Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie最新文献

The achievements of the Belgian Diabetes Registry (BDR) over a period of almost 20 years are described. This registry is a national and multicentric initiative that collects blood samples and information from diabetes patients and their relatives and treats the results in a confidential and protected way. Not only could the size of the health care problem 'diabetes' finally be quantified and monitored in Belgium for the age group 0-39 years, but in addition a platform was created for the early detection of individuals at high risk of the disease and its complications. This is a conditio sine qua non for the preparation of internationally competitive prevention studies and novel beta cell therapies, that could be effectively launched in Belgium with the help of BDR.

Potent thymidine phosphorylase (TP) inhibitors with anti-angiogenic activity are required to improve the prognosis of patients with TP-positive tumors. We have designed and developed novel structural and functional classes of TP inhibitors that also inhibit TP-induced angiogenesis, i.e. (i) the first purine analogue inhibitor of TP (7DX), (ii) the first multifunctional TP inhibitor (TP65), and (iii) the purine riboside analogue KIN59, which inhibits TP without interacting with the substrate-binding sites. The latter finding indicates that a, yet unidentified, allosteric site in TP contributes to its biological activities. In order to identify the amino acid residues in TP that interact with KIN59, we performed co-crystallograpy of the KIN59-TP complex. Our preliminary data suggest the existence of a putative KIN59 binding site. Identification of the allosteric site(s) in TP is important to gain more insight into the different biological activities of TP and may aid in the design of novel TP inhibitors. The nucleotide analogue cidofovir, which is being used clinically for the treatment of cytomegalovirus-induced retinitis in AIDS patients, emerged as a promising antitumor agent. So far, cidofovir has only been evaluated clinically for the treatment of HPV-associated tumors. Our results demonstrate the potent activity of cidofovir against tumors that are not associated with a virus. Cidofovir inhibits the growth of strongly vascularized tumors via inhibition of the growth factor FGF2, and by increasing the expression of the tumor suppressor p53, leading to apoptosis. These exciting results open new perspectives for the use of cidofovir as an anti-tumor agent in the therapy of tumors that are not associated with an oncogenic virus.

Under physiological conditions, the vaginal primarily harbours lactobacilli which ideally confer in mutualism with the vaginal epithelium colonisation resistance to other micro-organisms, thereby preventing ascending or systemic infection. Albeit only a few Lactobacillus species constitute the vaginal microflora, huge species- and strain-specific differences occur however, and these differences account for a wide variability in the intrinsic capability of the Lactobacillus microflora to maintain the vaginal ecosystem. Hence, among a substantial proportion of women, the picture of lactobacilli-driven mutualism is actually less ideal than one may assume. As the vagina is incessantly subjected to cyclic changes as well as behavioural exposures that may challenge the perpetuation of the Lactobacillus microflora, the intrinsic stability of the resident microflora is paramount to women's health. Considering the close concordance between the rectal and vaginal lactobacilli, future research may benefit from the study of food, oral, and intestinal microbiology in relation to the vaginal Lactobacillus microbiota. Loss of the hydrogen peroxide producing lactobacilli accompanied by massive anaerobic overgrowth is observed with bacterial vaginosis. Molecular studies of the bacterial vaginosis microflora have recently revealed a tremendous species variability further documenting the complex polymicrobial nature of this condition. Emerging issues include the predominance of G. vaginalis, a normal microflora constituent possibly eliciting a host of virulence mechanisms at increasing concentrations through quorum sensing, the associated abundance of A. vaginae as a rather specific marker of therapy failure and disease persistence or recurrence, and the discovery of an adherent, metronidazole-resistant biofilm consisting of the latter two species.

Arterial ageing is a complex continuously distributed phenotype, which comes about through the interaction between inherited susceptibility, life-style and environmental factors. We used an integrated approach combining methods from genetics, molecular biology and population sciences to study the role of genetic variation and environmental factors in biological ageing. The discussed work comprises four population based studies of which two had a prospective design and two integrated recently developed biomolecular markers of ageing with classical epidemiological tools. The striking variability in the age of the manifestation of cardiovascular diseases is not fully explained by conventional risk factors. Variation in biological age has been suggested. The initial telomere length of a person is mainly determined by genetic factors. In this regard, we noticed robust correlations in telomere length between fathers and daughters, between mothers and both sons and daughters, and among siblings. X-linked inheritance of telomere length is the most likely explanation for these findings. Telomere length shortens with each cell division, and exposition to harmful environmental factors results in shorter telomere length as we observed in smokers. Telomere length correlated with the distensibility of the carotid artery and oxidative stress and inflammation are major determinants of arterial and biological ageing. In this context, selenium a component of antioxidant enzymes such as glutathione peroxidase, correlated inversely with blood pressure in the population at large. Oxidative stress and inflammation are major determinants of arterial and biological ageing. If telomeres are indeed causally involved in the pathogenesis of arterial ageing, this might provide new avenues for future preventive and therapeutic strategies.

