Evaluating the efficacy of the selective orexin 1 receptor antagonist nivasorexant in an animal model of binge-eating disorder.

OBJECTIVE: Test the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge-eating disorder (BED) and study its dose-response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin-A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge-eating phenotype in the rat model used. METHOD: Binge-like eating of highly palatable food (HPF) in rats was induced through priming by intermittent, repeated periods of dieting and access to HPF, followed by an additional challenge with acute stress. Effects of nivasorexant were compared to the SO1RAs ACT-335827 and IDOR-1104-2408. OXA expression in neurons and neuronal fibers as well as ΔFosB and OXA-ΔFosB co-expression was studied in relevant brain regions using immuno- or immunofluorescent histochemistry. RESULTS: All SO1RAs dose-dependently reduced binge-like eating with effect sizes comparable to the positive control topiramate, at unbound drug concentrations selectively blocking brain OX1Rs. Nivasorexant's efficacy was maintained upon chronic dosing and under conditions involving more frequent stress exposure. Priming for binge-like eating or nivasorexant treatment resulted in only minor changes in OXA or ΔFosB expression in few brain areas. DISCUSSION: Selective OX1R blockade reduced binge-like eating in rats. Neither ΔFosB nor OXA expression proved to be a useful classifier for their binge-eating phenotype. The current results formed the basis for a clinical phase II trial in BED, in which nivasorexant was unfortunately not efficacious compared with placebo. PUBLIC SIGNIFICANCE: Nivasorexant is a new investigational drug for the treatment of binge-eating disorder (BED). It underwent clinical testing in a phase II proof of concept trial in humans but was not efficacious compared with placebo. The current manuscript investigated the drug's efficacy in reducing binge-like eating behavior of a highly palatable sweet and fat diet in a rat model of BED, which initially laid the foundation for the clinical trial.

[The multiple perspectives of the multipurpose home care service]. / Les multiples perspectives du service polyvalent d'aide et de soins à domicile.

The Cosi home nursing service (Ssiad), created in 2000, is committed to working in partnership, considering that cooperation and good coordination are at the origin of a sustainable and quality home care. With this in mind, the directors of Ssiad took over the management of a home assistance and support service in 2011 in order to offer personal assistance and care, and thus to provide comprehensive care. Now a multi-purpose home help and care service, Cosi continues to evolve to best meet the needs of users.

[Evaluation of the effect of hemolysis, bilirubin, lipemy, glucosis and natrium on mean concentration of hemoglobin (XN 2000® Sysmex®)]. / Évaluation de l'influence de l'hémolyse, de l'ictère, de la lipémie, d'un apport en glucose ou en sodium sur la concentration corpusculaire moyenne en hémoglobine (XN 2000® Sysmex®).

We evaluated the effect of haemolysis, bilirubin, lipemia, hyperglycemia and natremia on mean corpuscular haemoglobin concentration (MCHC) measured by XN 2000® (Sysmex®). Our evaluation had shown than correction is necessary for haemolysis and lipemia but not for icterus. There were not possible to reproduce variation of MCHC with hyperglycemia or variation of natremia. Blood smears show red blood cells abnormalities.

[Cholera in Brest, France]. / Le choléra en France, à Brest ?

This is a case report about a 54-year-old man with hypovolemic shock, due to diarrhea and major vomiting after his return from India. The isolation of Vibrio cholerae serogroup O1 (Ogawa serotype) explains this typical clinical presentation of cholera, seen in 10% of cholera cases only. The patient had co-infection with Vibrio cholerae and Campylobacter coli. Co-infections appear to be frequent in endemic areas. The purpose of this case report is to recall the relevance of Vibrio isolation when the clinical context is evocative (diarrhea on travel return, raw sea food consumption).

Self-induced drug intoxication in baclofen: of the calm hypotonic coma in the status epilepticus.

