Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

Immunological mechanisms underlying infectious and chronic lung diseases

Le système respiratoire permet l'échange de gaz entre un organisme et son environnement. Pour fonctionner efficacement, il doit lutter contre les infections tout en maintenant une tolérance aux particules inoffensives. Les cytokines sont des petites protéines qui permettent la communication entre les différentes cellules et jouent un rôle important dans la régulation de l'homéostasie et de l'immunité des surfaces pulmonaires. Une production altérée des cytokines sous-tend beaucoup de maladies du système pulmonaire. Ainsi, la compréhension de la biologie fondamentale des cytokines pourrait contribuer à la mise au point de nouveaux traitements. Dans le cadre de cette thèse, nous avons étudié le rôle de deux cytokines, le TSLP (Thymic stromal lymphopoietin) et l'IL-17 (Interleukin 17) dans les réponses immunitaires bénéfiques et nuisibles en utilisant des modèles précliniques de souris des maladies pulmonaires. L'asthme est une maladie qui est caractérisée par la bronchoconstriction réversible, l'inflammation des voies respiratoires inférieures, l'hyperréactivité bronchique et le remodelage tissulaire. Le type d'inflammation affectant les voies respiratoires et la présence ou non d'allergie permettent d'établir les différents types d'asthme. La TSLP est une cytokine qui est principalement exprimée à des niveaux élevés dans les poumons de patients souffrant d'asthme allergique. En conséquence, la majeure partie de la recherche sur la TSLP a mis l'accent sur le rôle joué par celle- ci dans les réponses négatives conduisant au développement de l'asthme allergique. Dans cette thèse, nous montrons que la TSLP joue aussi un rôle bénéfique dans les réponses immunitaires pulmonaires. Nous avons découvert que la TSLP atténue la grippe en augmentant les réponses des lymphocytes T cytotoxiques contre le virus. Nous avons également étudié la fonction de la TSLP dans l'asthme non allergique. Contrairement à l'asthme allergique, nous avons constaté que la TSLP diminue les réponses inflammatoires dans l'asthme non allergique en réglant la production de l'IL-17, une cytokine qui favorise la maladie. Ainsi, nous démontrons les fonctions pleiotropes de la TSLP dans des contextes spécifiques de la maladie. Nos résultats ont des implications importantes pour le développement de thérapies ciblant la TSLP dans l'asthme. Dans la deuxième partie de la thèse, nous avons étudié les mécanismes pathogéniques qui sous-tendent le développement de la broncho-pneumopathie chronique obstructive (BPCO). La BPCO est une maladie chronique le plus largement associée aux fumeurs. Elle est caractérisée par une limitation progressive et irréversible du débit d'air et la destruction de la structure des poumons. L'augmentation globale de l'incidence de la maladie encourage grandement la compréhension des mécanismes pathogéniques et l'identification de nouvelles cibles thérapeutiques. Nous avons découvert que les micro-organismes trouvés dans les voies respiratoires aggravent la maladie en augmentant la production de l'IL-17. L'IL-17 est une cytokine inflammatoire qui est impliquée dans plusieurs maladies pulmonaires chroniques, dont la BPCO. Dans notre modèle animal de la maladie, nous avons neutralisé 1ÌL-17A en utilisant un anticorps spécifique et observé une reprise de la fonction pulmonaire. Dans cette étude, nous avons identifié 2 axes potentiels pour l'intervention thérapeutique contre la BPCO. Cibler les bactéries dans les voies respiratoires soit par l'utilisation d'antibiotiques ou l'utilisation de thérapies à base immunitaire qui antagonisent l'activité spécifiques de l'IL-17. Dans l'avenir, notre laboratoire va collaborer avec des cliniciens pour acquérir des échantillons humains et tester la pertinence de nos résultats dans la maladie humaine. -- L'interaction avec l'environnement extérieur est vitale pour le fonctionnement du système respiratoire. Par conséquent, ce dernier a adopté une multitude de réseaux effecteurs et régulateurs qui permettent de distinguer les particules inhalées comme «dangereuses» ou «inoffensives» et de réagir en conséquence. L'équilibre entre ces réseaux est essentielle pour lutter contre le «danger» déclenché par une infection ou des dommages, et finalement pour le retour à l'homéostasie. Le milieu de cytokine local contribue de manière significative à la mise au point de ces réponses. Ainsi, la caractérisation du rôle des cytokines dans l'état d'équilibre et la maladie a des implications claires pour les interventions thérapeutiques dans les maladies respiratoires aiguës et chroniques. Cette thèse a porté sur le rôle des cytokines, la lymphopoïétine stromale thymique (TSLP) et TIL-17A dans l'élaboration de réponses immunitaires pulmonaires. La TSLP est principalement produite par les cellules épithéliales et peut cibler une myriade de cellules immunitaires. Bien qu'elle ait été montrée être un puissant inducteur des réponses de type Th2, son rôle dans d'autres contextes inflammatoires est relativement inexploré. Dans le premier projet de cette thèse, nous avons découvert une nouvelle fonction de la TSLP dans l'immunité antivirale contre la grippe, une infection virale. Nous avons constaté que la TSLP a réglementé la réponse neutrophile au début de l'infection, en amplifiant l'immunité adaptative spécifique du virus. Mécaniquement, la TSLP a augmenté l'expression de l'IL-15 et du CD70 sur les cellules dendritiques recrutées dans les poumons suite à l'infection et a renforcé leur capacité de stimuler localement les lymphocytes T CD8+ spécifiques du virus. En outre, nous avons étudié la TSLP dans le cadre de divers phénotypes de l'asthme et également démontré l'impact pléiotropique qu'elle a sur les réponses immunitaires pulmonaires. En accord avec les rapports précédents, nous avons constaté que la TSLP a exacerbé l'inflammation atopique médiée par le Th2. En revanche la TSLP a réduit les réponses de l'IL-17A et l'inflammation neutrophile subséquente dans le modèle non atopique, ainsi que l'exacerbation du modèle atopique provoqué par une infection virale. Nos résultats