[The possible contribution of community pharmacist upstream of drug prescription in France: An experiment of practice groups between general practitioners and community pharmacists]. / La possible contribution du pharmacien d'officine en amont de la prescription médicamenteuse en France : une expérimentation de groupes de pratique médecins généralistes ­ pharmaciens d'officine.

OBJECTIVES: The implementation of practice groups between general practitioners and community pharmacists in several European countries (Belgium, the Netherlands, Switzerland) emphasizes the possible and relevant role of the community pharmacist upstream of drug prescription. In these groups, the pharmacist provides knowledge and faciltates pluriprofessional exchanges on prescription practices. This research assesses the potential of implementing these practice groups in France. METHODS: An experiment was set up in France at 9 sites. Its evaluation was based on the use of questionnaires and semi-structured interviews. The operational feasibility and the adherence of pharmacists to these practice groups were assessed. RESULTS: Our results emphasize that the integration of this practice into the pharmacist's activity is possible but encounters limits, particularly in terms of time investment by the meeting leader pharmacists, regardless of their professional status. The satisfaction of the participating pharmacists with this practice, as well as the previous characteristics of their activity, such as an interprofessional practice already established, are positive factors for the adherence of these professionals to this practice. CONCLUSIONS: If these practice groups can represent a potential new activity for the community pharmacist, several conditions could facilitate their implementation: the possibility of animation in pairs, pharmacist-physician, in order to accentuate the interprofessional collaboration while mobilizing the skills of community pharmacists, an evolution of the initial training of community pharmacists in order to strengthen the skills required to facilitate these groups, as well as a financial or professional recognition in terms of continuing education.

A circuit perspective on narcolepsy.

The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or rapid eye movement (REM) sleep features including cataplexy, sleep paralysis, hallucinations, and sleep-onset REM sleep events (SOREMs). Although the loss of Hypocretin/Orexin (Hcrt/Ox) peptides or their receptors have been associated with the disease, here we propose a circuit perspective of the pathophysiological mechanisms of these narcolepsy symptoms that encompasses brain regions, neuronal circuits, cell types, and transmitters beyond the Hcrt/Ox system. We further discuss future experimental strategies to investigate brain-wide mechanisms of narcolepsy that will be essential for a better understanding and treatment of the disease.

Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature.

With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice¼ is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.

[Changes in clinical practice related to the arrival of next-generation sequencing in the genetic diagnosis of developmental diseases]. / Les modifications de pratique clinique liées à l'arrivée du séquençage haut débit dans le diagnostic génétique des maladies du développement.

INTRODUCTION: The arrival of high-throughput sequencing (HTS) has led to a sweeping change in the diagnosis of developmental abnormalities (DA) with or without intellectual deficiency (ID). With the prospect of deploying these new technologies, two questions have been raised: the representations of HTS among geneticists and the costs incurred due to these analyses. METHODS: Geneticists attending a clinical genetics seminar were invited to complete a questionnaire. The statistical analysis was essentially descriptive and an analysis of costs was undertaken. RESULTS: Of those responding to the questionnaire, 48% had already prescribed exome analysis and 25% had already had the occasion to disclose the results of such analyses. Ninety-six percent were aware that whole-exome sequencing (WES) had certain limits and 74% expressed misgivings concerning its use in medical practice. In parallel, the evaluation of costs showed that WES was less expensive than conventional procedures. DISCUSSION: The survey revealed that geneticists had already come to terms with HTS as early as 2015. Among the major concerns expressed were the complexity of interpreting these tests and the many ethical implications. Geneticists seemed to be aware of the advantages but also the limits of these new technologies. The cost analysis raises questions about the place of HTS and in particular WES in the diagnostic work-up: should it be used early to obtain an etiological diagnosis rather than as the last resort? CONCLUSION: It is essential for future generations of doctors and for the families concerned to learn about the concepts of HTS, which is set to become a major feature of new genomic medicine.

Endoscopic and surgical removal of oesophageal and gastric fishhook foreign bodies in 33 animals.

