Activation and inhibition of bimanual movements in school-aged children

The development of motor activation and inhibition was compared in 6-to-12 year-olds. Children had to initiate or stop the externally paced movements of one hand, while maintaining that of the other hand. The time needed to perform the switching task (RT) and the spatio-temporal variables show different agerelated evolutions depending on the coordination pattern (inor anti-phase) and the type of transition (activation, selective inhibition, non selective inhibition) required. In the anti-phase mode, activation perturbs the younger subjects' responses while temporal and spatial stabilities transiently decrease around 9 years when activating in the in-phase mode. Aged-related changes differed between inhibition and activation in the antiphase mode, suggesting either the involvement of distinct neural networks or the existence of a single network that is reorganized. In contrast, stopping or adding one hand in the in-phase mode shows similar aged-related improvement. We suggest that selectively stopping or activating one arm during symmetrical coordination rely on the two faces of a common processing in which activation could be the release of inhibition

Hyperaldostéronisme primaire sur adénome ou hyperplasie de la surrénale: opérer ou non [Primary hyperaldosteronism with adrenal adenoma or hyperplasia: surgical case or not?].

Primary hyperaldosteronism is one of the most frequent causes of secondary hypertension. Cardiovascular morbimortality is higher than in essential hypertonic and justifies diagnostic and specific treatment of this pathology. Therapeutic choice depends of health and desire of the patient. It is either medical with mineralocorticoid receptor antagonists, or surgical through adrenalectomy. In this case, a pre-surgery exam including a radiologic examination and a venous adrenal catheterism has to be done. Surgery allows a normalisation of kaliema and a blood pressure decrease in 50 to 88% of the patients. Beyond them, 30% are able to stop entirely their medication. Both therapeutic choices decrease cardiovascular risks equally if blood pressure is controlled.

A systematic review of longitudinal population-based studies on the predictors of smoking cessation in adolescent and young adult smokers.

OBJECTIVE: To describe the determinants of self-initiated smoking cessation of duration of at least 6 months as identified in longitudinal population-based studies of adolescent and young adult smokers. METHODS: A systematic search of the PubMed and EMBASE databases using smoking, tobacco, cessation, quit and stop as keywords was performed. Limits included articles related to humans, in English, published between January 1984 and August 2010, and study population aged 10-29 years. A total of 4502 titles and 871 abstracts were reviewed independently by 2 and 3 reviewers, respectively. Nine articles were retained for data abstraction. Data on study location, timeframe, duration of follow-up, number of data collection points, sample size, age/grade of participants, number of quitters, smoking status at baseline, definition of cessation, covariates and analytic method were abstracted from each article. The number of studies that reported a statistically significant association between each determinant investigated and cessation were tabulated, from among all studies that assessed the determinant. RESULTS: Despite heterogeneity in methods across studies, five factors robustly predicted quitting across studies in which the factor was investigated: not having friends who smoke, not having intentions to smoke in the future, resisting peer pressure to smoke, being older at first use of cigarette and having negative beliefs about smoking. CONCLUSIONS: The literature on longitudinal predictors of cessation in adolescent and young adult smokers is not well developed. Cessation interventions for this population will remain less than optimally effective until there is a solid evidence base on which to develop interventions.

Apprentissage automatique de la morphologie : le cas des structures racine-schème