démontrent une dichotomie dans le rôle de la TSLP dans la pathogenèse de l'asthme et soulignent la nécessité d'envisager plusieurs phénotypes d'asthme pour une évaluation approfondie de son potentiel thérapeutique dans cette maladie. Dans la seconde partie de cette thèse, nous avons caractérisé les mécanismes pathogènes qui sous-tendent la broncho-pneumopathie chronique obstructive (BPCO). La BPCO est une maladie hétérogène définie par une diminution progressive de la fonction pulmonaire. Bien que des déclencheurs environnementaux puissent aggraver la maladie, chez les personnes sensibles une maladie établie peut progresser à travers un cercle inflammatoire auto-entretenu. Nous avons cherché à définir les mécanismes sous-jacents à l'aide d'un modèle murin d'inflammation chronique, qui reproduit les caractéristiques pathologiques de la maladie humaine. Puisqu'ont été associés à la BPCO sévère des changements dans le microbiome des voies respiratoires, nous avons supposé que les signaux dérivés de certains microbes pourraient favoriser des voies inflammatoires chroniques de progression de la maladie. Nous avons observé que, en l'absence d un microbiome, la maladie s'est améliorée tel que démontré par une réduction de l'inflammation des voies respiratoires et une amélioration de la fonction pulmonaire. Cela a été lié spécifiquement à une production réduite d'IL-17A, une cytokine qui a été impliquée dans la maladie humaine. De plus la cinétique de production de 1IL- 17A dépendant du microbiote est corrélé à la sévérité de la maladie. Sur la base de ces données, la neutralisation de l'IL-17A a également eu un effet bénéfique sur l'évolution de la maladie. Le rôle significatif de 1TL-17A dans l'aggravation de la maladie a été couplé à sa capacité à engager un dialogue entre les voies inflammatoires innées et adaptatives. Il a influencé le recrutement et le phénotype des neutrophiles et des macrophages, ce qui a eu un impact direct et indirect sur la formation et la fonction des tissus lymphoïdes tertiaires associée à des stades sévères de la maladie. -- The interaction with the external environment is vital for the functioning of the respiratory system. Consequently, it has adopted a multitude of effector and regulatory networks that enable it to distinguish inhaled particles as 'dangerous' or 'innocuous' and respond accordingly. The balance between these networks is crucial to counteract the 'danger' triggered by infection or damage, and ultimately return to homeostasis. The local cytokine milieu contributes significantly to the fine- tuning of these responses. Thus, characterizing the role of cytokines in steady state and disease has clear implications for therapeutic interventions in acute and chronic respiratory disorders. This thesis focused on the role of the cytokines, thymic stromal lymphopoietin (TSLP) and IL-17A in shaping pulmonary immune responses. TSLP is primarily produced by barrier epithelial cells and can target a myriad of immune cells. Although it has been shown to be potent inducer of Th2 type responses, its role in other inflammatory settings is relatively unexplored. In the first project of this thesis, we discovered a novel function of TSLP in antiviral immunity to Influenza A infection. We found that while TSLP regulated the early neutrophilic response to infection, it amplified virus specific adaptive immunity. Mechanistically, TSLP enhanced the expression of IL-15 and CD70 on the lung recruited inflammatory dendritic cells and strengthened their ability to stimulate virus specific CD8+ T cell responses locally. In addition we investigated TSLP in the context of diverse asthma phenotypes and further demonstrated the pleiotropic impact it has on pulmonary immune responses. In concurrence with previous reports we found that TSLP exacerbated Th2 mediated atopic inflammation. In contrast TSLP curtailed IL-17A responses and subsequent neutrophilic inflammation in the non-atopic model as well as virus induced exacerbation of the atopic model. Our findings demonstrate a dichotomy in the role of TSLP in asthma pathogenesis and emphasize the need to consider multiple asthma phenotypes for a thorough evaluation of its therapeutic potential in this disease. In the next part of this thesis we characterized the pathogenic mechanisms underlying chronic obstructive pulmonary disease. COPD is a heterogeneous disease defined by a progressive decline in lung function. Although environmental triggers exacerbate the disease, in susceptible individuals the established disease can progress through a self-sustained inflammatory circle. We sought to delineate the underlying mechanisms by using a murine model of chronic inflammation, which reproduced key pathological features of the human disease. As changes in the airway microbiome have been linked to severe COPD, we speculated that microbial derived signals could facilitate the establishment of chronic inflammatory pathways that favour disease progression. We found that the absence of a microbiota ameliorated disease, exhibited by a reduction in airway inflammation and an improvement in lung function. This was linked specifically to an impaired production of IL-17A, a cytokine that has been implicated in human disease. Moreover the kinetics of microbiota-dependent IL-17A production correlated with the disease severity. Based on these data targeted neutralization of IL-17A also had a beneficiai effect on the disease outcome. The prominent role played by IL-I7A in driving the disease was coupled to its ability in engaging and mediating cross talk between pathogenic innate and adaptive immune pathways. It influenced the recruitment and phenotype of neutrophils and macrophages, as well as impacted upon the formation and function of tertiary lymphoid tissue associated with severe disease. Thus, temporal and spatial changes in cytokine production, their cellular targets and interaction with the local milieu determine the balance between immunity and pathology in the lung. Collectively our findings provide novel mechanistic insights in the complex role played by cytokines in orchestrating pulmonary immune responses and have clear implications for human disease.

