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The key to health promotion and disease prevention in the 21st century is to establish an environment that supports positive health behaviour and healthy lifestyle from childhood. The HELENA project includes cross-sectional, crossover and pilot community intervention multi-centre studies, as an integrated approach to the above-mentioned problem. Dietary intake, nutrition knowledge and eating attitudes, food choices and preferences, body composition, biochemical, physical activity and fitness and genotype (to analyse gene-nutrient and gene-environment interactions) assessment will provide the full information about the nutritional and lifestyle status of the European adolescents. The requirements for health promoting foods will be also identified, and three sensory acceptable products for adolescents will be developed. Harmonization and standardisation of the assessments for both scientific and technological objectives should result in reliable and comparable data of a representative sample of European adolescents. This will contribute to understand why health-related messages are not being as effective as expected in the adolescent population. A realistic intervention strategy will be proposed in order to achieve the goals of understanding and effectively enhancing nutritional and lifestyle habits of adolescents in Europe.

Les progrès du traitement des cancers de l’enfant posent le problème des séquelles dues aux thérapeutiques appliquées pendant l’odontogenèse. Si les effets iatrogènes des radiations ionisantes sont bien analysés, les répercussions des seuls antimitotiques sur la dentition sont moins connues. C’est pourquoi, afin d’éviter les biais liés à des observations rétrospectives, 13 enfants souffrant en majorité d’une leucémie aiguë lymphoblastique et tous traités par le même protocole chimiothérapique ont été suivis prospectivement ainsi que 11 enfants témoins. L’influence des antimitotiques sur la dentition est abordée sous deux angles : la mesure de la croissance de la deuxième molaire mandibulaire droite, dent choisie en référence, pendant les différentes phases du protocole chimiothérapique puis en rémission et la surveillance de l’apparition d’anomalies dentaires. Le support est l’utilisation d’orthopantomogrammes tirés à intervalles réguliers après étude du grandissement induit par le générateur. Les résultats convergent vers un ralentissement de la vitesse de minéralisation coronaire de la 47 par la chimiothérapie d’induction-consolidation alors que le rythme radiculaire semble insensible à toutes les phases de chimiothérapie. La non prise en compte possible pour le moment d’éventuels défauts structurels amélo-dentinaires sousestime certainement l’importance des troubles. Cependant déjà, 8 enfants sur 13 ont développé des anomalies dentaires corrélées à la période d’administration des antimitotiques. Les troubles les plus récurrents sont des racines dentaires grêles et/ou courtes (5 enfants) et les agénésies (3 enfants). Quelque soit l’anomalie, la dent la plus fréquemment touchée est la seconde prémolaire. Les atteintes les plus importantes (agénésies, microdonties) concernent les enfants traités les plus jeunes. (Med Buccale Chir Buccale 2003; 9: 7-20)

Un protocole expérimental a été mené sur 8 lapins afin d’évaluer la régénération du nerf alvéolaire inférieur (IAN) 6 mois après section complète et suture conventionnelle. Le risque de lésions nerveuses pouvant survenir à la suite de certains actes de chirurgie buccale, comme les extractions de dents de sagesse mandibulaires, reste trop souvent méconnu. Pourtant dans 0,05 % des cas, il existe à une lésion irréversible qui pourrait justifier une microsuture nerveuse. Dans cette étude, des tests électrophysiologiques ont été réalisés à J + 180 pour quantifier de façon objective la régénération du nerf. Une étude histologique a permis de comparer structurellement mais aussi quantitativement les fibres nerveuses saines et celles remaniées. Les résultats obtenus montrent une régénération fonctionnelle dans 7 cas traités. (Med Buccale Chir Buccale 2003; 9: 21-27)

Les progrès du traitement des cancers de l’enfant posent le problème des séquelles dues aux thérapeutiques appliquées pendant l’odontogenèse. Si les effets iatrogènes des radiations ionisantes sont bien analysés, les répercussions des seuls antimitotiques sur la dentition sont moins connues. C’est pourquoi, afin d’éviter les biais liés à des observations rétrospectives, 13 enfants souffrant en majorité d’une leucémie aiguë lymphoblastique et tous traités par le même protocole chimiothérapique ont été suivis prospectivement ainsi que 11 enfants témoins. L’influence des antimitotiques sur la dentition est abordée sous deux angles : la mesure de la croissance de la deuxième molaire mandibulaire droite, dent choisie en référence, pendant les différentes phases du protocole chimiothérapique puis en rémission et la surveillance de l’apparition d’anomalies dentaires. Le support est l’utilisation d’orthopantomogrammes tirés à intervalles réguliers après étude du grandissement induit par le générateur. Les résultats convergent vers un ralentissement de la vitesse de minéralisation coronaire de la 47 par la chimiothérapie d’induction-consolidation alors que le rythme radiculaire semble insensible à toutes les phases de chimiothérapie. La non prise en compte possible pour le moment d’éventuels défauts structurels amélo-dentinaires sousestime certainement l’importance des troubles. Cependant déjà, 8 enfants sur 13 ont développé des anomalies dentaires corrélées à la période d’administration des antimitotiques. Les troubles les plus récurrents sont des racines dentaires grêles et/ou courtes (5 enfants) et les agénésies (3 enfants). Quelque soit l’anomalie, la dent la plus fréquemment touchée est la seconde prémolaire. Les atteintes les plus importantes (agénésies, microdonties) concernent les enfants traités les plus jeunes. (Med Buccale Chir Buccale 2003; 9: 7-20)