RÉSUMÉ Cette thèse porte sur le développement de méthodes algorithmiques pour découvrir automatiquement la structure morphologique des mots d'un corpus. On considère en particulier le cas des langues s'approchant du type introflexionnel, comme l'arabe ou l'hébreu. La tradition linguistique décrit la morphologie de ces langues en termes d'unités discontinues : les racines consonantiques et les schèmes vocaliques. Ce genre de structure constitue un défi pour les systèmes actuels d'apprentissage automatique, qui opèrent généralement avec des unités continues. La stratégie adoptée ici consiste à traiter le problème comme une séquence de deux sous-problèmes. Le premier est d'ordre phonologique : il s'agit de diviser les symboles (phonèmes, lettres) du corpus en deux groupes correspondant autant que possible aux consonnes et voyelles phonétiques. Le second est de nature morphologique et repose sur les résultats du premier : il s'agit d'établir l'inventaire des racines et schèmes du corpus et de déterminer leurs règles de combinaison. On examine la portée et les limites d'une approche basée sur deux hypothèses : (i) la distinction entre consonnes et voyelles peut être inférée sur la base de leur tendance à alterner dans la chaîne parlée; (ii) les racines et les schèmes peuvent être identifiés respectivement aux séquences de consonnes et voyelles découvertes précédemment. L'algorithme proposé utilise une méthode purement distributionnelle pour partitionner les symboles du corpus. Puis il applique des principes analogiques pour identifier un ensemble de candidats sérieux au titre de racine ou de schème, et pour élargir progressivement cet ensemble. Cette extension est soumise à une procédure d'évaluation basée sur le principe de la longueur de description minimale, dans- l'esprit de LINGUISTICA (Goldsmith, 2001). L'algorithme est implémenté sous la forme d'un programme informatique nommé ARABICA, et évalué sur un corpus de noms arabes, du point de vue de sa capacité à décrire le système du pluriel. Cette étude montre que des structures linguistiques complexes peuvent être découvertes en ne faisant qu'un minimum d'hypothèses a priori sur les phénomènes considérés. Elle illustre la synergie possible entre des mécanismes d'apprentissage portant sur des niveaux de description linguistique distincts, et cherche à déterminer quand et pourquoi cette coopération échoue. Elle conclut que la tension entre l'universalité de la distinction consonnes-voyelles et la spécificité de la structuration racine-schème est cruciale pour expliquer les forces et les faiblesses d'une telle approche. ABSTRACT This dissertation is concerned with the development of algorithmic methods for the unsupervised learning of natural language morphology, using a symbolically transcribed wordlist. It focuses on the case of languages approaching the introflectional type, such as Arabic or Hebrew. The morphology of such languages is traditionally described in terms of discontinuous units: consonantal roots and vocalic patterns. Inferring this kind of structure is a challenging task for current unsupervised learning systems, which generally operate with continuous units. In this study, the problem of learning root-and-pattern morphology is divided into a phonological and a morphological subproblem. The phonological component of the analysis seeks to partition the symbols of a corpus (phonemes, letters) into two subsets that correspond well with the phonetic definition of consonants and vowels; building around this result, the morphological component attempts to establish the list of roots and patterns in the corpus, and to infer the rules that govern their combinations. We assess the extent to which this can be done on the basis of two hypotheses: (i) the distinction between consonants and vowels can be learned by observing their tendency to alternate in speech; (ii) roots and patterns can be identified as sequences of the previously discovered consonants and vowels respectively. The proposed algorithm uses a purely distributional method for partitioning symbols. Then it applies analogical principles to identify a preliminary set of reliable roots and patterns, and gradually enlarge it. This extension process is guided by an evaluation procedure based on the minimum description length principle, in line with the approach to morphological learning embodied in LINGUISTICA (Goldsmith, 2001). The algorithm is implemented as a computer program named ARABICA; it is evaluated with regard to its ability to account for the system of plural formation in a corpus of Arabic nouns. This thesis shows that complex linguistic structures can be discovered without recourse to a rich set of a priori hypotheses about the phenomena under consideration. It illustrates the possible synergy between learning mechanisms operating at distinct levels of linguistic description, and attempts to determine where and why such a cooperation fails. It concludes that the tension between the universality of the consonant-vowel distinction and the specificity of root-and-pattern structure is crucial for understanding the advantages and weaknesses of this approach.

