characterize tumour stroma. Intraperitoneal drug therapy may be administered in the adjuvant setting, where it is repeatedly administered through an implanted catheter and access port. Alternatively, chemotherapy may be instilled immediately after cytoreductive surgery (CRS) as a continuous chemoperfusion circuit, usually under hyperthermic conditions (HIPEC). In optimally resected stage III ovarian cancer, large randomized trials have shown that the addition of IP chemotherapy to adjuvant regimens significantly improved survival. The combination of CRS and HIPEC may benefit patients with carcinomatosis from ovarian and colorectal origin. The results of ongoing randomized trials will better define the place of IP therapy in the multimodal management of these patients.
Pathophysiology of Déjà Vu and Reminiscences in Epilepsy PDF
Patrick Chauvel 104-113
Illusions of inappriopriate familiarity with the current experience or hallucinatory recall of memories have been reported in temporal lobe epilepsies. Pathophysiological hypotheses have been put forward, involving either the limbic regions of the temporal lobe (Jackson), the temporal neocortex ("interpretive cortex", Penfield), or both (Bancaud). New data, acquired in the course of presurgical investigations through intracerebral electrodes recording, demonstrate a critical role of the sub- and para-hippocampal cortices. A new hypothesis of cortico-limbic network is developed. Déjà Vu would result from an abnormal synchronisation between rhinal cortices and hippocampus, and reminiscences (or "dreamy state") from exacerbation of associational function of hippocampus in re-assembling pieces of past experience cortical networks.
Development of Gene Therapy for von Willebrand disease PDF
Simon De Meyer 114-128
Von Willebrand disease (VWD) is the most common inherited bleeding disorder in man. It is caused by quantitative or qualitative defects in von Willebrand factor (VWF), a large multimeric glycoprotein that is crucial for normal hemostasis. Treatment of VWD is aimed at restoring normal hemostatic function. Current treatment strategies are based on replacement of the defective VWF protein. Although acute protein replacement therapy or desmopressin-induced VWF release is adequate for the majority of patients, only a short-term effect can be achieved due to the short half-life of VWF (<12 hours). Hence, the search for new and better treatment strategies for VWD is continuing. Gene therapy for VWD offers the potential of a long-term, if not life-long, correction of VWF deficiency, which would dramatically increase the patient’s personal comfort and quality of life. In this review, the current status on the development of gene therapy for VWD is discussed.
Pharmacokinetic model development and validation to improve pharmacotherapy in neonates PDF
Karel Allegaert 146-156
Drug therapy is important to improve the outcome of neonates. Despite this, paediatricians commonly still prescribe drugs developed for adults, extrapolating doses from to adult field of medicine and based on pathophysiology in adults. A powerful tool to improve neonatal pharmacotherapy and facilitate clinical studies is knowledge integration through pharmacokinetic (PK) modelling. PK modelling is through mechanism based PK or physiology-based (PB) PK. Mechanism based models apply a bottom-up ‘from compound to model’ concept: based on drug specific observations, covariates are described, resulting in mechanism-based models. PB-PK applies a top-down ‘from physiology to clinical observations’ concept: based on available data on neonatal physiology (e.g. weight, cardiac output, renal function), a PB-PK model is developed.
Such models can guide study design and convert neonatal pharmacotherapy from explorative to confirmatory. The consecutive steps taken to model neonatal renal drug clearance illustrate the feasibility of such an approach. Besides clinical relevance, the same observations also unveil maturational patterns, and guide research on gaps in the knowledge on developmental physiology. This will be illustrated based on cefazolin (maturation of renal tubular transport) and propylene glycol (hepatic compared to renal elimination) clearance.
The programming of ‘neuroendocrine self’ occurs in the thymus, a cross-talk organ the emergence of which some 450 millions years ago allowed an integrated and harmonious coevolution between the major systems of cell-to-cell communication, the nervous, endocrine and immune systems. Neuroendocrine self-peptides are secreted by thymic epithelial cells not according to the classic model of neurosecretion, but are processed for the presentation by, or in association with, the major histocompatibility complex proteins. The autoimmune regulator (Aire) gene/protein controls the transcription of neuroendocrine genes in thymic epithelial cells. The presentation of self-peptides in the thymus is responsible for the negative selection of self-reactive T cells and, paradoxically in the same time, for the positive selection of thymo-dependant regulatory T (tTreg) cells that can inhibit, in the periphery, those self-reactive T cells that escaped clonal deletion in the thymus. The development of autoimmunity towards endocrine glands first results from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or acquired, for example during an enteroviral infection. This novel knowledge of normal and pathological functions of the thymus constitutes a solid basis for the development of a novel type of tolerogenic/negative ‘self-vaccination’ against type 1 diabetes.
