A very rare cancer in Down syndrome: medulloblastoma. Epidemiological data from 13 countries.

Persons with Down syndrome (DS) uniquely have an increased frequency of leukemias but a decreased total frequency of solid tumors. The distribution and frequency of specific types of brain tumors have never been studied in DS. We evaluated the frequency of primary neural cell embryonal tumors and gliomas in a large international data set. The observed number of children with DS having a medulloblastoma, central nervous system primitive neuroectodermal tumor (CNS-PNET) or glial tumor was compared to the expected number. Data were collected from cancer registries or brain tumor registries in 13 countries of Europe, America, Asia and Oceania. The number of DS children with each category of tumor was treated as a Poisson variable with mean equal to 0.000884 times the total number of registrations in that category. Among 8,043 neural cell embryonal tumors (6,882 medulloblastomas and 1,161 CNS-PNETs), only one patient with medulloblastoma had DS, while 7.11 children in total and 6.08 with medulloblastoma were expected to have DS. (p 0.016 and 0.0066 respectively). Among 13,797 children with glioma, 10 had DS, whereas 12.2 were expected. Children with DS appear to be specifically protected against primary neural cell embryonal tumors of the CNS, whereas gliomas occur at the same frequency as in the general population. A similar protection against neuroblastoma, the principal extracranial neural cell embryonal tumor, has been observed in children with DS. Additional genetic material on the supernumerary chromosome 21 may protect against embryonal neural cell tumor development.

The zebrafish is an animal model in ophthalmic diseases : Fleck corneal dystrophy and Schorderet-Munier syndrome

RAPPORT DE SYNTHÈSE : Pip5k3 : Pip5k3 is a kinase responsible for fleck corneal dystrophy when mutated. It is a well conserved gene that has only been characterized in human and mouse. Characterization of pip5k3 in zebrafish was necessary before using it as a model. The protein is 70 % similar to the human homologue. The full coding sequence encompasses 6303 by and presented four isoforms. They were differentially expressed during development. All the analyzed organs of the adult zebrafish expressed pip5k3. The adult eye expressed pip5k3 in the cornea, lens, ganglion cell layer (GCL), inner nuclear layer (INL) and outer limiting membrane (OLM). During development, pip5k3 was first uniformly expressed before to be restricted to the head region and to the somites. The expression of pip5k3 in the cornea of the larval eye could make possible the study of fleck corneal dystrophy on this animal. NkxS-3 : NKXS-3 is a transcription factor responsible for a new oculo-auricular syndrome in human when mutated. This recessive disorder is characterized by defects in ear lobule and multiple defects in eye, including microphthalmia and cataract. During development, the zebrafish expressed nkx5-3 in the lens, in the anterior retina and in otic vesicles. Knockdown experiments partially phenocopied the human disease. Microphthalmia and cataract were reproduced, but zebrafish showed also defects in the cartilage of the jaw associated with a microcephaly and fins abnormalities. The retinal cell differentiation was delayed, possibly linked with the delayed expression of at`h5 and crx also observed in morphants. Shh, a regulator of ath5, was normally expressed in morphant. Overexpression of nkx5-3 lead to an anophthalmia, suggesting a role at the early organogenesis of the eye. All the phenotypes observed in morphants and embryos overexpressing nkx5-3 suggest a potential involvement of the FGF and hedgehog signaling pathways.

RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses.

The receptor for hyaluronic acid-mediated motility (RHAMM) is an antigen eliciting both humoral and cellular immune responses in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). We initiated a phase 1 clinical trial vaccinating 10 patients with R3 (ILSLELMKL), a highly immunogenic CD8(+) T-cell epitope peptide derived from RHAMM. In 7 of 10 patients, we detected an increase of CD8(+)/HLA-A2/RHAMM R3 tetramer(+)/CD45RA(+)/CCR7(-)/CD27(-)/CD28(-) effector T cells in accordance with an increase of R3-specific CD8(+) T cells in enzyme linked immunospot (ELISpot) assays. In chromium release assays, a specific lysis of RHAMM-positive leukemic blasts was shown. Three of 6 patients with myeloid disorders (1/3 AML, 2/3 MDS) achieved clinical responses: one patient with AML and one with MDS showed a significant reduction of blasts in the bone marrow after the last vaccination. One patient with MDS no longer needed erythrocyte transfusions after 4 vaccinations. Two of 4 patients with MM showed a reduction of free light chain serum levels. Taken together, RHAMM-R3 peptide vaccination induced both immunologic and clinical responses, and therefore RHAMM constitutes a promising target for further immunotherapeutic approaches. This study is registered at http://ISRCTN.org as ISRCTN32763606 and is registered with EudraCT as 2005-001706-37.