Organisational reforms in active welfare states: A comparative analysis of the turn to 'single gateways' in Western Europe

Based on the case of reforms aimed at integrating the provision of income protection and employment services for jobless people in Europe, this thesis seeks to understand the reasons which may prompt governments to engage in large-scale organisational reforms. Over the last 20 years, several European countries have indeed radically redesigned the organisational structure of their welfare state by merging or bundling existing front-line offices in charge of benefit payment and employment services together into 'one-stop' agencies. Whereas in academic and political debates, these reforms are generally presented as a necessary and rational response to the problems and inconsistencies induced by fragmentation in a context of the reorientation of welfare states towards labour market activation, this thesis shows that the agenda setting of these reforms is in fact the result of multidimensional political dynamics. More specifically, the main argument of this thesis is that these reforms are best understood not so such from the problems induced by organisational compartmentalism, whose political recognition is often controversial, but from the various goals that governments may simultaneously achieve by means of their adoption. This argument is tested by comparing agenda-setting processes of large-scale reforms of coordination in the United Kingdom (Jobcentre Plus), Germany (Hartz IV reform) and Denmark (2005 Jobcentre reform), and contrasting them with the Swiss case where the government has so far rejected any coordination initiative involving organisational redesign. This comparison brings to light the importance, for the rise of organisational reforms, of the possibility to couple them with the following three goals: first, goals related to the strengthening of activation policies; second, institutional goals seeking to redefine the balance of responsibilities between the central state and non-state actors, and finally electoral goals for governments eager to maintain political credibility. The decisive role of electoral goals in the three countries suggests that these reforms are less bound by partisan politics than by the particular pressures facing governments arrived in office after long periods in opposition.

Etude de Nkx5-3, un facteur de transcription impliqué dans le développement de l'oeil

Résumé :Une famille souffrant d'un nouveau syndrome oculo-auriculaire, appelé syndrome de Schorderet-Munier, a été identifiée. Ce syndrome est caractérisé par une déformation du lobe de l'oreille et des anomalies ophtalmiques, notamment une microphtalmie, une cataracte, un colobome et une dégénérescence rétinienne. Le gène impliqué dans ce syndrome est NKX5-3 codant un facteur de transcription contenant un homéodomaine. Chez les patient atteints, le gène comporte une délétion de 26 nucléotides provoquant probablement l'apparition d'un codon stop précoce. Ce gène n'est exprimé que dans certains organes dont les testicules et les ganglions cervicaux supérieurs, ainsi que dans les organes touchés par ce syndrome, à savoir le pavillon de l'oreille et l'oeil, surtout lors du développement embryonnaire. Au niveau de la rétine, NKX5-3 est présent dans la couche nucléaire interne et dans la couche dè cellules ganglionnaires et est exprimé de manière polarisée selon un axe temporal > nasal et ventral > dorsal. Son expression in vitro est régulée par Spl, un facteur de transcription exprimé durant le développement de l'oeil chez la souris. NKX5-3 semble lui-même provoquer une inhibition de l'expression de SHH et de EPHA6. Ces gènes sont tous les deux impliqués à leur manière dans le guidage des axones des cellules ganglionnaires de la rétine. Pris ensemble, ces résultats nous permettent donc d'émettre une hypothèse quant à un rôle potentiel de NKX5-3 dans ce processus.Abstract :A family with a new oculo-auricular syndrome, called syndrome of Schorderet-Munier, was identified. This disease is characterised by a deformation of the ear lobule and by several ophthalmic abnormalities, like microphthalmia, cataract, coloboma and a retinal degeneration. The gene, which causes this syndrome, is NKX5-3 coding for a transcription factor contaning a homeodomain. In the affectd patients, the defect consists of a deletion of 26 nucleotides probably producing a premature stop codon. This gene is only expressed in a few organs like testis and superior cervical ganglions, as well as in organs affected by this syndrome, namely the ear pinna and the eye, mainly during embryonic development. In the retina, NKX5-3 is present in the inner nuclear layer and in the ganglion cells layer. It is expressed along a gradient ranging from the temporal retina to nasal retina and from the ventral to the dorsal part. Its in vitro expression is regulated by Spl, a transcription factor expressed during the murine eye development. NKX5-3 seems to inhibit the expression of SHH and EPHA6. These genes are both implicated, in their own way, in the axon guidance of the retinal ganglion cells. Taken together, these results allow us to make an assumption about a potential role of NKX5-3 in this process.