Un protocole expérimental a été mené sur 8 lapins afin d’évaluer la régénération du nerf alvéolaire inférieur (IAN) 6 mois après section complète et suture conventionnelle. Le risque de lésions nerveuses pouvant survenir à la suite de certains actes de chirurgie buccale, comme les extractions de dents de sagesse mandibulaires, reste trop souvent méconnu. Pourtant dans 0,05 % des cas, il existe à une lésion irréversible qui pourrait justifier une microsuture nerveuse. Dans cette étude, des tests électrophysiologiques ont été réalisés à J + 180 pour quantifier de façon objective la régénération du nerf. Une étude histologique a permis de comparer structurellement mais aussi quantitativement les fibres nerveuses saines et celles remaniées. Les résultats obtenus montrent une régénération fonctionnelle dans 7 cas traités. (Med Buccale Chir Buccale 2003; 9: 21-27)

Ces travaux entrent dans le cadre des études nécessaires à la mise au point d'une structure déformable actionnée par fils en alliage à mémoire de forme. L'application visée est son utilisation comme module de locomotion d'un microrobot intratubulaire autonome de type “ lombric ”. Un module est constitué d'un cadre élastique carré forcé en post-flambement sur un squelette rigide, de manière à obtenir deux configurations symétriques d'équilibre stable correspondant au premier mode de flambage. Le passage d'un état d'équilibre à l'autre est obtenu par la contraction de fils AMF éduqués disposés sur le cadre post-flambé. Un assemblage par juxtaposition de cinq modules identiques compose le corps du microrobot. Suivant un cycle de locomotion adéquat, chacun de ces actionneurs “ tout ou rien ” permet la prise d'appui sur les parois du tube ou l'allongement local nécessaire à l'avance du microrobot. Nous présentons ici les résultats obtenus lors d'un chargement transversal d'un module, et en particulier les courbes reliant l'effort de réaction et le déplacement du point en contact avec le tube. L'influence du serrage subit par le module sur le maintien du microrobot dans un tube vertical est déterminée. Les résultats expérimentaux obtenus sont comparés avec les résultats numériques.

Inferior alveolar nerve (IAN) damage can occur in trauma, cyst enucleation, sagittal split osteotomy or third molar removal, and the consequences are a loss of sensation to the mandibular teeth, gingiva and lower lip. Because of its anatomical position in a bony canal, IAN suture is rarely evoked. The aim of this study was to demonstrate the reality of IAN regeneration by using electrophysiological and histological methods after experimental section and suture of this nerve in rabbits. Nine adult female animals were used for the experiments. Six months after section and suturing using 10.0 nylon with a conventional technique, electrical stimulation of the nerve was performed to record electrophysiological activity. Each rabbit was its own reference. In each case, an action potential was recorded after microsurgical repair and definitively suppressed by section of the nerve. Morphometric analysis showed a decrease in the number of nerve fibers in the operated nerve versus the control nerve. The histological study showed an increase in nerve fibers with a cross-sectional area of 19–36 and 37–73 µm2and a decrease in the smaller fibers (2–4 and 5–7 µm2). This preliminary study confirms the possibility of nerve regeneration in rabbits 6 months after section and conventional suturing. The French version of this article is available in the form of electronic supplementary material and can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00276-002-0068-8.

