Prescription, dispensation and marketing patterns of methylphenidate

OBJECTIVE To analyze the patterns and legal requirements of methylphenidate consumption. METHODS We conducted a cross-sectional study of the data from prescription notification forms and balance lists of drugs sales – psychoactive and others – subject to special control in the fifth largest city of Brazil, in 2006. We determined the defined and prescribed daily doses, the average prescription and dispensation periods, and the regional sales distribution in the municipality. In addition, we estimated the costs of drug acquisition and analyzed the individual drug consumption profile using the Lorenz curve. RESULTS The balance lists data covered all notified sales of the drug while data from prescription notification forms covered 50.6% of the pharmacies that sold it, including those with the highest sales volumes. Total methylphenidate consumption was 0.37 DDD/1,000 inhabitants/day. Sales were concentrated in more developed areas, and regular-release tablets were the most commonly prescribed pharmaceutical formulation. In some regions of the city, approximately 20.0% of the prescriptions and dispensation exceeded 30 mg/day and 30 days of treatment. CONCLUSIONS Methylphenidate was widely consumed in the municipality and mainly in the most developed areas. Of note, the consumption of formulations with the higher abuse risk was the most predominant. Both its prescription and dispensation contrasted with current pharmacotherapeutic recommendations and legal requirements. Therefore, the commercialization of methylphenidate should be monitored more closely, and its use in the treatment of behavioral changes of psychological disorders needs to be discussed in detail, in line with the concepts of the quality use of medicines.

A perturbation and observation routine used to control a power converter

This paper presents a programable perturbation and observation control implementation for a wind generation system and its power electronic converter. The objective of the method in this particular application is to adjust the power delivered to charge a battery to its maximum and allowable value, function of the real values of several parameters and their continuous variation, the most important the wind velocity and the turbine efficiency. Also, to improve the power throughput and to use the turbine and generator marginal zones of operation, an unusual power converter is used, allowing a wide range for the input voltage values. The implemented control is continuously measuring the actual power and looks for a new and powerful operation point. © 2014 IEEE.

Linear and sliding-mode control design for matrix converter-based unified power flow controllers

This paper presents the design and compares the performance of linear, decoupled and direct power controllers (DPC) for three-phase matrix converters operating as unified power flow controllers (UPFC). A simplified steady-state model of the matrix converter-based UPFC fitted with a modified Venturini high-frequency pulse width modulator is first used to design the linear controllers for the transmission line active (P) and reactive (Q) powers. In order to minimize the resulting cross coupling between P and Q power controllers, decoupled linear controllers (DLC) are synthesized using inverse dynamics linearization. DPC are then developed using sliding-mode control techniques, in order to guarantee both robustness and decoupled control. The designed P and Q power controllers are compared using simulations and experimental results. Linear controllers show acceptable steady-state behaviour but still exhibit coupling between P and Q powers in transient operation. DLC are free from cross coupling but are parameter sensitive. Results obtained by DPC show decoupled power control with zero error tracking and faster responses with no overshoot and no steady-state error. All the designed controllers were implemented using the same digital signal processing hardware.

Assessment and control of nanoparticles exposure in welding operations by use of a control banding tool

This paper describes the use of a Control Banding Tool to assess and further control of exposure of nanoparticles emitted during welding operations. The tool was applied to Metal Active Gas (MAG) arc welding of mild and stainless steel, providing semi-quantitative data on the process, so that protection measures could be derived, e.g. exhaust gas ventilation by hoods, local ventilation devices and containment measures. This tool is quite useful to compare and evaluate the characteristics of arc welding procedures so that more eco-friendly processes could be preferred over the more potentially noxious ones.