Molecular mechanisms of penicillin-induced killing and penicillin tolerance in Streptococcus gordonii

Abstract The main thesis topic relates to the 'molecular mechanisms of penicillin-induced bacterial death. Indeed, bacteria have developed two principal mechanisms to escape the killing effect of ß-lactam antibiotics: resistance and tolerance. Resistant bacteria are characterized by their ability to grow in the presence of drug concentrations higher than the one inhibiting the growth of susceptible members of the same species. Hence, resistant bacteria have an increased minimal inhibitory concentration (MIC) of the drug. Nevertheless, when exposed to antibiotic concentrations exceeding their new MIC, resistant bacteria remain sensitive to the antibiotic killing effect. In contrast, tolerant bacteria have an unchanged MIC. However, they have a considerably increased ability to survive drug-induced killing, even at concentrations exceeding their MIC by several orders of magnitude. In other words, in the presence of the antibiotic, tolerant bacteria become persister cells which stop growing but are not killed. In the present thesis, it is shown that the survival phenotype of a tolerant Streptococcus gordonii strain depends on two components belonging to sugar metabolism pathways. First, the transcription factor CcpA which mediates a global regulatory mechanism allowing bacteria to utilize the most efficient sugar source for their growth. We show that the inactivation of the ccpA gene leads to a partial loss of penicillin tolerance both in vitro and in a rat model of experimental endocarditis. Second, the Enzyme I of the phosphotransferase system which is involved in the uptake and phosphorylation of sugars. Here, we -show that a single nucleotide mutation in ptsI, the gene encoding the Enzyme I, is sufficient to confer a fully tolerant phenotype in S. gordonii both in vivo and in vivo. The mutation results in a radical proline to arginine substitution in the C-terminal domain of the protein, probably leading to a decrease in its homodimerization and subsequent activity. Taken together our results prove that tolerance is a global survival mechanism linked to sugar metabolism. We hypothesize that, in the presence of the antibiotic, the already altered metabolic processes of the tolerant strain are completely inactivated. Hence, bacteria may enter in a dormant state and become insensitive to the bactericidal effect of ß-lactams, which depends on actively dividing cells. This thesis manuscript also contains two other side-projects. The first one establishes that the ability to form a biofilm is not a requisite for the successful establishment of endocarditis due to S. gordonii. The second one characterizes the S. gordonii a-phosphoglucomutase gene, and shows that its inactivation results in a loss of in vitro fitness and in vivo virulence. Résumé Le sujet principal de cette thèse concerne les mécanismes moléculaires de la mort bactérienne induite par la pénicilline. En effet, les bactéries ont développé deux mécanismes principaux pour échapper à l'effet bactéricide des ß-lactamines : la résistance et la tolérance. Les bactéries résistantes sont caractérisées par leur capacité de croître en présence de concentration d'antibiotiques plus élevées que celles inhibant la croissance des organismes sensibles de la même espèce. Les bactéries résistantes ont donc une augmentation de leur concentration minimale inhibitrice (CMI) à l'antibiotique. Néanmoins, quand elles sont exposées à des concentrations dépassant leur nouvelle CMI, elles restent sensibles à l'effet bactéricide. Au contraire, les bactéries tolérantes ont une CMI inchangée. Toutefois, elles ont une très importante capacité à survivre à l'effet bactéricide des ß-lactamines, ceci même à des concentrations excédant leur CMI de plusieurs ordres de grandeur. En d'autres termes, en présence de l'antibiotique, les bactéries tolérantes deviennent des cellules persistantes qui arrêtent leur croissance mais ne sont pas tuées. Dans la présente thèse, il est montré que le phénotype de survie d'un Streptococcus gordonii tolérant dépend de deux composants appartenant aux voies du métabolisme des sucres. Premièrement, le facteur de transcription CcpA qui contrôle un système global de régulation permettant à la bactérie d'utiliser les sources de sucre les plus efficaces pour sa croissance. Il est montré que l'inactivation du gène ccpA résulte en la perte partielle de la tolérance à la pénicilline aussi bien in vitro que dans un modèle d'endocardite expérimentale chez le rat. Deuxièmement, l'Enzyme I du système de phosphotransfert impliqué dans l'import et la phosphorylation des sucres. Nous montrons qu'une mutation ponctuelle d'un nucléotide dans ptsl, le gène codant pour l'Enzyme I, suffit à complètement conférer un phénotype tolérant chez S. gordonii aussi bien in vitro qu'in vivo. La mutation induit la substitution radicale d'une proline en une arginine dans le domaine C-terminal de la protéine, résultant probablement en une diminution de sa capacité d'homodimérisation et donc d'activité. Dans leur ensemble, nos résultats prouvent que la tolérance est un mécanisme global de survie lié au métabolisme des sucres. Nous présentons l'hypothèse que, en présence de l'antibiotique, les processus métaboliques déjà altérés de la souche tolérante deviennent complètement inactifs. En conséquence, les bactéries entreraient dans un état dormant nonréplicatif, devenant ainsi insensibles à l'effet bactéricide des ß-lactamines qui nécessite des cellules en cours de division active. Le manuscrit de cette thèse contient également deux projets secondaires. Le premier montre que la capacité de former un biofilm n'est pas un prérequis pour le succès de l'initiation de l'endocardite à S. gordonii. Le second caractérise le gène de l'a-phosphoglucomutase de S. gordonii et montre que son inactivation résulte en une perte de fitness in vitro et de virulence in vivo.