Abstract. Inferior alveolar nerve (IAN) damage can occur in trauma, cyst enucleation, sagittal split osteotomy or third molar removal, and the consequences are a loss of sensation to the mandibular teeth, gingiva and lower lip. Because of its anatomical position in a bony canal, IAN suture is rarely evoked. The aim of this study was to demonstrate the reality of IAN regeneration by using electrophysiological and histological methods after experimental section and suture of this nerve in rabbits. Nine adult female animals were used for the experiments. Six months after section and suturing using 10.0 nylon with a conventional technique, electrical stimulation of the nerve was performed to record electrophysiological activity. Each rabbit was its own reference. In each case, an action potential was recorded after microsurgical repair and definitively suppressed by section of the nerve. Morphometric analysis showed a decrease in the number of nerve fibers in the operated nerve versus the control nerve. The histological study showed an increase in nerve fibers with a cross-sectional area of 19-36 and 37-73 µm² and a decrease in the smaller fibers (2-4 and 5-7 µm²). This preliminary study confirms the possibility of nerve regeneration in rabbits 6 months after section and conventional suturing. The French version of this article is available in the form of electronic supplementary material and can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00276-002-0068-8. Résumé. Les lésions du nerf alvéolaire inférieur (NAI) peuvent survenir en cas de traumatisme, d'énucléation de kyste, d'ostéotomie sagittale ou d'avulsion de troisième molaire et entraînent une perte de sensibilité des dents mandibulaires, de la gencive et de la lèvre inférieure. En raison de sa situation anatomique au sein d'un canal osseux, la suture du NAI est rarement envisagée. Le but de cette étude était de démontrer la réalité de la régénération du NAI à l'aide de méthodes électrophysiologique et histologique après section expérimentale et suture chez le lapin. Neuf animaux adultes femelles ont été utilisés pour l'expérimentation. Six mois après section et suture conventionnelle à l'aide de fils de suture en nylon 10.0, une stimulation électrique du nerf a été réalisée afin d'enregistrer l'activité électrophysiologique. Chaque lapin était sa propre référence. Dans chaque cas, un potentiel d'action a été enregistré après réparation microchirurgicale et définitivement supprimé par la section du nerf. Une analyse morphométrique a souligné la diminution du nombre des fibres nerveuses chez le lapin opéré versus le lapin témoin. Une étude histologique a montré une augmentation du nombre des fibres nerveuses ayant une surface, en section transversale, comprise entre 19-36 µm² et 37-73 µm², et une diminution de celles ayant une surface comprise entre 2-4 et 5-7 µm². Cette étude préliminaire confirme la possibilité d'une régénération nerveuse chez le lapin, six mois après section et suture conventionnelle.

Summary A radioanatomical study of serial cuts in the frontal and sagittal planes leads to a better appreciation of the elementary precautions which should be taken during surgery to the dental apices.

Résumé Les sinus annexés aux cavités nasales sont souvent considérés comme d'apparition tardive. Ils apparaissent en réalité précocement et peuvent être le siège de rhino-sinusites qui sont assez fréquentes au cours de l'enfance.

To identify markers (phenotypic, genetic, or environmental) of blood pressure (BP) response profiles to angiotensin converting enzyme inhibitors (ACEIs) and diuretics.

Dans le contexte d’une prise en charge implantaire, l’existence d’un déficit osseux augmente la durée du traitement car elle impose classiquement deux temps chirurgicaux : le premier concerne le traitement du défaut osseux et le second la pose de l’implant. Une technique moins conventionnelle permet d’effectuer la greffe et la mise en place de l’implant dans le même temps chirurgical. Le greffon, prélevé dans la cavité buccale, vient combler le déficit osseux. La préparation du logement de l’implant intéresse le greffon et l’os alvéolaire, et l’implant est utilisé pour solidariser le greffon avec l’os alvéolaire.

Based on the observation that over the last 30 years the cost of development has risen regularly as the number of new chemical entities reaching the market has fallen, how can “savings” be made in terms of clinical development, the objective being more rapid access to a drug for medical needs that are not covered? Several instruments exist to enable innovative products to be made available more quickly: temporary use authorisations, which are not concerned by this work (ATUs), conditional marketing authorisations (MAs) and MAs under exceptional circumstances.

Partant de la constatation que depuis 30 ans, le coût du développement augmente régulièrement à mesure que le nombre de nouvelles entités chimiques atteignant le marché décroît, comment faire des « économies » en termes de développement clinique, l’objectif étant un accès plus rapide au médicament, pour les besoins médicaux non couverts ? Plusieurs instruments existent pour permettre une mise à disposition plus rapide de produits innovants : les autorisations temporaires d’utilisation ou ATU (qui ne sont pas concernées par ce travail), les autorisations de mise sur le marché (AMM) conditionnelles, les AMM sous circonstances exceptionnelles.

The aim of the Round Table was to make recommendations with regard to the imminent revision of the European Directive on clinical drug trials (2001/20/CE).

L’objet de cette Table Ronde était de proposer des recommandations en vue d’une prochaine révision de la Directive communautaire portant sur les essais cliniques de médicaments (2001/20/CE).

The collection of human biological samples is of major importance for future research in France and Europe. In recent years, new regulatory procedures have been designed to monitor these activities; but they are somewhat complex and some clarifications are needed. The law needs also to be amended. The definition of biobanking activities should be clarified, and regulatory procedures, including consultation of the Ethics Committee, declarations to the Ministry of Research and the protection of personal data, should be simplified. It is also of great importance to correctly define the modalities in which Biobanks are granted their authorisations. The role of Ethics Committees regarding the evaluation of information and the consent procedures should also be clarified, particularly when samples from children are used, or when the samples are used for genetic analyses. As well as scientific and public health aspects, the storage of human biological samples may also have important economic consequences. It is hence crucial to adapt the procedure for submitting patents, particularly when several public or private partners are working together. The possible changes to both French and European laws planned in the next months would be an ideal time to introduce these changes.