Schistosoma mansoni circulating polysaccharide and protein antigens recognized by sheep antisera in patients with different clinical forms of schistosomiasis before and after treatment

Two sheep antisera, one of which raised against polysaccharide (Po) and other against protein (Pt) components of Schistosoma mansoni adult worms, were assessed by ELISA for their ability to detect circulating parasite antigens in patients with different clinical forms of chronic schistosomiasis mansoni. The former antiserum detected parasite antigens in liver granulomata and the latter in renal glomeruli from schistosomiasis patients and mice experimentally infected with S. mansoni. In general, the levels and/or positivity rate of circulating antigens and specific IgG antibodies were significantly higher in patients with hepatointestinal (HI) and hepatosplenic (HS) forms than in mild intestinal (I) forms. An association between Po antigens and clinical features of the disease was observed, as the level of these antigens was low (137 ng/ml) as well as the positivity rate (7.9%) in patients with I forms; values that were intermediate (593 ng/ml and 33.3%) in those with HI forms, and high (1.563 ng/ml and 50.0%) in more severe HS forms. The Pt antigens were detected in the studied clinical forms not differing statistically but, the positivity rate was significantly higher in HS forms comparatively to I forms. The antisera studied revealed distinct circulating antigen profiles, and the prognostic value of Po and Pt antigens was suggested.

LACK OF ASSOCIATION BETWEEN HERPESVIRUS DETECTION IN SALIVA AND GINGIVITIS IN HIV‑INFECTED CHILDREN

The aims of this study were to compare the detection of human herpesviruses (HHVs) in the saliva of HIV-infected and healthy control children, and to evaluate associations between viral infection and gingivitis and immunodeficiency. Saliva samples were collected from 48 HIV-infected and 48 healthy control children. Clinical and laboratory data were collected during dental visits and from medical records. A trained dentist determined gingival indices and extension of gingivitis. Saliva samples were tested for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) by nested polymerase chain reaction assays. Thirty-five HIV-infected and 16 control children had gingivitis. Seventeen (35.4%) HIV-infected children and 13 (27%) control children were positive for HHVs. CMV was the most commonly detected HHV in both groups (HIV-infected, 25%; control, 12.5%), followed by HSV-1 (6.2% in both groups) and HSV-2 (HIV-infected, 4.2%; control, 8.3%). The presence of HHVs in saliva was not associated with the presence of gingivitis in HIV-1-infected children (p = 0.104) or healthy control children (p = 0.251), or with immunosuppression in HIV-infected individuals (p = 0.447). Gingivitis was correlated with HIV infection (p = 0.0001). These results suggest that asymptomatic salivary detection of HHVs is common in HIV-infected and healthy children, and that it is not associated with gingivitis.

Development Process and Cognitive Testing of CARATkids - Control of Allergic Rhinitis and Asthma Test for Children

Background: Allergic rhinitis and asthma (ARA) are chronic inflammatory diseases of the airways that often coexist in children. The only tool to assess the ARA control, the Control of Allergic Rhinitis and Asthma Test (CARAT) is to be used by adults. We aimed to develop the Pediatric version of Control of Allergic Rhinitis and Asthma Test (CARATkids) and to test its comprehensibility in children with 4 to 12 years of age. Methods: The questionnaire development included a literature review of pediatric questionnaires on asthma and/or rhinitis control and two consensus meetings of a multidisciplinary group. Cognitive testing was carried out in a cross-sectional qualitative study using cognitive interviews. Results: Four questionnaires to assess asthma and none to assess rhinitis control in children were identified. The multidisciplinary group produced a questionnaire version for children with 17 questions with illustrations and dichotomous (yes/no) response format. The version for caregivers had 4-points and dichotomous scales. Twenty-nine children, 4 to 12 years old, and their caregivers were interviewed. Only children over 6 years old could adequately answer the questionnaire. A few words/expressions were not fully understood by children of 6 to 8 years old. The drawings illustrating the questions were considered helpful by children and caregivers. Caregivers considered the questionnaire complete and clear and preferred dichotomous over the 4-points scales. The proportion of agreement between children and their caregivers was 61%. The words/expressions that were difficult to understand were amended. Conclusion: CARATkids, the first questionnaire to assess a child’s asthma and rhinitis control was developed and its content validity was assured. Cognitive testing showed that CARATKids is well-understood by children 6 to 12 years old. The questionnaire’s measurement properties can now be assessed in a validation study.

