Gene expression mapping in neuropathic pain : molecular plasticity in nociceptors and superficial dorsal horn

RESUME : La douleur neuropathique est le résultat d'une lésion ou d'un dysfonctionnement du système nerveux. Les symptômes qui suivent la douleur neuropathique sont sévères et leur traitement inefficace. Une meilleure approche thérapeutique peut être proposée en se basant sur les mécanismes pathologiques de la douleur neuropathique. Lors d'une lésion périphérique une douleur neuropathique peut se développer et affecter le territoire des nerfs lésés mais aussi les territoires adjacents des nerfs non-lésés. Une hyperexcitabilité des neurones apparaît au niveau des ganglions spinaux (DRG) et de la corne dorsale (DH) de la moelle épinière. Le but de ce travail consiste à mettre en évidence les modifications moléculaires associées aux nocicepteurs lésés et non-lésés au niveau des DRG et des laminae I et II de la corne dorsale, là où l'information nociceptive est intégrée. Pour étudier les changements moléculaires liés à la douleur neuropathique nous utilisons le modèle animal d'épargne du nerf sural (spared nerve injury model, SNI) une semaine après la lésion. Pour la sélection du tissu d'intérêt nous avons employé la technique de la microdissection au laser, afin de sélectionner une sous-population spécifique de cellules (notamment les nocicepteurs lésés ou non-lésés) mais également de prélever le tissu correspondant dans les laminae superficielles. Ce travail est couplé à l'analyse à large spectre du transcriptome par puce ADN (microarray). Par ailleurs, nous avons étudié les courants électriques et les propriétés biophysiques des canaux sodiques (Na,,ls) dans les neurones lésés et non-lésés des DRG. Aussi bien dans le système nerveux périphérique, entre les neurones lésés et non-lésés, qu'au niveau central avec les aires recevant les projections des nocicepteurs lésés ou non-lésés, l'analyse du transcriptome montre des différences de profil d'expression. En effet, nous avons constaté des changements transcriptionnels importants dans les nocicepteurs lésés (1561 gènes, > 1.5x et pairwise comparaison > 77%) ainsi que dans les laminae correspondantes (618 gènes), alors que ces modifications transcriptionelles sont mineures au niveau des nocicepteurs non-lésés (60 gènes), mais important dans leurs laminae de projection (459 gènes). Au niveau des nocicepteurs, en utilisant la classification par groupes fonctionnels (Gene Ontology), nous avons observé que plusieurs processus biologiques sont modifiés. Ainsi des fonctions telles que la traduction des signaux cellulaires, l'organisation du cytosquelette ainsi que les mécanismes de réponse au stress sont affectés. Par contre dans les neurones non-lésés seuls les processus biologiques liés au métabolisme et au développement sont modifiés. Au niveau de la corne dorsale de la moelle, nous avons observé des modifications importantes des processus immuno-inflammatoires dans l'aire affectée par les nerfs lésés et des changements associés à l'organisation et la transmission synaptique au niveau de l'aire des nerfs non-lésés. L'analyse approfondie des canaux sodiques a démontré plusieurs changements d'expression, principalement dans les neurones lésés. Les analyses fonctionnelles n'indiquent aucune différence entre les densités de courant tétrodotoxine-sensible (TTX-S) dans les neurones lésés et non-lésés même si les niveaux d'expression des ARNm des sous-unités TTX-S sont modifiés dans les neurones lésés. L'inactivation basale dépendante du voltage des canaux tétrodotoxine-insensible (TTX-R) est déplacée vers des potentiels positifs dans les cellules lésées et non-lésées. En revanche la vitesse de récupération des courants TTX-S et TTX-R après inactivation est accélérée dans les neurones lésés. Ces changements pourraient être à l'origine de l'altération de l'activité électrique des neurones sensoriels dans le contexte des douleurs neuropathiques. En résumé, ces résultats suggèrent l'existence de mécanismes différenciés affectant les neurones lésés et les neurones adjacents non-lésés lors de la mise en place la douleur neuropathique. De plus, les changements centraux au niveau de la moelle épinière qui surviennent après lésion sont probablement intégrés différemment selon la perception de signaux des neurones périphériques lésés ou non-lésés. En conclusion, ces modulations complexes et distinctes sont probablement des acteurs essentiels impliqués dans la genèse et la persistance des douleurs neuropathiques. ABSTRACT : Neuropathic pain (NP) results from damage or dysfunction of the peripheral or central nervous system. Symptoms associated with NP are severe and difficult to treat. Targeting NP mechanisms and their translation into symptoms may offer a better therapeutic approach.Hyperexcitability of the peripheral and central nervous system occurs in the dorsal root ganglia (DRG) and the dorsal horn (DH) of the spinal cord. We aimed to identify transcriptional variations in injured and in adjacent non-injured nociceptors as well as in corresponding laminae I and II of DH receiving their inputs.We investigated changes one week after the injury induced by the spared nerve injury model of NP. We employed the laser capture microdissection (LCM) for the procurement of specific cell-types (enrichment in nociceptors of injured/non-injured neurons) and laminae in combination with transcriptional analysis by microarray. In addition, we studied functionál properties and currents of sodium channels (Nav1s) in injured and neighboring non-injured DRG neurons.Microarray analysis at the periphery between injured and non-injured DRG neurons and centrally between the area of central projections from injured and non-injured neurons show significant and differential expression patterns. We reported changes in injured nociceptors (1561 genes, > 1.5 fold, >77% pairwise comparison) and in corresponding DH laminae (618 genes), while less modifications occurred in non-injured nociceptors (60 genes) and in corresponding DH laminae (459 genes). At the periphery, we observed by Gene Ontology the involvement of multiple biological processes in injured neurons such as signal transduction, cytoskeleton organization or stress responses. On contrast, functional overrepresentations in non-injured neurons were noted only in metabolic or developmentally related mechanisms. At the level of superficial laminae of the dorsal horn, we reported changes of immune and inflammatory processes in injured-related DH and changes associated with synaptic organization and transmission in DH corresponding to non-injured neurons. Further transcriptional analysis of Nav1s indicated several changes in injured neurons. Functional analyses of Nav1s have established no difference in tetrodotoxin-sensitive (TTX-S) current densities in both injured and non-injured neurons, despite changes in TTX-S Nav1s subunit mRNA levels. The tetrodotoxin-resistant (TTX-R) voltage dependence of steady state inactivation was shifted to more positive potentials in both injured and non-injured neurons, and the rate of recovery from inactivation of TTX-S and TTX-R currents was accelerated in injured neurons. These changes may lead to alterations in neuronal electrogenesis. Taken together, these findings suggest different mechanisms occurring in the injured neurons and the adjacent non-injured ones. Moreover, central changes after injury are probably driven in a different manner if they receive inputs from injured or non-injured neurons. Together, these distinct and complex modulations may contribute to NP.