La constitution de collections d’échantillons biologiques humains à des fins scientifiques constitue un enjeu majeur en France et en Europe. Dans ce contexte, ces dernières années ont été marquées par la volonté de mettre en place un meilleur encadrement réglementaire. La complexité de celui-ci nécessite cependant quelques éclaircissements. En effet, il convient de préciser la définition de ce qui relève des collections ou des activités de collection biologique, de simplifier les procédures réglementaires de déclaration auprès des Comités de Protection des Personnes (CPP) et du Ministère de l’Enseignement Supérieur et de la Recherche, de discuter de la mise en place d’une méthodologie de référence CNIL (Commission Nationale Informatique et Libertés) dédiée aux modalités particulières de traitement des données associées aux collections biologiques. Il apparait d’autre part indispensable de préciser les modalités d’habilitation et de pérennisation des Centres de Ressources Biologiques, structures dédiées aux activités de collection biologique. Il convient aussi de clarifier le rôle des CPP, notamment dans l’appréciation des modalités d’information et de consentement des sujets au cours de situations particulières comme les collections sur mineurs, les collections avec examen des caractéristiques génétiques ou encore les modalités d’utilisation de collections anciennes. Enfin, en dehors des aspects scientifiques et de santé publique, les collections biologiques d’échantillons humains sont l’objet d’enjeux économiques importants. Dans ce contexte, il est nécessaire d’adapter les procédures permettant par exemple le dépôt de brevets, notamment lorsque plusieurs partenaires publics et/ou privés sont associés. Les prochaines échéances législatives avec la modification du Code de Santé Publique au travers de la loi Jardé et de la révision de la loi de bioéthique permettront peut être de faire valoir ces nécessaires évolutions.

Non-interventional research is an essential approach to gathering data in different situations and it often complements other research methodologies, such as biomedical research and research aimed at evaluating usual care. Yet the legislative framework for this type of research is nonexistent, and this void poses a number of problems for non-interventional researchers, including an absence of any guarantee of quality and therefore of reliability, a limited recognition of the research beyond our borders, cumbersome administrative procedures, and a lack of visibility. In light of the growing demand for data, particularly in post marketing authorisation for drugs, which largely relies on non-interventional methods, the Round Table participants have issued a set of proposals for a future legislative framework for this type of research.

Les recherches non interventionnelles sont indispensables et souvent complèmentaires des autres techniques de recherche (recherche biomédicale et recherche visant à évaluer les soins courants) et permettent d’enrichir les connaissances dans différentes situations. Pour autant leur cadre réglementaire est inexistant et ce vide pose plusieurs types de problèmes aux acteurs de cette recherche : absence de garantie de qualité et donc de fiabilité, difficulté de reconnaissance des travaux au-delà de nos frontières, procédures administratives inadaptées, manque de visibilité. Dans un contexte de demande accrue de données, en particulier sur les effets des médicaments aprés commercialisation, et qui font largement appel à des méthodologies non interventionnelles, les participants de la Table Ronde ont émis un certain nombre de propositions pour l’élaboration d’un futur cadre réglementaire adapté à ce type de recherche.

Une lésion blanche non détachable de la muqueuse buccale correspond le plus souvent à une kératose de surface. Pour ces lésions à risque de transformation, le traitement reste controversé. Pour évaluer l'efficacité du laser CO2, deux études ont été menées. La première, rétrospective, a porté sur 61 patients présentant 64 lésions traitées sur une période de 17 ans ; la seconde, prospective, a concerné 12 patients présentant 13 lésions, pendant un an. L'âge, le sexe, le praticien référent, le type et le site de la lésion, la présence de dysplasie, un facteur favorisant, la survenue d'une récidive ou d'une transformation maligne ont été recherchés. Le lichen plan touche davantage la femme, tandis que les lésions papillomateuses ou verruqueuses prédominent chez l'homme. Les lésions se situent préférentiellement sur la face interne des joues. Des facteurs favorisants ont été retrouvés (terrain dépressif, tabac, traumatisme, éléments métalliques). Le taux de récidive a été de 26,6 % dans l'étude rétrospective, celui de transformation maligne de 7,8 %. Dans l'étude prospective, ils ont été respectivement de 33,3 % et de 0% (pour la période d'observation). Compte-tenu de ces résultats et des facilités opératoires, et sous couvert d'une biopsie pré-opératoire, l'utilisation du laser CO2semble être une alternative intéressante aux autres techniques chirurgicales (excision, électrocoagulation, cryothérapie) pour le traitement des lésions superficielles, non dysplasiques. Dans tous les cas, une surveillance régulière et à long terme s'impose. (Med Buccale Chir Buccale 2008 ; 14: 209-219).