Treatment of T. cruzi infected human platelet concentrates with aminomethyltrimethyl psoralen (AMT) and ultravioleta (UV-A) light: preliminary results

The present measures adopted to prevent transfusion-associated Chagas' disease include screening of blood donors. and/or the inactivation of T. cruzi in collected blood using gentian violet (GV) as a trypanocidal agent. In this study, we investigated the efficacy of the combined use of AMT and UV-A in inactirating T. cruzi in infected human platelet cuncentrates. Human platelet concentrates were infected with T. cruzi (2x10/ml) of the Y strain transfered to PL 269 (Fenwal Laboratories) containers and treated with GV (250řg,/ml). and ascorbic acid (1 mg/ml); GV. ascorbic acid and UV-A; GV and UV-A; AMT (40/tG/ml) and ascorbic acid; AMT, ascorbic acid and UV-A; AMT and UV-A; UV-A alone; and untreated (control). All UV-A treated platelet concentrates were exposed to UV-A doses of 24, 92, 184, 276, 368 and 644 kj/m². and the microscopical research of active T. cruzi was performed, using the microhematocrit technique, 1, 6 and 24 hours after each treatment. A high number of active forms of T. cruzi was observed in all condictions, except when GV was used as the trypanocidal agent, providing evidence of the failure of AMT and UV-A in inactivating T cruzi in infected human platelet concentrates.

Problems and perspectives for Chagas disease control: in search of a realistic analysis

Chagas disease was an important medical and social problem in almost all of Latin America throughout the twentieth century. It has been combated over a broad swath of this continent over recent decades, with very satisfactory results in terms of vector and transfusional transmission. Today, a surveillance stage still remains to be consolidated, in parallel with appropriate care required for some millions of infected individuals who are today living in endemic and non-endemic areas. Contradictorily, the good results attained have generated excessive optimism and even disregard among health authorities, in relation to this disease and its control. The loss of visibility and priority may be a logical consequence, particularly in Latin American healthcare systems that are still disorganized and overburdened due to insufficiencies of financial and human resources. Consolidation of the victories against Chagas disease is attainable but depends on political will and continual attention from the most consequential protagonists in this struggle, especially the Latin American scientific community.

Control system for actuation and sensing in digital microfluidics devices

Digital Microfluidics (DMF) is a second generation technique, derived from the conventional microfluidics that instead of using continuous liquid fluxes, it uses only individual droplets driven by external electric signals. In this thesis a new DMF control/sensing system for visualization, droplet control (movement, dispensing, merging and splitting) and real time impedance measurement have been developed. The software for the proposed system was implemented in MATLAB with a graphical user interface. An Arduino was used as control board and dedicated circuits for voltage switching and contacts were designed and implemented in printed circuit boards. A high resolution camera was integrated for visualization. In our new approach, the DMF chips are driven by a dual-tone signal where the sum of two independent ac signals (one for droplet operations and the other for impedance sensing) is applied to the electrodes, and afterwards independently evaluated by a lock-in amplifier. With this new approach we were able to choose the appropriated amplitudes and frequencies for the different proposes (actuation and sensing). The measurements made were used to evaluate the real time droplet impedance enabling the knowledge of its position and velocity. This new approach opens new possibilities for impedance sensing and feedback control in DMF devices.

Historical analysis of the records of sylvan yellow fever in the State of Amazonas, Brazil, from 1996 to 2009

IntroductionYellow fever is a non-contagious infectious disease, highly lethal, transmitted by the Aedes, Haemagogus and Sabethes.MethodsDescriptive retrospective study of the yellow fever cases in Amazonas, between 1996 and 2009.ResultsForty two cases of yellow fever were confirmed, with 30 deaths, 10% of which were foreigners.ConclusionsThe presence of Aedes aegypti and Aedes albopictus in both rural Amazonas and its capital demonstrates the dispersion of these vectors and underscores the need for better and continuous epidemiological and entomological control.

A historical overview of leprosy epidemiology and control activities in Amazonas, Brazil

Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.

Quality control and conduct of genome-wide association meta-analyses.

Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Contact metamorphism and emplacement of the western Adamello tonalite