Dynamic visual information plays a critical role for spatial navigation in water but not on solid ground.

In the Morris water maze (MWM) task, proprioceptive information is likely to have a poor accuracy due to movement inertia. Hence, in this condition, dynamic visual information providing information on linear and angular acceleration would play a critical role in spatial navigation. To investigate this assumption we compared rat's spatial performance in the MWM and in the homing hole board (HB) tasks using a 1.5 Hz stroboscopic illumination. In the MWM, rats trained in the stroboscopic condition needed more time than those trained in a continuous light condition to reach the hidden platform. They expressed also little accuracy during the probe trial. In the HB task, in contrast, place learning remained unaffected by the stroboscopic light condition. The deficit in the MWM was thus complete, affecting both escape latency and discrimination of the reinforced area, and was thus task specific. This dissociation confirms that dynamic visual information is crucial to spatial navigation in the MWM whereas spatial navigation on solid ground is mediated by a multisensory integration, and thus less dependent on visual information.

Response to the discussion paper on proposed Health Information Bill

The Institute of Public Health in Ireland is an all-island body which aims to improve health in Ireland by working to combat health inequalities and influence public policies in favour of health. The Institute promotes North-South co-operation in research, training, information and policy. The Institute commends the Department of Health and Children for producing the Discussion Paper on Proposed Health Information Bill (June 2008) and welcomes the opportunity to comment on it. The first objective of the Health Information: A National Strategy (2004) is to support the implementation of Quality and Fairness: A Health System for You (2001).The National Health Goals - such as ‘Better health for everyone’, ‘Fair access’ and ‘Responsive and appropriate care delivery’ - are expressed in terms of the health of the public as well as patients. The Discussion Paper focuses on personal information, and the data flows within the health system, that are needed to enhance medical care and maximise patient safety. The Institute believes that the Health Information Bill should also aim to more fully support the achievement of the National Health Goals and the public health function. This requires the development of more integrated information systems that link the healthcare sector and other sectors. Assessment of health services performance - in terms of the public’s health, health inequalities and achievement of the National Health Goals - require such information systems. They will enable the construction of public health key performance indicators for the healthcare services.