The purpose of the clinical trial guidelines is to harmonise legislation in order to ensure consistency within Europe and thereby promote Europe’s attractiveness for clinical research while maintaining or improving the protection of subjects who agree to participate.

La directive essais cliniques avait pour but une harmonisation des législations afin de favoriser la cohérence du système européen et par la même l’attractivité de l’Europe en matière de recherche clinique tout en maintenant ou renforçant la protection des personnes qui acceptent d’y participer.

Lors de la radiothérapie des voies aérodigestives supérieures, l’irradiation des glandes salivaires entraîne une hyposialie qui génère, entre autres, des conditions cariogènes dans le milieu buccal. La prévention de ces complications repose essentiellement sur le port, cinq à dix minutes chaque soir, de gouttières de fluoration thermoformées. Le but de l’étude était d’évaluer la compliance de 100 patients irradiés pour le port des gouttières, et d’étudier l’incidence de ce port sur la carie dentaire. Au total, 48 % des patients n’ont jamais porté leurs gouttières et l’augmentation de l’incidence des caries est liée de façon significative (chi-deux, p<10-6) au non-port des gouttières. L’étude montre à nouveau l’importance indéniable de la fluorothérapie dans le cadre des complications liées à la radiothérapie. Cependant, il y a lieu de s’interroger sur les raisons du faible pourcentage de patients respectant le protocole de fluorothérapie, et donc d’améliorer la prise en charge des patients irradiés. Med Buccale Chir Buccale 2007 ; 13 : 77-81.

La régénération du nerf mentonnier après écrasement et pose d’une membrane, constituée de polyélectrolytes et fonctionnalisée par le Nerve Growth Factor (NGF), est évaluée chez le rat à l’aide d’enregistrements électrophysiologiques. Le NGF semble faciliter la régénération. Med Buccale Chir Buccale 2007 ; 13 : 103-106.

To establish the incidence of early adverse events surrounding direct current (DC) cardioversion of persistent atrial fibrillation in an unselected patient cohort and to describe and analyse these complications.

To determine clinical and pharmacologic factors that could influence the initial severity and short-term outcome of cerebral ischemia.

The conduct of clinical trials falls within a strict regulatory framework. The objective of the round table was to develop reasonable recommendations for the implementation of GCP according to the type of research and taking in account the risks and challenges related to this research. Two types of risks have been identified: those related to the characteristics of the research and those related to the impact of the study results. The group designed an evaluation table of these risks. The round table focused its investigations on 3 main themes: monitoring, the investigational medicinal product and undesirable effects. Three methods of monitoring adaptation were analysed in terms of advantages and disadvantages: the gradual approach, the central monitoring, monitoring on the basis of sampling. Examination of the investigational medicinal product focused on the medicinal product circuit. The group recommends using the following ‘basic’ decision-making tree, which takes three elements into account: 1) is it an investigational medicinal product?, 2) do the trial objectives and design require packaging specific to the research?, 3) is the risk of use higher than that in standard practice? Finally, adaptation of the implementation of GCP in terms of pharmacovigilance appeared very limited and could possibly be considered for the medicinal product, the subject of the research, which already holds a marketing authorisation, and for which the safety profile is well known; in this case, only simplified collection of non-serious adverse events may be envisaged, which may be implemented by designing and using a standard collection listing.

La réalisation des essais cliniques se fait dans un cadre réglementaire strict. L’objectif de cette table ronde était d’élaborer des recommandations raisonnables pour la mise en œuvre des bonnes pratiques cliniques (BPCs) dans certains types de recherches, compte-tenu de leurs caractéristiques et enjeux. Deux types de risque à prendre en compte ont été identifiés: ceux liés aux caractéristiques de la recherche et ceux liés à l’impact des résultats de la recherche. Une grille d’évaluation de ces risques a été élaborée. Les travaux de la table ronde se sont articulés autour de 3 thématiques principales: l’adaptation du monitoring, le médicament expérimental, les effets indésirables. Trois méthodes d’adaptation du monitoring ont été passées en revue avec liste des avantages et inconvénients: l’approche graduelle, le monitoring centralisé, le monitoring par sondage. La réflexion sur le médicament expérimental s’est organisée autour du circuit du (des) médicament(s). L’arbre décisionnel « de base » suivant est recommandé: 1) le médicament est-il expérimental ? 2) la conception et les objectifs de l’essai nécessitent ils un conditionnement spécifique à la recherche ? 3) le risque d’utilisation est-il supérieur à celui de la pratique courante ?