The geodynamic forces acting in the Earth's interior manifest themselves in a variety of ways. Volcanoes are amongst the most impressive examples in this respect, but like with an iceberg, they only represent the tip of a more extensive system hidden underground. This system consists of a source region where melt forms and accumulates, feeder connections in which magma is transported towards the surface, and different reservoirs where it is stored before it eventually erupts to form a volcano. A magma represents a mixture of melt and crystals. The latter can be extracted from the source region, or form anywhere along the path towards their final crystallization place. They will retain information of the overall plumbing system. The host rocks of an intrusion, in contrast, provide information at the emplacement level. They record the effects of thermal and mechanical forces imposed by the magma. For a better understanding of the system, both parts - magmatic and metamorphic petrology - have to be integrated. I will demonstrate in my thesis that information from both is complementary. It is an iterative process, using constraints from one field to better constrain the other. Reading the history of the host rocks is not always straightforward. This is shown in chapter two, where a model for the formation of clustered garnets observed in the contact aureole is proposed. Fragments of garnets, older than the intrusive rocks are overgrown by garnet crystallizing due to the reheating during emplacement of the adjacent pluton. The formation of the clusters is therefore not a single event as generally assumed but the result of a two-stage process, namely the alteration of the old grains and the overgrowth and amalgamation of new garnet rims. This makes an important difference when applying petrological methods such as thermobarometry, geochronology or grain size distributions. The thermal conditions in the aureole are a strong function of the emplacement style of the pluton. therefore it is necessary to understand the pluton before drawing conclusions about its aureole. A study investigating the intrusive rocks by means of field, geochemical, geochronologi- cal and structural methods is presented in chapter three. This provided important information about the assembly of the intrusion, but also new insights on the nature of large, homogeneous plutons and the structure of the plumbing system in general. The incremental nature of the emplacement of the Western Adamello tonalité is documented, and the existence of an intermediate reservoir beneath homogeneous plutons is proposed. In chapter four it is demonstrated that information extracted from the host rock provides further constraints on the emplacement process of the intrusion. The temperatures obtain by combining field observations with phase petrology modeling are used together with thermal models to constrain the magmatic activity in the immediate intrusion. Instead of using the thermal models to control the petrology result, the inverse is done. The model parameters were changed until a match with the aureole temperatures was obtained. It is shown, that only a few combinations give a positive match and that temperature estimates from the aureole can constrain the frequency of ancient magmatic systems. In the fifth chapter, the Anisotropy of Magnetic Susceptibility of intrusive rocks is compared to 3D tomography. The obtained signal is a function of the shape and distribution of ferromagnetic grains, and is often used to infer flow directions of magma. It turns out that the signal is dominated by the shape of the magnetic crystals, and where they form tight clusters, also by their distribution. This is in good agreement with the predictions made in the theoretical and experimental literature. In the sixth chapter arguments for partial melting of host rock carbonates are presented. While at first very surprising, this is to be expected when considering the prior results from the intrusive study and experiments from the literature. Partial melting is documented by compelling microstructures, geochemical and structural data. The necessary conditions are far from extreme and this process might be more frequent than previously thought. The carbonate melt is highly mobile and can move along grain boundaries, infiltrating other rocks and ultimately alter the existing mineral assemblage. Finally, a mineralogical curiosity is presented in chapter seven. The mineral assemblage magne§site and calcite is in apparent equilibrium. It is well known that these two carbonates are not stable together in the system Ca0-Mg0-Fe0-C02. Indeed, magnesite and calcite should react to dolomite during metamorphism. The presented explanation for this '"forbidden" assemblage is, that a calcite melt infiltrated the magnesite bearing rock along grain boundaries and caused the peculiar microstructure. This is supported by isotopie disequilibrium between calcite and magnesite. A further implication of partially molten carbonates is, that the host rock drastically looses its strength so that its physical properties may be comparable to the ones of the intrusive rocks. This contrasting behavior of the host rock may ease the emplacement of the intrusion. We see that the circle closes and the iterative process of better constraining the emplacement could start again. - La Terre est en perpétuel mouvement et les forces tectoniques associées à ces mouvements se manifestent