OBJECTIVES: To describe the location, retrieval, frequency of surgery and complications associated with fishhook foreign bodies. MATERIALS AND METHODS: Retrospective evaluation of the medical records of cats and dogs admitted between 2010 and 2016 after fishhook ingestion. RESULTS: A total of 33 cases (2 cats and 31 dogs) were included. The most common locations were the proximal oesophagus [12/33 (36%)] and stomach [11/33 (33%)]. Endoscopic retrieval was successful in 27 of 33 cases (82%); oesophageal perforation was the only recorded complication, occurring in six of 33 (18%) cases. Surgery was performed in six cases (18%), and no early complications were recorded. The survival rate was 100%. CLINICAL SIGNIFICANCE: The endoscopic removal of ingested fishhooks is highly successful. In the present study, survival to discharge was 100%, even in cases of oesophageal perforation or in cases requiring surgery.

Neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid.

BACKGROUND: Devic's neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial. METHODS: To explore the intrinsic effect of intrathecal AQP4-IgG, independent from additional inflammatory effector mechanisms, and to evaluate its clinical impact, we developed a new animal model, based on a prolonged infusion of purified immunoglobulins from NMO patient (IgG(AQP4+), NMO-rat) and healthy individual as control (Control-rat) in the cerebrospinal fluid (CSF) of live rats. RESULTS: We showed that CSF infusion of purified immunoglobulins led to diffusion in the brain, spinal cord, and optic nerves, the targeted structures in NMO. This was associated with astrocyte alteration in NMO-rats characterized by loss of aquaporin-4 expression in the spinal cord and the optic nerves compared to the Control-rats (p = 0.001 and p = 0.02, respectively). In addition, glutamate uptake tested on vigil rats was dramatically reduced in NMO-rats (p = 0.001) suggesting that astrocytopathy occurred in response to AQP4-IgG diffusion. In parallel, myelin was altered, as shown by the decrease of myelin basic protein staining by up to 46 and 22 % in the gray and white matter of the NMO-rats spinal cord, respectively (p = 0.03). Loss of neurofilament positive axons in NMO-rats (p = 0.003) revealed alteration of axonal integrity. Then, we investigated the clinical consequences of such alterations on the motor behavior of the NMO-rats. In a rotarod test, NMO-rats performance was lower compared to the controls (p = 0.0182). AQP4 expression, and myelin and axonal integrity were preserved in AQP4-IgG-depleted condition. We did not find a major immune cell infiltration and microglial activation nor complement deposition in the central nervous system, in our model. CONCLUSIONS: We establish a link between motor-deficit, NMO-like lesions and astrocytopathy mediated by intrathecal AQP4-IgG. Our study validates the concept of the intrinsic effect of autoantibody against surface antigens and offers a model for testing antibody and astrocyte-targeted therapies in NMO.

Sacroiliac joints imaging in axial spondyloarthritis.

Imaging of the sacroiliac joints is the key point in diagnosing and classifying spondyloarthritis. Since the integration of MRI criteria to the Assessment of Spondyloarhtitis Society (ASAS) classification in 2009, the attention was focused on the presence of bone marrow edema to characterize sacroiliitis. However, returning to basics and analysing structural signs is of utmost importance to avoid overdiagnosis of spondyloarthritis.

An evaluation of the EOS X-ray imaging system in pelvimetry.

OBJECTIVES: To demonstrate the reliability of the EOS imaging system in measuring the internal diameters of the bony pelvis. MATERIALS AND METHODS: A prospective study comparing the results of the pelvimetry of 18 dry pelvises carried out on the EOS imaging system to measurements taken manually and using the two current gold standard CT methods. Pelvimetric measurements of each pelvic bone were obtained using four methods and compared: direct manual measurements, spiral and sequential CT pelvimetry, and 2D-3D low-dose biplanar X-rays. The various obstetric diameters were measured to the millimetre and compared. RESULTS: There was no significant difference in the different diameters assessed, with the exception of the interspinous diameter. There was a highly significant correlation (P < 0.001) between the values measured manually and by EOS for the Magnin index (Pearson = 0.98), the obstetric conjugate diameter (Pearson = 0.99), and the median transverse diameter (Pearson = 0.87). CONCLUSION: The EOS imaging system allows for an ex vivo determination of the obstetrical diameters that is reliable enough to estimate obstetric prognosis, producing comparable measurements to CT. In view of concerns about protection from radiation, this low-dose imaging technique could become, after in vivo prospective validation, the new gold standard for pelvimetry and therefore a good alternative to CT.

Animal models of REM dysfunctions: what they tell us about the cause of narcolepsy and RBD?