Stage of change of cigarette smoking in alcohol-dependent patients.

Despite the heavy burden of tobacco-related problems in alcohol-dependent patients, little effort has been directed toward reducing the prevalence of smoking in these patients. It seems reasonable to develop nicotine addiction treatments for alcohol-dependent patients based on the smoker's stage of change. To assess the stage of change for tobacco consumption and possible quitting barriers in alcohol-dependent patients, 88 consecutively admitted inpatients of a Swiss university-affiliated alcohol withdrawal clinic were interviewed with a semistructured schedule. More than half of the alcohol-dependent smokers (50.7%) considered the possibility of smoking cessation or had already decided to stop, although the majority (83.1%) were highly dependent smokers. Positive reinforcers were factors influencing motivation both to stop smoking as well as to continue smoking, whereas negative reinforcers had no influence. As recovering alcoholic patients are often interested in smoking cessation and the introduction of nicotine treatment interventions has been shown not to jeopardize the outcome of alcohol treatment, alcohol treatment programs should include counseling for smoking cessation. Education and training for staff is essential, as their beliefs and habits remain an important barrier.

Outcome of smoking cessation counselling of HIV-positive persons by HIV care physicians.

OBJECTIVES: Smoking is the most prevalent modifiable risk factor for cardiovascular diseases among HIV-positive persons. We assessed the effect on smoking cessation of training HIV care physicians in counselling. METHODS: The Swiss HIV Cohort Study (SHCS) is a multicentre prospective observational database. Our single-centre intervention at the Zurich centre included a half day of standardized training for physicians in counselling and in the pharmacotherapy of smokers, and a physicians' checklist for semi-annual documentation of their counselling. Smoking status was then compared between participants at the Zurich centre and other institutions. We used marginal logistic regression models with exchangeable correlation structure and robust standard errors to estimate the odds of smoking cessation and relapse. RESULTS: Between April 2000 and December 2010, 11 056 SHCS participants had 121 238 semi-annual visits and 64 118 person-years of follow-up. The prevalence of smoking decreased from 60 to 43%. During the intervention at the Zurich centre from November 2007 to December 2009, 1689 participants in this centre had 6068 cohort visits. These participants were more likely to stop smoking [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.07-1.42; P=0.004] and had fewer relapses (OR 0.75; 95% CI 0.61-0.92; P=0.007) than participants at other SHCS institutions. The effect of the intervention was stronger than the calendar time effect (OR 1.19 vs. 1.04 per year, respectively). Middle-aged participants, injecting drug users, and participants with psychiatric problems or with higher alcohol consumption were less likely to stop smoking, whereas persons with a prior cardiovascular event were more likely to stop smoking. CONCLUSIONS: An institution-wide training programme for HIV care physicians in smoking cessation counselling led to increased smoking cessation and fewer relapses.

Structural genes for salicylate biosynthesis from chorismate in Pseudomonas aeruginosa.