Inherited peripheral neuropathies belong to the most common neuromuscular disorders and occur worldwide (1/2500). The best known is Charcot Marie Tooth (CMT), an inherited disorder first described in 1886. Most patients have progressive weakness and wasting of foot and hand muscles. Treatment is currently supportive (braces and foot surgery) and a therapy that fundamentally alters the course of these diseases is still lacking. The involvement of a specific subset of neurons is a key hallmark in the disease process. One subgroup, distal hereditary motor neuropathy (distal HMN) is characterized by the selective loss of motor neurons and/or their long axons in the peripheral nervous system. Apart from the absence of sensory abnormalities, distal HMN closely resembles axonal CMT2. A better understanding of the molecular architecture of the peripheral nerve, the functional pathways, the myelination process and the complex interaction between the axon, the myelinating Schwann cells and muscle is crucial to identify targets for therapeutic interventions. Identification of loci, genes and disease-causing mutations is the first step in this understanding and opens new perspectives for molecular genetic diagnosis. Genotype-phenotype correlations guide the selection of specific mutations suitable for functional analysis in cellular and animal models. The knowledge gained from the molecular genetic and biological research will also help to make progress in the study of acquired peripheral neuropathies. Some of these neuropathies are often therapy-resistant, have a profound influence on the quality of life of the patients, and constitute a financial burden for both the individual and the community.

Aortic aneurysms are an important cause of mortality in the western world. Monogenic disorders such as the Marfan syndrome (MFS) are good genetic models for the pathogenesis of aortic aneurysm. In the MFS, progressive dilatation of the aortic root leads to aortic aneurysm and dissection, often associated with precocious death. Early pathogenetic models for MFS focused upon structural weakness of the tissues imposed by microfibrillar deficiency. However, recent studies of transgenic mouse models have challenged this model and demonstrated a central role for the upregulation of the TGFbeta signaling pathway. The discovery of a new aortic aneurysm syndrome, the Loeys-Dietz syndrome (LDS), confirmed the importance of the cytokine TGFbeta in aneurysm pathogenesis. The main distinguishing features between LDS and MFS include the presence of hypertelorism, cleft palate/bifid uvula and arterial tortuosity. LDS is caused by mutations in the genes encoding the receptors for TGFbeta (TGFBR1/2). This insight helped to elucidate the pathogenesis of another rare autosomal recessive connective tissue disorder, arterial tortuosity syndrome. This disease is caused by mutations in the SLC2A10 gene, coding for GLUT10, a member of the glucose transporter family. In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS. Finally, all these insights have also lead to new therapeutic insights. In transgenic mouse models it was shown that losartan, an angiotensin II type 1 receptor with known inhibiting effects on TGFbeta, rescues the aortic phenotype. If these promising results are confirmed in human trials, losartan might have beneficial effects in the treatment of more common nonhereditary aortic aneurysms.

Vascular calcification or ectopic calcification ofblood vessels forms an important element of the increased cardiovascular risk observed in patients with chronic kidney disease. In addition to the classical Framingham risk factors, specific uremia-related factors such as hyperphosphatemia and disturbed calcium and phosphorus metabolism contribute to the development of vascular calcification. To gain a better insight into the mechanism of this calcification process, experimental techniques were developed to induce and detect vascular calcification in rats with in vivo micro-CT imaging. By means of synchrotron-based micro-X-ray diffraction the mineral phase deposited in arteries of rats with adenine-induced chronic renal failure was found to consist mainly of hydroxyapatite, whereas calcifications induced with high dose vitamin D administration additionally contained whitlockite, a magnesium-containing mineral. Vascular calcification is an active, cell-regulated process. By immunohistochemically investigating the expression of bone-specific proteins in calciying arteries, we demonstrated that calcifying vascular smooth muscle cells are not only able to acquire an osteoblast-like phenotype, but can moreover transdifferentiate to chondrocyte-like cells, expressing the cartilage transcription factor sox9 and the cartilage extracellular matrix protein collagen II. This cartilage phenotype was also found in human aortic tissue. Finally, treatment of uremic rats with the calcium-free phosphate binder lanthanum carbonate was shown to inhibit the development of vascular calcification, implying that adequate phosphorus control without additional calcium load reduces vascular calcification. In the future, we will map the proteome of calcifying vascular smooth muscle cells and investigate the paradoxical association of vascular calcification with impaired bone mineralisation.