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). Conversely, cataplexy, one of the key symptoms of narcolepsy, is a striking sudden episode of muscle weakness triggered by emotions during wakefulness, and comparable to REM sleep atonia. The neuronal dysfunctions responsible for RBD and cataplexy are not known. In the present review, we present the most recent results on the neuronal network responsible for PS. Based on these results, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD and cataplexy. We propose that RBD is due to a specific degeneration of a subpopulation of PS-on glutamatergic neurons specifically responsible of muscle atonia, localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD). Another possibility is the occurrence in RBD patients of a specific lesion of the glycinergic/GABAergic premotor-neurons localized in the medullary ventral gigantocellular reticular nucleus. Conversely, cataplexy in narcoleptics would be due to the activation during waking of the caudal PS-on SLD neurons responsible for muscle atonia. A direct or indirect pathway activated during positive emotion from the central amygdala to the SLD PS-on neurons would induce such activation. In normal conditions, the activation of SLD neurons would be blocked by the simultaneous excitation by the hypocretins of the PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus gating the activation of the PS-on SLD neurons.

Gastric carcinoma associated with Menetrier's-like disease in a West Highland white terrier.

A seven-year-old West Highland white terrier was presented for chronic vomiting associated with mild regenerative anaemia and hypoalbuminaemia. Further examination showed a giant polypoid cerebriform mass located in the lesser curvature of the stomach. Partial gastrectomy was performed and histology was consistent with hypertrophic gastritis with typical features of Ménétrier's disease. Five years after surgery, the dog was re-examined for recurrence of vomiting episodes. Endoscopy showed ulceration of the lesser curvature of the stomach and histological analysis revealed a poorly differentiated superficial gastric carcinoma surrounded by hypertrophic gastritis. To the authors' knowledge, this is the second time that coexistence of these two types of lesions is reported, suggesting that recurrence of gastritis could be the starting point of the tumoural process.

Excess of infections due to a multi-drug sensitive Salmonella enterica serotype Typhimurium in France in June 2008.

An unusually high number of cases of Salmonella Typhimurium was reported in France in June 2008. In the course of epidemiological investigations 112 cases were ascertained, of whom 75 were interviewed. Subtyping by PFGE and MLVA identified a strain named "majority profile". Subtyping results were available for 45 interviewed cases, 30 of whom (majority below 15 years of age) were found to be infected with the majority profile strain. Evidence suggested the occurrence of an outbreak due to a monoclonal S. Typhimurium strain with the single PFGE profile XTYM-50. Cases with identical PFGE profile were also detected in Switzerland but no link with outbreaks occurring in the same period in Denmark and in the Netherlands was found. Contamination of a product distributed nationally was suggested as the cause of the outbreak but investigations did not reveal any specific food source.

Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip study.

Previous studies have demonstrated that macromolecular synthesis in the brain is modulated in association with the occurrence of sleep and wakefulness. Similarly, the spectral composition of electroencephalographic activity that occurs during sleep is dependent on the duration of prior wakefulness. Since this homeostatic relationship between wake and sleep is highly conserved across mammalian species, genes that are truly involved in the electroencephalographic response to sleep deprivation might be expected to be conserved across mammalian species. Therefore, in the rat cerebral cortex, we have studied the effects of sleep deprivation on the expression of immediate early gene and heat shock protein mRNAs previously shown to be upregulated in the mouse brain in sleep deprivation and in recovery sleep after sleep deprivation. We find that the molecular response to sleep deprivation and recovery sleep in the brain is highly conserved between these two mammalian species, at least in terms of expression of immediate early gene and heat shock protein family members. Using Affymetrix Neurobiology U34 GeneChips , we also screened the rat cerebral cortex, basal forebrain, and hypothalamus for other genes whose expression may be modulated by sleep deprivation or recovery sleep. We find that the response of the basal forebrain to sleep deprivation is more similar to that of the cerebral cortex than to the hypothalamus. Together, these results suggest that sleep-dependent changes in gene expression in the cerebral cortex are similar across rodent species and therefore may underlie sleep history-dependent changes in sleep electroencephalographic activity.

Brainstem structures responsible for paradoxical sleep onset and maintenance.

This paper is dedicated to our mentor, Michel Jouvet who inspired our career and transmitted to us his passion for the study of the mechanisms responsible for paradoxical sleep genesis and also that of its still mysterious functions. We expose in the following the progresses in the knowledge in this field brought during 40 years by Michel Jouvet and his team and more recently by the members of a new CNRS laboratory in which we aim to pursue in the path opened by Michel Jouvet.