Haemorrhagic shock and encephalopathy syndrome: report of two cases with special reference to hypoglycaemia.

Haemorrhagic shock and encephalopathy syndrome (HSES) is a devastating disorder affecting infants. So far no cases have been reported in Switzerland. It is characterised by the abrupt onset of hyperpyrexia, shock, encephalopathy, diarrhoea, disseminated intravascular coagulation (DIC) and renal and hepatic failure in previously healthy infants. Severe hypoglycaemia has been repeatedly reported in association with HSES. However, the pathophysiology of the hypoglycaemia is not clear. We report on two infants (2 and 7 months old) with typical HSES, both of whom were presented with nonketotic hypoglycaemia. In the first case, plasma insulin was 23 pmol/l at the time of hypoglycaemia (0.1 mmol/l). In the second case, increased values for interleukin-6 (IL-6) (319 pg/ml) and IL-8 (1382 pg/ml) were found 24 hours after admission, whereas IL-1 and tumour necrosis factor-alpha (TNF-alpha) were not measurable. Alpha-1-antitrypsin was decreased (0.6 g/l). In hyperpyrexic, unconscious and shocked infants, HSES should be considered and hypoglycaemia should be specifically looked for. Hypoglycaemia is not caused by hyperinsulinism but may be secondary to the release of cytokines.

Le syndrome d'épuisement professionnel (burnout) des médecins

Les médecins sont soumis à différents facteurs de stress qui les prédisposent à l'épuisement professionnel, mais aussi à d'autres problèmes de santé psychique : dépression, abus de substances, suicide sont des thèmes que l'on retrouve souvent lorsque l'on parle de la santé des médecins. Le burnout est un syndrome qui peut toucher toute les professions, mais ce sont celles en lien à la relation d'aide qui sont les plus susceptibles d'en développer les stigmates. Car le burnout est une véritable maladie de la relation d'aide. Maslach et Jackson ont le mieux défini cet incendie intérieur : conséquence d'une exposition chronique et répétitive à un stress émotionnel, il se manifeste par : 1. L'épuisement relationnel 2. La déshumanisation de la relation à l'autre. 3. Le sentiment d'échec professionnel ou la diminution de l'accomplissement personnel. [Auteur]

The dark sides of capillary morphogenesis gene 2.

Capillary morphogenesis gene 2 (CMG2) is a type I membrane protein involved in the homeostasis of the extracellular matrix. While it shares interesting similarities with integrins, its exact molecular role is unknown. The interest and knowledge about CMG2 largely stems from the fact that it is involved in two diseases, one infectious and one genetic. CMG2 is the main receptor of the anthrax toxin, and knocking out this gene in mice renders them insensitive to infection with Bacillus anthracis spores. On the other hand, mutations in CMG2 lead to a rare but severe autosomal recessive disorder in humans called Hyaline Fibromatosis Syndrome (HFS). We will here review what is known about the structure of CMG2 and its ability to mediate anthrax toxin entry into cell. We will then describe the limited knowledge available concerning the physiological role of CMG2. Finally, we will describe HFS and the consequences of HFS-associated mutations in CMG2 at the molecular and cellular level.

Syndrome métabolique et antipsychotiques atypiques : recommandations et prise en charge clinique

L'introduction des antipsychotiques atypiques (AA) avec leurs effets secondaires métaboliques a attiré une plus grande attention sur le risque iatrogène éventuel de maladies cardiovasculaires dans la population des patients atteints de schizophrénie ou de trouble bipolaire. À cet égard, l'analyse du rapport risque/bénéfice dans l'utilisation des ces médicaments se révèle souvent délicate, nécessitant la coordination de plusieurs savoirs et ressources des réseaux somatiques et psychiatriques. Dans cet article, les auteurs présentent une revue sur le syndrome métabolique (SM) et la maladie cardiovasculaire (MCV) dans la population psychiatrique. Sur la base des dernières recommandations internationales, ils proposent des directives de prise en charge des effets secondaires, notamment métaboliques, à l'introduction d'un AA.