Salicylate is a precursor of pyochelin in Pseudomonas aeruginosa and both compounds display siderophore activity. To elucidate the salicylate biosynthetic pathway, we have cloned and sequenced a chromosomal region of P. aeruginosa PAO1 containing two adjacent genes, designated pchB and pchA, which are necessary for salicylate formation. The pchA gene encodes a protein of 52 kDa with extensive similarity to the chorismate-utilizing enzymes isochorismate synthase, anthranilate synthase (component I) and p-aminobenzoate synthase (component I), whereas the 11 kDa protein encoded by pchB does not show significant similarity with other proteins. The pchB stop codon overlaps the presumed pchA start codon. Expression of the pchA gene in P. aeruginosa appears to depend on the transcription and translation of the upstream pchB gene. The pchBA genes are the first salicylate biosynthetic genes to be reported. Salicylate formation was demonstrated in an Escherichia coli entC mutant lacking isochorismate synthase when this strain expressed both the pchBA genes, but not when it expressed pchB alone. By contrast, an entB mutant of E. coli blocked in the conversion of isochorismate to 2,3-dihydro-2,3-dihydroxybenzoate formed salicylate when transformed with a pchB expression construct. Salicylate formation could also be demonstrated in vitro when chorismate was incubated with a crude extract of P. aeruginosa containing overproduced PchA and PchB proteins; salicylate and pyruvate were formed in equimolar amounts. Furthermore, salicylate-forming activity could be detected in extracts from a P. aeruginosa pyoverdin-negative mutant when grown under iron limitation, but not with iron excess. Our results are consistent with a pathway leading from chorismate to isochorismate and then to salicylate plus pyruvate, catalyzed consecutively by the iron-repressible PchA and PchB proteins in P. aeruginosa.

Self-reported smoking cessation activities among Swiss primary care physicians.

ABSTRACT: BACKGROUND: Individual counselling, pharmacotherapy, and group therapy are evidence-based interventions that help patients stop smoking. Acupuncture, hypnosis, and relaxation have no demonstrated efficacy on smoking cessation, whereas self-help material may only have a small benefit. The purpose of this study is to assess physicians' current clinical practice regarding smokers motivated to stop smoking. METHODS: The survey included 3385 Swiss primary care physicians. Self-reported use of nine smoking cessation interventions was scored. One point was given for each positive answer about practicing interventions with demonstrated efficacy, i.e. nicotine replacement therapy, bupropion, counselling, group therapy, and smoking cessation specialist. No points were given for the recommendation of acupuncture, hypnosis, relaxation, and self-help material. Multivariable logistic analysis was performed to identify factors associated with a good practice score, defined as >1. RESULTS: The response rate was 55%. Respondents were predominately over the age of 40 years (88%), male (79%), and resided in urban areas (74%). Seventeen percent reported being smokers. Most of the physicians prescribed nicotine replacement therapy (84%), bupropion (65%), or provided counselling (70%). A minority of physicians recommended acupuncture (26%), hypnosis (8%), relaxation (7%), or self-help material (24%). A good practice score was obtained by 85% of respondents. Having attended a smoking cessation training program was the only significant predictor of a good practice score (odds ratio: 6.24 , 95% CI 1.95-20.04). CONCLUSION: The majority of respondents practice recommended smoking cessation interventions. However, there is room for improvement and implementing an evidence-based smoking cessation-training program could provide additional benefit.

Peri-operative management of antiplatelet therapy in patients with coronary artery disease. Joint position paper by members of the working group on Perioperative Haemostasis of the Society on Thrombosis and Haemostasis Research (GTH), the working group on Perioperative Coagulation of the Austrian Society for Anesthesiology, Resuscitation and Intensive Care (ÖGARI) and the Working Group Thrombosis of the European Society for Cardiology (ESC).