DBS in Dystonia and Other Hyperkinetic Movement Disorders.

OPINION STATEMENT: The diagnosis and appropriate treatment of hyperkinetic movement disorders require a work up of potentially reversible metabolic, infectious and structural disorders as well as side effects of current medication. In pharmacoresistant movement disorders with a disabling impact on quality of life, deep brain stimulation (DBS) should be considered. At different targets, DBS has become an established therapy for Parkinson's disease (GPi-STN), tremor (VIM) and primary dystonia (GPi) with reasonable perioperative risks and side effects, established guidelines and some clinical and radiological predictive factors. In contrast, for other hyperkinetic movement disorders, including secondary dystonia, Gilles de la Tourette, chorea and ballism, only few data are available. Definite targets are not well defined, and reported results are of less magnitude than those of the recognized indications. In this expanding therapeutical field without worked out recommendations, an individual approach is needed with DBS indication assessment only after rigorous multidisciplinary scrutiny, restricted to expert centres.

Maladies infectieuses [Infectious diseases]

In 2008, several publications have highlighted the role of climate change and globalization on the epidemiology of infectious diseases. Studies have shown the extension towards Europe of diseases such as Crimea-Congo fever (Kosovo, Turkey and Bulgaria), leismaniosis (Cyprus) and chikungunya virus infection (Italy). The article also contains comments on Plasmodium knowlesi, a newly identified cause of severe malaria in humans, as well as an update on human transmission of the H5NI avian influenza virus. It also mentions new data on Bell's palsy as well as two vaccines (varicella-zoster and pneumococcus), and provides a list of recent guidelines for the treatment of common infectious diseases.

Intervention précoce dans la phase initiale des troubles psychotiques à Lausanne: quels problèmes et quelles solutions [Early intervention for the initial phase of psychotic disorders in Lausanne: what problems and what solutions?]