OBJECTIVE: To determine the effects over one year of contacting patients by telephone one month or three months after being discharged from an emergency department for deliberate self poisoning compared with usual treatment. Design Multicentre, randomised controlled trial. Setting 13 emergency departments in the north of France. Participants 605 people discharged from an emergency department after attempted suicide by deliberate self poisoning. Intervention The intervention consisted of contacting patients by telephone at one month or three months after discharge from an emergency department for attempted suicide to evaluate the success of recommended treatment or to adjust treatment. Control patients received treatment as usual, in most cases referral back to their general practitioner. MAIN OUTCOME MEASURES: The primary outcome measures were proportion of participants who reattempted suicide, number of deaths by suicide, and losses to follow-up at 13 months' follow-up. Secondary outcome measures were types and number of contacts with health care. RESULTS: On an intention to treat basis, the three groups did not differ significantly for further suicide attempts, deaths by suicide, or losses to follow-up: contact at one month (intervention 23% (34/147) v controls 30% (93/312), difference 7%, 95% confidence interval - 2% to 15%), three months (25% (36/146) v 30%, difference 5%, - 4% to 14%). Participants contacted at one month were less likely at follow-up to report having reattempted suicide (12% v 22% in control group, difference 10%, 2% to 18%). CONCLUSION: Contacting people by telephone one month after being discharged from an emergency department for deliberate self poisoning may help reduce the number of reattempted suicides over one year.

The work presented here concerns the design and manufacturing possibility of a polymodular autonomous microrobot moving like an earthworm. The study consists of the development of a new locomotion actuator based on shape memory alloys. This actuator is formed by a flexible frame forced in post-buckling by its assembly on a rigid skeleton cage. This mechanical structure, forming a knot in the microrobot chain, uses its two post-buckling equilibrium positions to achieve first the support and second the local lengthening enabling the movement of the microrobot. Initially, we present the technical solution designed for the locomotion actuator and the mechanical characterization of its malleable structure. Then, we present the instrumentation by educated SMA of a malleable structure and the capability of microrobot locomotion task in a vertical tube.

Purpose:To study the vasomotor responses of the renal microcirculation in patients with essential hypertension. Methods:We studied the reactivity of the renal microcirculation to papaverine, with intraarterial Doppler and quantitative arteriography, in 34 renal arteries of 19 hypertensive patients without significant renal artery stenosis. Isosorbide dinitrate was given to maximally dilate proximal renal arteries. APV (average peak blood flow velocity) was used as an index of renal blood flow. Results:Kidneys could be divided into two distinct subgroups based on their response to papaverine. An increase in APV of up to 55% occurred in 21 kidneys, an increase > 55% in 13 kidneys. Within each group the values were normally distributed. Both baseline APV and the effect of papaverine on mean velocity differed significantly between groups. Conclusion:There seems to be a subgroup of patients with essential hypertension that has an impaired reactivity to papaverine, consistent with a functional impairment of the renal microcirculation. Further studies are required to determine whether this abnormality contributes to or results from elevated blood pressure.

Background & Aims: Myelosuppression in patients with Crohn's disease (CD) treated with azathioprine has been attributed to low activity of thiopurine S-methyltransferase (TPMT). Allelic variants of the TPMT gene responsible for changes in the enzyme activity have been characterized. We investigated the distribution of mutant alleles associated with TPMT deficiency in patients with CD and myelosuppression during azathioprine/6-mercaptopurine therapy. Methods: Forty-one patients with CD were included. They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment. Polymerase chain reaction-based methods were used to search for mutations associated with TPMT deficiency. Results: Four patients (10%) had 2 mutant alleles associated with TPMT deficiency, 7 (17%) had 1 mutant allele, and 30 (73%) had no known TPMT mutation. The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles, and ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype. Conclusions: Twenty-seven percent of patients with CD and myelosuppression during azathioprine therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine. GASTROENTEROLOGY 2000;118:1025-1030

Summary Anatomical characteristics of the internal carotid arteries are detailed in 50 anatomical preparations of frontal, sagittal and transversal sections from subjects aged between 42 and 76 years. The results obtained are compared with those reported in the literature and the following points are emphasized:

Résumé Les caractères anatomiques du système constitué par les deux artères vertébrales, leur trajet extracrânien intimement lié au rachis cervical, leurs collatérales, les possibilités de suppléance ainsi offertes expliquent les particularités de la pathologie circulatoire vertébro-basilaire.

