Bulletin et memoires de l'Academie royale de medecine de Belgique最新文献

The notion that cognitive and behavioural dysfunctions of epileptic origin can be prolonged and with an insidious onset, has meant a radical conceptual change about epilepsy considered so far uniquely as a paroxysmal disorder. Also, these dysfunctions can be the only observable manifestations of the disorder. It is particularly true in some epileptic syndromes with onset in childhood. Epileptic dysfunctions are characterized by a discontinuity in time (intermittent, recurrent), in space (cerebral localization of the dysfunction and its spread). They often have a significant relationship with sleep. These features, with sometimes the existential dimension of some symptoms (intermittent loss of the flux of consciousness, intermittent perceptual distortions or cognitive-emotional dysfunction) are not seen in any other congenital or acquired disorders of the human brain. Longitudinal clinical studies in which the epileptic variable can be directly correlated with the precise study of the cognitive dysfunction (also with increasingly complex methods of brain imaging) are a difficult, relatively new multidisciplinary task, especially in the very young child. Case examples of children followed from early childhood to adulthood will illustrate the diversity of observed cognitive and behavioural abnormalities directly caused by the epileptic activity which can be massive or very discrete. One is only beginning to document precisely the late consequences (or absence of) of some early childhood epilepsies that had a direct impact on developing brain function at some point.

Recent statistics on the global HIV epidemic illustrate that HIV incidence continues to increase and provide stark reminders of the urgent need for new and more effective HIV prevention tools. The new paradigm of HIV prevention strategies consists on a biomedical approach including circumcision, vaginal microbicides, pre and post exposure prophylaxis and the treatment of the infected individual. The goal of the ARV therapy is to reach level of plasma HIV indetectability. At less than 20c/ml the risk of sexual transmission is equal to zero. A mathematical model shows that by universal testing associated with immediate therapy the epidemic could be driven towards elimination by the year 2020. It is anticipated that there will be substantial barriers to making biomedical HIV prevention tools available to individuals who are the highest risk of infection. Operationalizing biomedical approaches will require tight links between HIV testing and treatment programs, as HIV testing will be the common entry point for people to receive either biomedical prevention tools or treatment.

Together with that of obesity, the prevalence of non-alcoholic fatty liver disease is increasing. NAFLD is associated with insulin resistance and participate to the metabolic syndrome. A proportion of NAFLD patient will present a progressive disease characterized by, in addition to steatosis, hepatocellualr damage, chronic inflammation and progressive fibrosis and termed non-alcoholic steatohepatitis (NASH). NAHS is recognized as the hepatic complication of the metabolic syndrome. Its severity is related to fibrosis progression. Pathophysiological mechanisms underlying NASH remain ill-defined, the tools to identify NAFLD patients at risk for NASH progression and validate therapy are lacking. In this review, we concentrate on 2 aspects of NAFLD/NASH pathogenesis: the mechanisms of hepatic insulin resistance and the determinants of fibrosis in the context of metabolic syndrome.

Anosognosia corresponds to a lack of awareness about the own clinical disease of a patient. Anosognosia is frequent in Alzheimer's disease (AD). Researchers explore several hypotheses, psychological (deny) or cognitive (an association of memory and executive impairment), and recently models describing the dynamics of self representation provided convincing interpretations. Self models are modular. They comprise a central executive organising information processing according to subject's objectives. The central executive takes into account personal beliefs and social schemata and it uses autobiographical memory. The analysis of information by the self system leads to decision taking that relies on two principles, self continuity and adaptation. Neuroimaging studies showed that self reflection activates specific brain regions, comprising the ventromedial prefrontal cortex, the medial parietal and posterior cingulate cortex and the inferior parietal lobule. Other studies demonstrated that the same regions are particularly affected by AD. Experimental data currently allows making relationships between regional brain involvement, diverse difficulties in self representation and different forms of anosognosia for clinical status in AD patients.