Intestinal transplantation: from the laboratory to the clinics PDF
Laurens J. Ceulemans 1-12
Intestinal transplantation (ITx) is a valuable treatment for patients suffering from irreversible short bowel syndrome and debilitating complications of total parenteral nutrition. However, the results of ITx remain inferior to other solid organ transplants due to the profound immunogenicity of the organ and the subsequent demand for high levels of immunosuppression with its associated side effects. Since 2000, 10 consecutive cadaveric intestinal transplantations have been performed in our center. All were treated with the same “... Tolerogenic Protocol” - an experimentally proven, multifactorial immunomodulatory regimen - which includes the administration of donor specific whole blood, low-dose steroids, low-dose tacrolimus, and limitation of peritransplant intestinal ischemia reperfusion injury.
The first patient transplanted in this series was the first successful ITx performed in the Benelux. The 5-year patient and graft survival rate is 90% (follow-up: 11 months – 11 years and 10 months), which compares favorably with the average 50% patient survival rate reported by the Intestinal Transplant Registry. Only one patient (10%) developed an early acute rejection, reversible with immediate steroid treatment. Three patients (30%) faced a later episode of acute rejection (at 4 months, 18 months and 46 months). Wider application of ITx depends upon the development of these immunosuppressive protocols which prohibit intestinal rejection while reducing the need for immunosuppression.
Modelling tools are available to increase our understanding related to the normal physiology of the musculoskeletal system (MSS) and clinical implications of MSS dysfunctions. Grossly, three modelling approaches can be adopted (direct, inverse and hybrid modelling).
Materials and methods:
Inverse modelling is based on validated data combined using data fusion methods. Direct modelling is processing more complex models based on Physics law and less on measurements. Hybrid models are built from measured data fused with direct-like models.
Modelling methods are illustrated in this paper on aponeurosis role, thorax behaviour during breathing, hand functions, etc.
From a physiological point-of-view, inverse modelling seems to bring more satisfactory results because all model data can be validated. The clinical usefulness from direct and hybrid modelling are more difficult to assess because result validation cannot be fully performed.
Before adopting a modelling strategy, one must carefully assess the aim of the research to be attempted. If validation is of importance, such as during clinical activities, then inverse modelling is advised. Direct and most hybrid models seem to be limited because of the lack of extensive validation. Some hybrid models can be used in applied research when results focus on the measured data.
Immunity and vaccine development against Streptococcus pyogenes: is emm-typing enough? PDF
Pierre Smeesters 89-98
Serious disease caused by Streptococcus pyogenes (group A streptococcus, GAS), particularly rheumatic heart disease and invasive GAS infection, is responsible for more than half a million deaths worldwide per year. With no effective control strategies available for these diseases, a GAS vaccine is urgently needed. The development of a global GAS vaccine has been hindered by the large diversity of circulating strains (emm-types) of GAS in low-incomes settings. While approximately 80% coverage of the common emm-types in the USA and in Europe is theoretically possible with the 26 emm-type vaccine, the coverage in low-income settings, where serious GAS disease is most common, would be as low as 30%. Recent in vitro and in silico discoveries offer an exciting new approach to developing vaccines that protect against the broad range of strains in different regions of the world. These data suggest that antibodies against some emm-types may cross-protect against other emm-types. Cross protection between emm-types would represent a new paradigm in our understanding of immunity against GAS and an avenue for future GAS vaccine formulations.
A potential new antibiotic (CSA-13) on biofilms formed by P. aeruginosa clinical isolates PDF
Carole Nagant 99-103
The effect of an antimicrobial peptide mimic, the compound CSA-13, was studied on the different stages of the development of a biofilm formed by P. aeruginosa including on clinical strains isolated from the expectorations of patients with cystic fibrosis. Our results showed promising potential in using this cationic antibiotic steroid for the eradication of the biofilms formed by P. aeruginosa that are so deleterious in cystic fibrosis patients. The drug had also some synergy with tobramycin suggesting that a co-administration of CSA-13 and tobramycin should be considered for the treatment of chronic pulmonary infections provoked by P. aeruginosa.
The control of glucagon secretion by glucose and katp channel modulators PDF
Patrick Gilon 129-145
Glucagon secreted by pancreatic α-cells is a hyperglycemic hormone which plays a major role in the correction of hypoglycemia. Its secretion is physiologically controlled by nutrients, hormones and neurotransmitters. The mechanisms by which glucose inhibits its release are poorly known. In particular, it is unclear whether the glucagonostatic effect of glucose results from a direct action on α-cells or an indirect mechanism involving the release of an inhibitory paracrine factor from insulin-secreting β-cells or somatostatin-secreting δ–cells. We briefly review the different hypotheses of the glucagonostatic effect of glucose, and present our own data. In particular, we show that in α-cells, as in β-cells, KATP channels transduce changes in cell metabolism into changes in membrane potential and Ca2+ influx through voltage-dependent Ca2+ channels. A direct closure of α-cell KATP channels stimulates glucagon release and, hence, would not be responsible of the glucagonostatic effect of glucose. By contrast, glucagon secretion is inhibited by somatostatin released from δ-cells and a direct closure of δ-cell KATP channels stimulates somatostatin release leading to inhibition of glucagon secretion. These direct and indirect effects of KATP channel closure from, respectively, α- and δ-cells should be kept in mind when using hypoglycemic sulfonylureas to treat diabetes and correct the chronic hyperglycemia.
MicroRNAs: new actors in acute myeloid leukemia. PDF
Violaine Havelange 157-170
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at post-transcriptional level mainly by messenger RNA (mRNA) degradation. Altered miRNA expression has been described in acute myeloid leukemia (AML) patients. The functions of most of these miRNAs in leukemogenesis are still unclear. By correlating miRNA and mRNA expression profiles in AML patients, we identified functional miRNA-mRNA interactions taking place within pathways controlling hematopoiesis, innate immunity, inflammation, apoptosis and chromatin remodeling. To explore the roles of miR-29b which is frequently down-regulated in AML patients, we showed that miR-29b restoration reduced cell growth and induced apoptosis in AML cell lines. MiR-29b dramatically reduced tumorigenecity in a xenograft model providing rationale for the use of miR-29b synthetic oligonucleotides as a novel strategy to improve treatment response in AML. MiR-29b was also involved in aberrant DNA methylation by targeting DNA methyltransferases suggesting another therapeutic role of synthetic miR-29b as hypomethylating agent in AML. Finally, miR-29b expression level was associated with clinical response to decitabine. Levels of miR-29b expression should be validated as a predictive factor for stratification of older AML patients to decitabine treatment (an hypomethylating agent).
Antisense strategies against DUX4 as a therapeutic approach for FSHD PDF
Eugénie Ansseau 194-204
Facioscapulohumeral muscular dystrophy (FSHD) is a rare hereditary disease linked to a chromatin opening on the D4Z4 repeat array in 4q35 that allows expression of the DUX4 gene mapped by Prof. Alexandra Belayew’s group in the D4Z4 unit. We have characterized the DUX4 messenger RNAs (mRNA) in FSHD muscle: they derive from the last D4Z4 element and extend to the flanking pLAM region to a polyA signal which helps stabilize the mRNA. The DUX4 protein is a transcription factor and initiates a gene deregulation cascade causing defects, which are characteristics of the pathology. We propose to suppress DUX4 expression as a therapy for FSHD. In collaboration with Prof. Steve Wilton (Murdoch University - Western Australia), we have developed antisense oligomers (AO) specifically targeting the DUX4 mRNA which decreased DUX4 protein expression in myoblast cultures as well as its toxic effects.
For in vivo assays we used Prof. Scott Harper’s (Ohio State University, Columbus, USA) myopathy model caused by the injection of an AAV.DUX4 viral vector in a mouse hind limb muscle. In a first experiment our best AOs strongly decreased the amount of DUX4 mRNA in vivo.
Il existe, en trois langues, un très bel ouvrage sous la direction d'Hervé Hasquin et Francis Strauven, Aedes Academiarum. Les Académies et leur palais, richement illustré qui reprend l'histoire du bâtiment et des institutions qu'il abrite:
Il est disponible au Secrétariat de l'Académie de médecine ou à l'accueil lors des séances. Il nous reste des exemplaires en anglais aussi.
Les collections constituant la bibliothèque de l'Institution ont été transférées à la Bibliothèque royale Albert Ier.
Les collections du " Bulletin et Mémoires de l'Académie royale de Médecine de Belgique ", depuis leur origine (1841), peuvent être consultées au siège de l'Académie.
Diverses revues scientifiques récentes, belges et étrangères, sont également accessibles aux lecteurs.