Schizophrenia has long been considered with pessimism, but the recent interest in the early phase of psychotic disorders has modified this often unjustified perception. Literature has demonstrated the benefit of the development of programs specialised in the treatment of early psychosis, which tend to be developed in many countries. It is however important to match them to local needs as well as to the structure of local health services. This paper reviews elements that justify such a development in Lausanne, Switzerland, and describe its various elements.

Sleep disorders in boys with Duchenne muscular dystrophy.

Aim:  Determine the frequency and predictors of sleep disorders in boys with Duchenne Muscular Dystrophy (DMD). Method:  Cross-sectional study by postal questionnaire. Sleep disturbances were assessed using the Sleep Disturbance Scale for Children (validated on 1157 healthy children). A total sleep score and six sleep disturbance factors representing the most common sleep disorders were computed. Potential associations between pathological scores and personal, medical and environmental factors were assessed. Results:  Sixteen of 63 boys (25.4%) had a pathological total sleep score compared with 3% in the general population. The most prevalent sleep disorders were disorders of initiating and maintaining sleep (DIMS) 29.7%, sleep-related breathing disorders 15.6% and sleep hyperhydrosis 14.3%. On multivariate analysis, pathological total sleep scores were associated with the need to be moved by a carer (OR = 9.4; 95%CI: 2.2-40.7; p = 0.003) and being the child of a single-parent family (OR = 7.2; 95%CI: 1.5-35.1; p = 0.015) and DIMS with the need to be moved by a carer (OR = 18.0; 95%CI: 2.9-110.6; p = 0.002), steroid treatment (OR = 7.7; 95%CI: 1.4-44.0; p = 0.021) and being the child of a single-parent family (OR = 7.0; 95%CI: 1.3-38.4; p = 0.025). Conclusion:  Sleep disturbances are frequent in boys with DMD and are strongly associated with immobility. Sleep should be systematically assessed in DMD to implement appropriate interventions.

Prise en charge des troubles oculomoteurs après effraction iatrogène de l'orbite au cours d'interventions sinusiennes endoscopiques [Management of motility disorders secondary to iatrogenic orbital fracture during endoscopic sinus surgery.]

PURPOSE: Orbital wall fracture may occur during endoscopic sinus surgery, resulting in oculomotor disorders. We report the management of four cases presenting with this surgical complication. METHODS: A non-comparative observational retrospective study was carried out on four patients presenting with diplopia after endoscopic ethmoidal sinus surgery. All patients underwent full ophthalmologic and orthoptic examination as well as orbital imaging. RESULTS: All four patients presented with diplopia secondary to a medial rectus lesion confirmed by orbital imaging. A large horizontal deviation as well as limitation of adduction was present in all cases. Surgical management consisted of conventional recession-resection procedures in three cases and muscle transposition in one patient. A useful field of binocular single vision was restored in two of the four patients. CONCLUSION: Orbital injury may occur during endoscopic sinus surgery and cause diplopia, usually secondary to medial rectus involvement due to the proximity of this muscle to the lamina papyracea of the ethmoid bone. Surgical management is based on orbital imaging, duration of the lesion, evaluation of anterior segment vasculature, results of forced duction testing and intraoperative findings. In most cases, treatment is aimed at the symptoms rather than the cause, and the functional prognosis remains guarded.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

Troubles de l'humeur et VIH: épidémiologie, clinique et prise en charge thérapeutique [Mood disorders in HIV patients: a challenge for liaison psychiatry consultation].

Mood disorders represent the most prevalent psychiatric condition in patients infected by HIV virus. Screening and treatment of depression as well as the evaluation of the risk suicide is of the utmost importance. When psychopharmacological treatment is required, interaction with antiretroviral treatment must be carefully considered. More generally a close collaboration between the physician and the psychiatrist is recommended.

Controversies about a common etiology for eating and mood disorders.

Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors.

Intervention précoce dans les troubles psychotiques: quel rôle pour les praticiens de premier recours [Early intervention in psychotic disorders: which role for primary care practitioners?]

The development of early intervention in psychotic disorders has allowed a more optimistic approach and the development of more adapted and more efficient treatments. Primary care practitioners are often the first professional contact for patients developing psychosis, but diagnostic difficulties and patients' reluctance to engage in treatment are often an obstacle to private practice treatment. It is therefore important to provide more information to primary care practitioners on specific characteristics of these disorders and about locally available treatment structures in order to allow them to suspect this relatively rare diagnosis, facilitate the collaboration with flexible and accessible specialist services, that ideally should provide home treatment, and to improve prognosis.