Systemic acid-base balance is primarily controlled by the renal excretion of acids and the exhalation of CO2 and both processes are tightly regulated and coordinated. Acid excretion into urine requires the formation of ammonium and its transport into urine as gaseous ammonia. Until recently it has been believed that NH3 would move across membranes by free diffusion according to Overton's rule. Recent structural, functional, and in vivo data show now that Rhesus proteins act as gas channels for NH3 and mediate renal acid excretion. Lack of the renal isoform RhCG in mice causes reduced ammonium excretion and metabolic acidosis. Breathing and exhalation of CO2 is stimulated and regulated by CO2 and acid sensors in the carotid bodies and the brain stem. GPR4 belongs to a small subfamily of G protein-coupled receptors and is activated by extracellular protons. Mice lacking GPR4 develop respiratory acidosis and are not able to increase ventilation appropriately in response to high CO2 levels or systemic acidosis. Thus, RhCG and GPR4 present novel paradigms of membrane proteins involved in controlling and regulating systemic acid-base balance in the major organs involved in this task.

Growth factors of the PDGF and FGF families act through receptor tyrosine kinases. These receptors can be activated by chromosomal rearrangements in myeloid neoplasms associated with hypereosinophilia. We identified a new fusion gene between KANK1 and PDGFRbeta in a patient with thrombocythemia. We showed that such fusion oncoproteins derived from PDGF and FGF receptors escape the normal degradation pathways, leading to their accumulation in cells. This process amplifies signalling leading to cell proliferation. Using microarrays and bioinformatics, we showed that several transcription factors contribute to the control cell growth, including STATS, FOXO and SREBP.

One of the parameters characterizing leukemia is an increase in the peripheral blood cell numbers. As a deregulation of homeostasis, this pathological process might result from an alteration of different parameters modulating cell dynamics. In this context, we studied homeostasis during infection of sheep infected by bovine leukemia virus (BLV). In this experimental model, we demonstrated that the cell death rates are increased after BLV infection and that the spleen exerts a key role in this process. We next proposed, elaborated and tested a novel therapeutic approach based on activation of viral expression. Finally, we summarized our observations in a recapitulative model.

Survival of lung transplant recipients is currently limited by the primary graft dysfunction, an acute phenomenon occurring within 72 hours after the transplantation, but also by the chronic rejection that appears more than one year later. IL-17 might be implicated in these two diseases. The heterotopic trachea transplantation in mice generates epithelial lesions mimicking the human pathology. Using this model, we show that IL-17 was crucially implicated in early, but not chronic lesions after transplantation. The main intragraft cellular sources of IL-17 are recipient-derived gammadelta T cells. However, the IL17-dependent lesions in our model are not mediated by a direct effect of IL-17 on donor-derived cells. Nevertheless, its inhibition protects CK-14+ basal epithelial stem cells that are known to be capable of renewing of the whole epithelium.

Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from an inappropriate immune response towards the microbial flora in a genetically susceptible host. Several epidemiological and animal studies have demonstrated the essential role of the microbial flora in the triggering and perpetuation of intestinal inflammation. IBD are multigenic and heterogeneous diseases, and result from multiple low penetrant genes or group of genes. The genetic strategy for gene hunting in multigenic studies relies on two separate approaches. A candidate gene approach which is based on a robust biological hypothesis. A more systematic/global approach is either based on linkage studies (in late 90s) on IBD families or, since 2000 on gene arrays, the genome wide arrays (GWAS) on patients and controls. In 2001, the first CD susceptible gene, NOD2, was discovered, and found to be a pattern recognition receptor for bacteria, shedding light on the role of bacterial recognition in the triggering of the disease. Since 2000, GWAs have greatly accelerated the discoveries of new genes or signalling pathways in Crohn's disease and ulcerative colitis, confirming the importance of bacterial recognition, but also of bacterial defence (i.e. autophagy genes) as well as the role of the adaptive immune response (i.e. IL-23R/Th17 pathway). Despite the role of genetics in the development of IBD, changes in the development and composition of the microbial flora, known as dysbiosis, (possibly induced by our Western life style) must alter the development and function of the mucosal immune system, and leads to disease expression.