sous différentes formes. Les volcans en sont l'un des exemples les plus impressionnants, mais comme les icebergs, les laves émises en surfaces ne représentent que la pointe d'un vaste système caché dans les profondeurs. Ce système est constitué d'une région source, région où la roche source fond et produit le magma ; ce magma peut s'accumuler dans cette région source ou être transporté à travers différents conduits dans des réservoirs où le magma est stocké. Ce magma peut cristalliser in situ et produire des roches plutoniques ou alors être émis en surface. Un magma représente un mélange entre un liquide et des cristaux. Ces cristaux peuvent être extraits de la source ou se former tout au long du chemin jusqu'à l'endroit final de cristallisation. L'étude de ces cristaux peut ainsi donner des informations sur l'ensemble du système magmatique. Au contraire, les roches encaissantes fournissent des informations sur le niveau d'emplacement de l'intrusion. En effet ces roches enregistrent les effets thermiques et mécaniques imposés par le magma. Pour une meilleure compréhension du système, les deux parties, magmatique et métamorphique, doivent être intégrées. Cette thèse a pour but de montrer que les informations issues de l'étude des roches magmatiques et des roches encaissantes sont complémentaires. C'est un processus itératif qui utilise les contraintes d'un domaine pour améliorer la compréhension de l'autre. Comprendre l'histoire des roches encaissantes n'est pas toujours aisé. Ceci est démontré dans le chapitre deux, où un modèle de formation des grenats observés sous forme d'agrégats dans l'auréole de contact est proposé. Des fragments de grenats plus vieux que les roches intru- sives montrent une zone de surcroissance générée par l'apport thermique produit par la mise en place du pluton adjacent. La formation des agrégats de grenats n'est donc pas le résultat d'un seul événement, comme on le décrit habituellement, mais d'un processus en deux phases, soit l'altération de vieux grains engendrant une fracturation de ces grenats, puis la formation de zone de surcroissance autour de ces différents fragments expliquant la texture en agrégats observée. Cette interprétation en deux phases est importante, car elle engendre des différences notables lorsque l'on applique des méthodes pétrologiques comme la thermobarométrie, la géochronologie ou encore lorsque l'on étudie la distribution relative de la taille des grains. Les conditions thermales dans l'auréole de contact dépendent fortement du mode d'emplacement de l'intrusion et c'est pourquoi il est nécessaire de d'abord comprendre le pluton avant de faire des conclusions sur son auréole de contact. Une étude de terrain des roches intrusives ainsi qu'une étude géochimique, géochronologique et structurale est présente dans le troisième chapitre. Cette étude apporte des informations importantes sur la formation de l'intrusion mais également de nouvelles connaissances sur la nature de grands plutons homogènes et la structure de système magmatique en général. L'emplacement incrémental est mis en évidence et l'existence d'un réservoir intermédiaire en-dessous des plutons homogènes est proposé. Le quatrième chapitre de cette thèse illustre comment utiliser l'information extraite des roches encaissantes pour expliquer la mise en place de l'intrusion. Les températures obtenues par la combinaison des observations de terrain et l'assemblage métamorphique sont utilisées avec des modèles thermiques pour contraindre l'activité magmatique au contact directe de cette auréole. Au lieu d'utiliser le modèle thermique pour vérifier le résultat pétrologique, une approche inverse a été choisie. Les paramètres du modèle ont été changés jusqu'à ce qu'on obtienne une correspondance avec les températures observées dans l'auréole de contact. Ceci montre qu'il y a peu de combinaison qui peuvent expliquer les températures et qu'on peut contraindre la fréquence de l'activité magmatique d'un ancien système magmatique de cette manière. Dans le cinquième chapitre, les processus contrôlant l'anisotropie de la susceptibilité magnétique des roches intrusives sont expliqués à l'aide d'images de la distribution des minéraux dans les roches obtenues par tomographie 3D. Le signal associé à l'anisotropie de la susceptibilité magnétique est une fonction de la forme et de la distribution des grains ferromagnétiques. Ce signal est fréquemment utilisé pour déterminer la direction de mouvement d'un magma. En accord avec d'autres études de la littérature, les résultats montrent que le signal est dominé par la forme des cristaux magnétiques, ainsi que par la distribution des agglomérats de ces minéraux dans la roche. Dans le sixième chapitre, une étude associée à la fusion partielle de carbonates dans les roches encaissantes est présentée. Si la présence de liquides carbonatés dans les auréoles de contact a été proposée sur la base d'expériences de laboratoire, notre étude démontre clairement leur existence dans la nature. La fusion partielle est documentée par des microstructures caractéristiques pour la présence de liquides ainsi que par des données géochimiques et structurales. Les conditions nécessaires sont loin d'être extrêmes et ce processus pourrait être plus fréquent qu'attendu. Les liquides carbonatés sont très mobiles et peuvent circuler le long des limites de grain avant d'infiltrer d'autres roches en produisant une modification de leurs assemblages minéralogiques. