Académie royale de Médecine de Belgique


Review Articles

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.

The VDV-VVOG-Domus Medica consensus 2012 on screening for pregestational diabetes in early pregnancy and screening for gestational diabetes.     PDF
Katrien Benhalima     24-42

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.

Three-dimensional rapid prototyping models in cranio-maxillofacial surgery: systematic review and new clinical applications     PDF
Raphael Olszewski     43-77

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.