Baclofen is an agonist of peripheral and central B gamma-aminobutyric acid receptors, whose activation causes a myorelaxation and a powerfull depression of the central nervous system. Moreover, it has an action against addiction, in reducing craving. Commercialized since 1975 in France, to control muscle spasticity due to medullar affection or multiple sclerosis, it receives a temporary recommendation of use in march 2014, as a last-line adjuvant treatment in alcohol withdrawal. Beyond its therapeutic use, baclofen is involved in many self-induced intoxications. We report the case of a patient who develops, after a massive ingestion of baclofen (supposed dose ingested: 1 200 mg), a hypotonic and calm coma, requiring her admission in our intensive care unit, and then a status epilepticus.

Serpine2/PN-1 Is Required for Proliferative Expansion of Pre-Neoplastic Lesions and Malignant Progression to Medulloblastoma.

BACKGROUND: Medulloblastomas are malignant childhood brain tumors that arise due to the aberrant activity of developmental pathways during postnatal cerebellar development and in adult humans. Transcriptome analysis has identified four major medulloblastoma subgroups. One of them, the Sonic hedgehog (SHH) subgroup, is caused by aberrant Hedgehog signal transduction due to mutations in the Patched1 (PTCH1) receptor or downstream effectors. Mice carrying a Patched-1 null allele (Ptch1∆/+) are a good model to study the alterations underlying medulloblastoma development as a consequence of aberrant Hedgehog pathway activity. RESULTS: Transcriptome analysis of human medulloblastomas shows that SERPINE2, also called Protease Nexin-1 (PN-1) is overexpressed in most medulloblastomas, in particular in the SHH and WNT subgroups. As siRNA-mediated lowering of SERPINE2/PN-1 in human medulloblastoma DAOY cells reduces cell proliferation, we analyzed its potential involvement in medulloblastoma development using the Ptch1∆/+ mouse model. In Ptch1∆/+ mice, medulloblastomas arise as a consequence of aberrant Hedgehog pathway activity. Genetic reduction of Serpine2/Pn-1 interferes with medulloblastoma development in Ptch1∆/+ mice, as ~60% of the pre-neoplastic lesions (PNLs) fail to develop into medulloblastomas and remain as small cerebellar nodules. In particular the transcription factor Atoh1, whose expression is essential for development of SHH subgroup medulloblastomas is lost. Comparative molecular analysis reveals the distinct nature of the PNLs in young Ptch1∆/+Pn-1Δ/+ mice. The remaining wild-type Ptch1 allele escapes transcriptional silencing in most cases and the aberrant Hedgehog pathway activity is normalized. Furthermore, cell proliferation and the expression of the cell-cycle regulators Mycn and Cdk6 are significantly reduced in PNLs of Ptch1∆/+Pn-1Δ/+ mice. CONCLUSIONS: Our analysis provides genetic evidence that aberrant Serpine2/Pn-1 is required for proliferation of human and mouse medulloblastoma cells. In summary, our analysis shows that Serpine2/PN-1 boosts malignant progression of PNLs to medulloblastomas, in which the Hedgehog pathway is activated in a SHH ligand-independent manner.

[A melanesian smile ]. / Un sourire mélanésien

We have detected an ovalo-stomatocytosis in a military 24-years-old man. We have sent a blood specimen to haematology laboratory in Kremlin-Bicetre (France) to test ektacytometry. The test concludes to an asymptomatic Melanesian ovalocytosis.

[Extensive bone marrow necrosis and sickle cell disease]. / Complication rare de la drépanocytose: la nécrose médullaire étendue.

A 24-years old Gabonese women with sickle cell disease had a severe vaso-occlusive crisis, which was treated by exchange transfusion. Then, she developed an extended bone marrow necrosis and needed repeated blood transfusion. The aim of this article is to relate an rare sickle cell disease complication.

Prevalence of early repolarization patterns in a French military population at low cardiovascular risk: implications for preventive medicine.