The aim of this study was to evaluate the effect of an angiotensin-converting enzyme (ACE) inhibitor, ramipril, on heart rate variability in patients with heart failure simultaneously treated with digitalis. This study was a multicentric, randomized, double-blind, placebo-controlled study including 50 patients with chronic heart failure (CHF). All patients were in NYHA functional class II and III. The etiology of CHF was mainly idiopathic dilated cardiomyopathy and ischemic heart disease. After a 4-week placebo run-in period with digoxin and diuretics, patients were randomized to receive additional ramipril or placebo. To assess heart rate variability (HRV) and arrhythmias, 24-hour ECGs were recorded at the end of the placebo run-in period, 8 and 24 weeks after randomization. Spectral analysis of HRV was performed during one diurnal and one nocturnal 5-minute time period. No statistically significant differences in HRV within low-, high-, and total-frequency bands were induced by ramipril in either the diurnal or nocturnal periods, both at 8 and 24 weeks after randomization. Ramipril produced a significant decrease in nonsustained ventricular tachycardia at 24 weeks of treatment (p = 0.01). These results run against previous observations showing an increase in parasympathetic tone with ACE inhibitors in heart failure. The present study thus suggests that the effects of ACE inhibitors in CHF are variable and depend on the patient and concomitant treatment that might influence HRV such as digoxin treatment.

To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ) hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K(2.7 mM) Tyrode's solution. The concentration C-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was C-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively at the C of 50 μM, Vmaxdepression attained 26.7 ± 2.6 with OH-Q versus 45.9 ± 1.6 with Q and 32.3 ± 1.9 with OH-HQ versus 54.6 ± 1.4 with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent C, recovery kinetics of Vmaxwas significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90 of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90and ERP were increased in a C-dependent manner, whereas the Q- and HQ-induced lengthening in APD90and ERP was observed only at low concentration and low frequency. In addition, the OH-Q– and OH-HQ-induced APD90lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmaxthan Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.

Encainide is a new antiarrhythmic class IC agent. Eleven patients were given 1 mgkg of encainide i.v. over a 15-min period. Electrophysiological studies were done before and 1 h after drug administration. Blood levels of encainide and its principle metabolites O-demethyl-encainide, 3 metoxy-O-demetyl-encainide and N-demethyl-encainide were measured serially after drug administration. Heart rate, blood pressure, and conduction intervals were monitored. Sixty minutes after drug administration there was a marked increase of the QRS, PA, AH, and HV intervals of 28.1 (p < 0.01), 17.2 (p < 0.01), 22.4 (p < 0.01), and 32.2 (p < 0.01), respectively, and a slight increase of the Wenckebach cycle length of 8 (p < 0.05). BP, RR, QT, CSNRT, ESACT, ERP, and FRP did not vary significantly. The HV interval already was increased significantly 2 min after drug administration, while AH was not increased until 15 min after drug administration. The average blood levels of encainide and ODE 60 min after drug administration were 0.410 ± 0.12 and 0.176 ± 0.09 μgml, respectively (mean ± SE of the mean). There was a positive correlation between the increase of the AH and the blood level of ODE, which points out the importance of prolonged electrophysiological studies when testing drug with possibly active metabolites.

Ten patients suffering from chronic premature ventricular complexes (>60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia.

Summary The intracellular electrophysiologic effects of encainide (E) and its main metabolite, O-desmethyl-encainide (ODE), were studied in guinea-pig papillary muscle preparations and related to the in-vivo electrophysiologic effects observed after intravenous (IV) infusion of E in 11 patients undergoing electrophysiologic study (EPS).

Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels.

Mexiletine, a class lb antiarrythmic drug, is used clinically as a racemic mixture of two enantiomers. Aromatic and aliphatic hydroxylation are the two major metabolic steps. In the liver, this metabolism is catalyzed by the cytochrome P450IID6, an isoenzyme of cytochrome P450 due to genetic polymorphism in humans. In the present study, the metabolism of the two stereoisomers was compared in vitro in human liver microsomes. Parahydroxylation (aromatic hydroxylation) is favored for S (+)-mexiletine with a mean intrinsic clearance higher than for R(-)-mexiletine. The R(-) enantiomer exhibits a threefold higher mean Vmaxvalue for aliphatic hydroxylation than S(+)-mexiletine. We showed that (i) the high-affinity component of dextrometorphan O-demethylation was competitively inhibited by R(-)-and S(+)-mexiletine and that (ii) hydroxylations of the two enantiomers were very strongly competitively inhibited by quinidine. Hydroxylation reactions of mexiletine exhibit stereoselectivity in vitro in human liver microsomes and are catalyzed by P450IID6.