An increasing number of patients suffering from cardiovascular disease, especially coronary artery disease (CAD), are treated with aspirin and/or clopidogrel for the prevention of major adverse events. Unfortunately, there are no specific, widely accepted recommendations for the perioperative management of patients receiving antiplatelet therapy. Therefore, members of the Perioperative Haemostasis Group of the Society on Thrombosis and Haemostasis Research (GTH), the Perioperative Coagulation Group of the Austrian Society for Anesthesiology, Reanimation and Intensive Care (ÖGARI) and the Working Group Thrombosis of the European Society of Cardiology (ESC) have created this consensus position paper to provide clear recommendations on the perioperative use of anti-platelet agents (specifically with semi-urgent and urgent surgery), strongly supporting a multidisciplinary approach to optimize the treatment of individual patients with coronary artery disease who need major cardiac and non-cardiac surgery. With planned surgery, drug eluting stents (DES) should not be used unless surgery can be delayed for ≥12 months after DES implantation. If surgery cannot be delayed, surgical revascularisation, bare-metal stents or pure balloon angioplasty should be considered. During ongoing antiplatelet therapy, elective surgery should be delayed for the recommended duration of treatment. In patients with semi-urgent surgery, the decision to prematurely stop one or both antiplatelet agents (at least 5 days pre-operatively) has to be taken after multidisciplinary consultation, evaluating the individual thrombotic and bleeding risk. Urgently needed surgery has to take place under full antiplatelet therapy despite the increased bleeding risk. A multidisciplinary approach for optimal antithrombotic and haemostatic patient management is thus mandatory.

Immune response to HIV.

PURPOSE OF REVIEW: Major advances have been made in the delineation of HIV-specific immune response and in the mechanisms of virus escape. The kinetics of the immunological and virological events occurring during primary HIV infection indicate that the establishment of the latent HIV reservoir, the major obstacle to HIV eradication likely occurs during the very early stages of primary infection, that is, the 'eclipse phase', prior to the development of the HIV-specific immune response which has limited efficacy in the control of the early events of infection. Therefore, the window of opportunity to develop effective interventions either to clear HIV during primary infection or to prevent rebound of HIV in patients successfully treated who stop antiretroviral therapy is very narrow. RECENT FINDINGS: Genetic factors most strongly associated with nonprogressive infection are human leukocyte antigen (HLA) class I alleles and particularly HLA-B5701. CD4 and CD8 T-cell responses with polyfunctional profile are associated with nonprogressive infection. Broader neutralizing antibodies are detected 3-4 years after infection, generated only in 20% of individuals but show no efficacy in the control of HIV replication. SUMMARY: In the present review, we shall discuss the different components of the HIV-specific immune response elicited by the infection, the kinetics of these responses during primary infection and the changes following transition to the chronic phase of infection, and the functional profile of 'effective' versus 'noneffective' HIV-specific immune responses.

A hypomorphic mutation in lpin1 induces progressively improving peripheral neuropathy in the rat

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat with a mutated Lpin1 gene (Lpin11Hubr ), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin11Hubr rats are characterized by hindlimb paralysis that is detectable from the second postnatal week. Sequencing of Lpin1 identified a missense mutation in the 5'-end splice site of exon 18 resulting in mis-splicing, a reading frame shift and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. As a consequence, Lpin11Hubr rats develop hypomyelination rather than the pronounced demyelination defect characteristic of Lpin1fld/fld mice, which carry a null allele for Lpin1. Furthermore, histological and molecular analyses revealed that this lesion improve in older Lpin11Hubr rats as compared to young Lpin11Hubr rats and Lpin1fld/fld mice. The observed differences between the murine Lpin1fld/fld mutant, with a complete loss of Lipin 1 function, and the Lpin1Hubr rat, with a truncated PAP1 activitydeficient form of Lipin 1, provide additional evidence for suggested non-enzymatic Lipin1 function residing outside of its PAP1 domain. While we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into pathogenicity of recently identified human Lpin1 mutations. *These authors contributed equally.

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Integration of social and employment policies has been a highly topical issue over past decades in Europe. Faced with the complex task of facilitating the return to employment of jobless people with multiple barriers to work, several countries have developed integrated structures for delivering labour market and social support.'One stop-shops','integrated jobcenters' and 'interagency collaboration'are some of the tools that are being developed in this context (Askim et al, 2011).