BACKGROUND: Early repolarization pattern (ERP) associated with a risk of sudden death has recently been described. Very few studies have examined the prevalence of this pattern in a military population characterized by a predominance of young, active male subjects. Therefore, the main objective of this study was to evaluate the prevalence of ERP in a healthy military population free of heart disease but subjected to extreme and potentially arrhythmogenic physical activity. METHODS: This prospective, multicenter study was carried out from November 2010 to November 2011 and included 746 individuals undergoing ECG screening; 466 were men (62.4%) and 280 were women (37.5%). Each ECG was interpreted twice by trained cardiologists. RESULTS: The total prevalence of ERP was 13.8% (103/746); 16% (46/280) in women and 12% (57/466) in men (P > 0.05). It declined with age and the pattern of slurring in inferior location was the most common. Heart rate was significantly lower in military officers with ERP. CONCLUSIONS: ERP was commonly found in this healthy military population. Preventing the risk of sudden death in this population requires systematic ECG screening, medical history analysis and clinical examination to identify symptomatic patients.

[Campylobacter fetus endocarditis: a case report]. / Endocardite à Campylobacter fetus: à propos d'un cas.

Campylobacter are known to be a cause of enteritidic infections but Campylobacter fetus is more often a cause of systemic infections, mainly in fragilized patients. We report a C. fetus endocarditis. The prognosis seemstobe improved by a prolonged betalactam antibiotic treatment.

[Fulminant Neisseria meningitidis B revealing multiple myeloma]. / Purpura fulminans à Neisseiria meningitidis B révélateur d'un myélome multiple.

We report the case of a 64 years-old woman, presenting in our hospital with purpura fulminans due to invasive meningococcal B infection. Biological exams led to the diagnosis of multiple myeloma. This case illustrates the importance of immunosuppression in this hematologic disease and allows us to insist on the prophylactic measures to be implemented.

[Why are soluble transferrin receptor levels increased in Biermer's anemia?]. / Pourquoi le récepteur soluble de la transferrine est-il augmenté dans l'anémie de Biermer ?

This report is devoted to a case report where a pernicious anemia is diagnostic associated with an increased soluble transferrin receptors. The soluble transferring receptor measurement represents a significant advance in assessment of iron status, specially in the diagnosis of iron deficiency associated with inflammation, but also in the evaluation of red blood mass during erythroid hyperplasias.

Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor.

BACKGROUND: Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise), hippocampal-dependent tasks, NMDA receptor (NMDAR) activity, sonic hedgehog (SHH) and/or other factors. RESULTS: previously, we showed that Protease Nexin-1 (PN-1), a potent serine protease inhibitor, regulates the NMDAR availability and activity as well as SHH signaling. Compared with wild-type (WT), we detected a significant increase in BrdU-labeled cells in the dentate gyrus of mice lacking PN-1 (PN-1 -/-) both in controls and after running exercise. Patched homologue 1 (Ptc1) and Gli1 mRNA levels were higher and Gli3 down-regulated in mutant mice under standard conditions and to a lesser extent after running exercise. However, the number of surviving BrdU-positive cells did not differ between WT and PN-1 -/- animals. NMDAR availability was altered in the hippocampus of mutant animals after exercise. CONCLUSION: All together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability.

SHH pathway and cerebellar development.

The morphogenetic factor Sonic hedgehog (SHH) has been discovered as one of the masterplayers in cerebellar patterning and was subjected to intensive investigation during the last decade. During early postnatal development, this continuously secreted cholesterol-modified protein drives the expansion of the largest neuronal population of the brain, the granular cells. Moreover, it acts on Bergmann glia differentiation and would potentially affect Purkinje cells homeostasis at adult age. The cerebellar cortex constituted an ideal developmental model to dissect out the upstream mechanisms and downstream targets of this complex pathway. Its deep understanding discloses some of the mechanistic disorders underlying pediatric tumorigenesis, congenital ataxia, and mental retardation. Therapeutical use of its regulators has been consolidated on murine transgenic models and is now considered as a realistic human clinical application. Here, we will review the most recent advances made in the comprehensive understanding of SHH involvement in cerebellar development and pathology.