β-Adrenergic blocking drugs are effective in reducing sudden cardiac death after acute myocardial infarction but the precise mechanism of this effect is unclear. We investigated the acute and chronic effects of acebutolol, a β-adrenergic blocker, on electrocardiographic parameters, diastolic excitability threshold (DET), and right ventricular effective refractory period (RVERP) in chronically instrumented conscious dogs. These parameters were determined during spontaneous sinus rhythm and at a fixed pacing rate (200 beats/min). Acebutolol (0.5, 1, and 5 mg/kg i.v.) decreased the heart rate (HR) (by 23, 26, and 24, respectively) without effects on any electrocardiographic parameters or on the DET. The maximal increases in ERP were 4.7, 7, and 7.8, respectively, during pacing and 8.5, 13.3, and 10.3, respectively, during sinus rhythm. Acebutolol, 10 mg/kg/day P.O. for 6 weeks, reduced the HR from the third day onward without altering the PR, QRS, QT, or QTCintervals or the DET. The increase in ERP was significant from the third day (14) during pacing and from the seventh day (15.5) during sinus rhythm. The degree of prolongation of the ERP subsequently remained stable during the 6 weeks of treatment. The ERP returned to the baseline value 7 days after acebutolol withdrawal. This increase in ERP, which was more marked during chronic oral treatment, could contribute to the documented protective effect of the p-blocking drugs against sudden cardiac death after myocardial infarction.

Summary The arteries supplying the hand are arranged at three levels: the superficial palmar plane, the deep palmar loop and the dorsal network. Despite a terminology suggesting symmetry (superficial arcade and deep arcade; palmar metacarpal arteries and dorsal metacarpal arteries; palmar digital arteries and dorsal digital arteries), the appearances at each level are in fact quite distinct. We have made a study of the arteries of the palm of the hand based on 100 radioanatomical preparations and have classified them into ten types taking into account their calibre, course, origin and the territory they supply.

Conclusion En raison de l'âge des sujets examinés, un certain nombre d'aspects pathologiques athéromateux et athéroscléreux ont été découverts (Fig. 17). D'autre part, les multiples sinuosités observées paraissent présentes précocement, l'allongement relatif ultérieur dû à la sénescence ne fait que les accentuer. Elles conditionnent cependant le type d'écoulement dans l'artère et favorisent les lésions pariétales, facteur important dans le processus complexe de l'athérosclérose. Il convient d'insister enfin sur un point particulier, la fragilité du siphon carotidien au-delà de 60 ans. Les modifications anatomiques observées augmentent les difficultés de progression et les risques du cathétérisme sélectif ainsi que de la chirurgie de ces vaisseaux.

1Characterization of allelic variants of the TPMT gene (TPMT) responsible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importance of this polymorphism for patients receiving thiopurine drugs.2We defined the mutational and allelic spectrum of TPMTin a group of 191 Europeans. Using PCR–SSCP, we screened for mutation the entire coding sequence, the exon‐intron boundaries, the promoter region and the 3′‐flanking region of the gene. Six mutations were detected throughout the ten exons and seven TPMTalleles were characterized. Four of them, TPMT*2, *3A, *3Cand *7, harbouring the known mutations, G238C, G460A, A719G or T681G, were nonfunctional and accounted for 0.5, 5.7, 0.8 and 0.3% of the allele totality, respectively.3Within the promoter region, six alleles corresponding to a variable number of tandem repeats (VNTR), were identified. VNTR*V4and *V5awhich harbour four or five repeats of a 17–18 bp unit, were the most frequent (55% and 34%, respectively). The other VNTRalleles, having from five to eight repeats, were rarer.4The TPMT phenotype was correctly predicted by genotyping for 87% of individuals. A clear negative correlation between the total number of repeats from both alleles and the TPMT activity level was observed, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter region of TPMT can improve the phenotype prediction rate by genotyping.

Considering the Survival With ORal D-sotalol (SWORD) study results, in which mortality was higher in patients treated by the pure class III agent D-sotalol, we tested DL- and D-sotalol (5 and 10 μM) in an in vitro model of "border zone" arrhythmias. Isolated guinea-pig ventricular strips were partly exposed to normoxia ("Normal Zone," NZ) and partly to modified Tyrode's solution ("Ischemic Zone," IZ) for 15 or 30 min ("ischemia"), followed by return to normoxia for 30 min ("reperfusion"). Resting membrane potential, action potential (AP) amplitude, and maximal upstroke velocity of AP were not significantly modified. DL- And D-sotalol, 5 and 10 μM,lengthened AP duration 90% (APD90) in NZ (p < 0.05), whereas these drugs were unable to prevent ischemia-induced APD shortening. By using the accelerated failure time Weibull's model, and a large number of reference experiments to control random variability of analyzed covariates, DL- and D-sotalol increased significantly the incidence of spontaneous arrhythmias during ischemia (χ2= 24.79; p = 0.0367): 83 (5 μMD- and DL-sotalol), 86, and 62% (10 μMD- and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 μMDL-sotalol prevented the occurrence of spontaneous arrhythmias (χ2= 46.74; p = 0.0001) similar to what seen with the β-blocking agent propranolol (10 μM). These data, providing evidence for proarrhythmic effects of DL- and D-sotalol on border-zone arrhythmias, concomitant with differential class III actions on NZ versus IZ, might be considered for understanding the SWORD study results.