Response to the Health Information and Quality Authority on their Corporate Plan

The Institute of Public Health in Ireland is an all-island body which aims to improve health in Ireland, by working to combat health inequalities and influence public policies in favour of health. The Institute promotes co-operation in research, training, information and policy in order to contribute to policies which tackle inequalities in health. He Institute houses the all-Ireland population health observatory, INIsPHO. The Institute has enjoyed good working relations with HIQA and welcomes the opportunity to submit its views for inclusion in HIQA’s forthcoming Corporate Plan. Our response highlights the inter-relatedness of the four Functions of HIQA. The Institute believes that HIQA’s first Corporate Plan should aim to develop all four Functions in a co-ordinated manner that recognizes and takes advantage of their inter-dependence. For example; the Health Information Function should include a strong focus on, but not be limited to, information requirements to support the delivery of the other three Functions. As well as gathering relevant information in a complementary way, these other Functions can help define priorities for the Health Information Function. This approach will have implications for the organizational structures and processes within HIQA, and the way it conducts its business.

Manuel du programme « Qualité » des Hospices

[Table des matières] 1. Généralités : Politique et objectifs qualité - Cadre général - Responsabilité des directeurs d'établissements - Système d'information - Financement. 2. Organisation du Programme Qualité : Organisation générale - Revue de direction. 3. Procédures : Procédure d'élaboration et de sélection des projets (avec demande de financement;avec demande de soutien technique; pour information; appel d'offres) - Procédure de suivi. 4. Annexes : Contrat pour la réalisation d'un projet qualité : pour information, sans soutien - avec demande de soutien technique - avec demande de soutien financier. Ce document à usage interne définit la politique "qualité" et décrit l'ensemble des dispositions générales prises en matière de qualité pour la période 97-98.

Ambulatory healthcare information system: a conceptual framework

Despite the tremendous amount of data collected in the field of ambulatory care, political authorities still lack synthetic indicators to provide them with a global view of health services utilization and costs related to various types of diseases. Moreover, public health indicators fail to provide useful information for physicians' accountability purposes. The approach is based on the Swiss context, which is characterized by the greatest frequency of medical visits in Europe, the highest rate of growth for care expenditure, poor public information but a lot of structured data (new fee system introduced in 2004). The proposed conceptual framework is universal and based on descriptors of six entities: general population, people with poor health, patients, services, resources and effects. We show that most conceptual shortcomings can be overcome and that the proposed indicators can be achieved without threatening privacy protection, using modern cryptographic techniques. Twelve indicators are suggested for the surveillance of the ambulatory care system, almost all based on routinely available data: morbidity, accessibility, relevancy, adequacy, productivity, efficacy (from the points of view of the population, people with poor health, and patients), effectiveness, efficiency, health services coverage and financing. The additional costs of this surveillance system should not exceed Euro 2 million per year (Euro 0.3 per capita).

Strategies to promote translational research within the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group: a report from the Translational Research Subcommittee.

Head and neck squamous cell cancer (HNSCC) is the sixth leading cause of cancer-related deaths worldwide. These tumors are commonly diagnosed at advanced stages and mortality rates remain high. Even cured patients suffer the consequences of aggressive treatment that includes surgery, chemotherapy, and radiotherapy. In the past, in clinical trials, HNSCC was considered as a single disease entity. Advances in molecular biology with the development of genomic and proteomic approaches have demonstrated distinct prognostic HNSCC patient subsets beyond those defined by traditional clinical-pathological factors such as tumor subsite and stage [Cho W (ed). An Omics Perspective on Cancer Research. New York/Berlin: Springer 2010]. Validation of these biomarkers in large prospective clinical trials is required before their clinical implementation. To promote this research, the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Program will develop the following strategies-(i) biobanking: prospective tissue collection from uniformly treated patients in the setting of clinical trials; (ii) a group of physicians, physician-scientists, and EORTC Headquarters staff devoted to patient-oriented head and neck cancer research; (iii) a collaboration between the basic scientists of the Translational Research Division interested in head and neck cancer research and the physicians of the Head and Neck Cancer Group; and (iv) funding through the EORTC Grant Program and the Network Core Institutions Consortium. In the present report, we summarize our strategic plans to promote head and neck cancer research within the EORTC framework.

Code of Practice on Confidentiality of Patient Information (PDF 108 KB)

Code of Practice on Confidentiality of Patient Information

The Protection and Use of Patient and Client Information (PDF 274 KB)

Guidance for the HPSS on the protection and use of patient and client information