Type 1 diabetes is caused by an immune mediated destruction of the insulin-secreting beta cells in the pancreas. The disease can become clinically apparent at any age. At clinical diagnosis, there is invariably some residual beta cell function. Recent studies--including one mainly conducted in Belgium--have provided proof of principle that short-term humanized anti-T-cell antibody treatment is able to preserve residual beta cell function for at least 18 months in adult type 1 diabetic patients with a recent clinical onset of disease. The effect of anti-T-cell antibody treatment is more pronounced among patients with initial higher residual beta-cell function. The resultant stabilizing effect on metabolic control is expected to delay chronic complications and avoid hypoglycemia in these patients. With a similar goal in mind, non-uremic C-peptide negative type 1 diabetic patients are offered beta cell transplantation. During the last years the one year survival of these grafts under immune suppression with Anti-Thymocyte-Globulin, tacrolimus and mycophenolate mofetil exceeds 80% with virtually no cases of primary non-function. Widespread application will however only occur if ways are found to induce operational graft tolerance and the shortage of viable human donor cells can be overcome. Both islet xenotransplantation and stem cell therapy provide possible strategies to solve this problem and represent areas of intense investigation. The ultimate goal is prevention of clinical disease. Studies by the Belgian Diabetes Registry and others in first degree family members of type 1 diabetic patients have refined identification of individuals at very high risk of hyperglycemia so that new immunological treatments can be tested in the prediabetic phase.

Despite the progress in the treatment of Crohn's disease and ulcerative colitis, there is a dire need to improve the benefit to risk ration of clinical care for young patients with chronic diseases. Most of the effective therapies for IBD are immunosuppressants and carry a burden of toxicity. The present work has focused on improving the tolerance of medical therapy while preserving efficacy. We have demonstrated that a reduction of the i.v. cyclosporine dose to 2 mg/kg preserves clinical efficacy and opens the perspective to a reduced toxicity. This study has been internationally implemented in treatment guidelines. In a case of progressive multifocal leukencephalopathy, al lethal brain infection caused by JC virus, in a patient with Crohn's disease, we were able to link JC reactivation to a specific therapy inhibiting leukocyte trafficking. We took this observation further and attempted to develop a screening algorithm for early detection of JC viral replication. Although further studies are needed this may be a first step to safer treatment with anti integrin therapies. Finally we have demonstrated that patients with myenteric plexitis at the ileal resection margins at surgery for ileocolonic Crohn's disease have a higher endoscopic relapse rate throughout one year. Myenteric plexitis is the first histological marker guiding prophyalictic therapy in the postoperative setting.

In order to infect a target cell, the HIV envelope glycoprotein gp120 has to interact with the CD4 receptor, which serves as the primary virus receptor. For most HIV strains, the successful infection of their target cells is mainly dependent on the expression of the CD4 surface molecule which can be considered as an ideal target with multiple windows of opportunity for therapeutic intervention. Therefore, drugs that interfere with the CD4 receptor, and thus inhibit viral entry, may be promising agents for the treatment of AIDS. Here we describe the discovery and characterization of the CD4-targeted HIV entry inhibitors cyclotriazadisulfonamides. They repesent a novel class of small molecule antiviral agents with an unique mode of action. The lead compound, CADA, specifically interferes with cellular CD4 receptor expression and is active against a wide variety of HIV strains at submicromolar levels when evaluated in different cell-types such as T cells, monocytes and dendritic cells. Moreover, a strict correlation has been demonstrated between anti-HIV activity and CD4 down-modulation of about 20 different CADA analogs. In addition, CADA acted synergistically in combination with other FDA-approved anti-HIV drugs. The broad spectrum antiviral activity of CADA against several different subtypes of HIV supports the possible application of this compound as a microbicide. Finally, the development of fluorescent CADA analogs made it feasible to study receptor and its down-modulator simultaneously. These CADA-compounds with reversible CD4 down-modulating potency will be valuable tools in further studies on receptor modulation, and in deciphering the process that plays a role during the complicated interactions between HIV-gp120 and the cellular membrane, which ultimately will lead to a more efficient treatment of HIV-infections.