Protease nexin 1 and its receptor LRP modulate SHH signalling during cerebellar development.

Development of the postnatal cerebellum relies on the tight regulation of cell number by morphogens that control the balance between cell proliferation, survival and differentiation. Here, we analyze the role of the serine-protease inhibitor protease nexin 1 (PN-1; SERPINE2) in the proliferation and differentiation of cerebellar granular neuron precursors (CGNPs) via the modulation of their main mitogenic factor, sonic hedgehog (SHH). Our studies show that PN-1 interacts with low-density lipoprotein receptor-related proteins (LRPs) to antagonize SHH-induced CGNP proliferation and that it inhibits the activity of the SHH transcriptional target GLI1. The binding of PN-1 to LRPs interferes with SHH-induced cyclin D1 expression. CGNPs isolated from Pn-1-deficient mice exhibit enhanced basal proliferation rates due to overactivation of the SHH pathway and show higher sensitivity to exogenous SHH. In vivo, the Pn-1 deficiency alters the expression of SHH target genes. In addition, the onset of CGNP differentiation is delayed, which results in an enlarged outer external granular layer. Furthermore, the Pn-1 deficiency leads to an overproduction of CGNPs and to enlargement of the internal granular layer in a subset of cerebellar lobes during late development and adulthood. We propose that PN-1 contributes to shaping the cerebellum by promoting cell cycle exit.

HP1 modulates the transcription of cell-cycle regulators in Drosophila melanogaster.

Heterochromatin protein 1 (HP1) was originally described as a non-histone chromosomal protein and is required for transcriptional gene silencing and the formation of heterochromatin. Although it is localized primarily at pericentric heterochromatin, a scattered distribution over a large number of euchromatic loci is also evident. Here, we provide evidence that Drosophila HP1 is essential for the maintenance of active transcription of euchromatic genes functionally involved in cell-cycle progression, including those required for DNA replication and mitosis. Depletion of HP1 in proliferating embryonic cells caused aberrant progression of the cell cycle at S phase and G2/M phase, linked to aberrant chromosome segregation, cytokinesis, and an increase in apoptosis. The chromosomal distribution of Aurora B, and the level of phosphorylation of histone H3 serine 10 were also altered in the absence of HP1. Using chromatin immunoprecipitation analysis, we further demonstrate that the promoters of a number of cell-cycle regulator genes are bound to HP1, supporting a direct role for HP1 in their active transcription. Overall, our data suggest that HP1 is essential for the maintenance of cell-cycle progression and the transcription of cell-cycle regulatory genes. The results also support the view that HP1 is a positive regulator of transcription in euchromatin.

MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum.

Matrix metalloproteinases (MMPs) are responsible for the extensive extracellular proteolysis that plays a central role in regulating the pericellular environment, contributing to morphogenesis and developmental remodeling. In the CNS, there is increasing in vitro evidence for the involvement of MMPs in neurite elongation and axonal guidance. Here, we show that expression of MMP-9 is spatiotemporally related to cerebellar granule cell migration during postnatal development. Using cerebellar explant cultures, we demonstrated that a specific MMP-9-blocking antibody affects granular cell axonal outgrowth and migration in a dose-dependent manner. In addition, the in vivo analysis of MMP-9-deficient mice revealed abnormal accumulation of granular precursors (GPs) in the external granular layer (EGL) at a time when migration is normally extensive. Furthermore, GP migration was delayed and their programmed cell death was reduced in MMP-9-deficient mice, suggesting that MMP-9 is involved in the control of granule cell migration and apoptosis. These results provide direct evidence for a physiological role of MMP-9 in neuronal precursor migration and apoptosis in the developing cerebellum, and emphasize the importance of MMP-9 in the temporal regulation of the cerebellar microenvironment.