[Hypocretins/orexins and narcolepsy: from molecules to disease]. / Hypocrétines/orexines et narcolepsie: de la molécule à la pathologie.

In order to foresee a curative treatment for narcolepsy, it is crucial to determine whether or not human narcolepsy is a neurodegenerative disorder, as we suggested, and to understand the mechanisms involved. The current hypothesis regarding the etiology of human narcolepsy is that it is an autoimmune disorder, because of its strong association with the human leukocyte antigen (HLA DQB1*0602), with the Hcrt neurons as the target. This hypothesis is supported by our results (Peyron et al., 2000) and others (Thannickal et al., 2000) showing that Hcrt messengers RNA and mature peptides are absent or greatly reduced in the brain of HLA DQB1*0602 positive narcoleptic patients examined to date. It is of great importance to determine whether the absence of Hcrt is due to a neurodegenerative process or to a default in the transcription process. After a brief review on hypocretins and narcolepsy, we discuss on how to tackle the issue.

Sleep deprivation elevates plasma corticosterone levels in neonatal rats.

Plasma corticosterone (CORT) levels were measured after short periods of sleep deprivation in rats at postnatal days 12, 16, 20, and 24. There was an age-dependent increase in basal CORT levels and sleep deprivation significantly elevated CORT at all ages compared to non-sleep deprived controls. The levels of CORT after sleep deprivation in P16, P20 and P24 animals were similar, resulting in an age-dependent decrease of the magnitude of the response. Sleep deprived P12 animals had lower levels of CORT. However, the observed response to sleep deprivation suggests that sleep loss is a significant stressor at this age. These observations suggest that younger animals are more sensitive to the effects of mild sleep deprivation than older ones.

Fibrolytic activities and cellulolytic bacterial community structure in the solid and liquid phases of rumen contents.

Four sheep were fed an alfalfa hay diet. Rumen content samples were collected three hours after feeding in order to total microorganism population (TP), solid attached population (SAP) and solid attached firmly population (SAFP). Fibrolytic specific activities (xylanase, CMCase and beta-glycosidases) were estimated by the amount of reducing sugars or p-nitrophenol released from the appropriate substrate. The distribution of the three main cellulolytic bacterial species (Fibrobacter succinogenes, Ruminococcus albus and Ruminococcus flavefaciens) was quantified by dot-blot hybridisation using specific 16S-rRNA-targeting probes. Specific activities of polysaccharidase enzymes were higher in SAP than in TP, and in SAFP than in SAP. The sum of RNA of the three cellulolytic bacterial species represented on average 9% of the total bacterial RNA, and increased after filtration. In all samples, the relative population size of F. succinogenes was higher than that of R. albus and of R. flavefaciens. These results demonstrate that the most active enzymes are secreted by the particle-associated microorganisms. The differences in composition of the microflora between the solid and liquid phase suggest that bacteria are not equally distributed throughout the rumen content: the cellulolytic species are present in a higher proportion in the solid phase of rumen contents.

Prepro-hypocretin (prepro-orexin) expression is unaffected by short-term sleep deprivation in rats and mice.

The hypocretin/orexin ligand-receptor system has recently been implicated in the sleep disorder narcolepsy. During the dark (active) period, null mutants of the prepro-orexin (prepro-hypocretin) gene have cataplectic attacks and increased levels of both rapid eye movement (REM) and non-REM (NREM) sleep. Intracerebroventricular injection of one of the encoded neuropeptides, orexin-A, early in the light period increases wakefulness and reduces REM sleep in the rat, suggesting that this system may be involved in the normal regulation of sleep and wakefulness. To further test this hypothesis, we measured hypocretin (hcrt) mRNA levels by both Northern hybridization and Taqman analysis in mouse and rat hypothalamus after short-term (6 h) sleep deprivation (SD) and 2-4 hours after recovery from SD. Although our SD procedures effectively induced a sleep debt and increased c-fos mRNA expression in the cortex and hypothalamus as described by other investigators, we found that hcrt mRNA levels were not significantly changed in either species either after SD or after recovery from SD. If the hcrt system is involved in normal regulation of sleep and wakefulness, longer periods of SD may be necessary to affect hcrt mRNA levels or changes may occur at the protein rather than mRNA level. Alternatively, this system may also be involved in another function that counterbalances any SD-induced changes in hcrt mRNA levels.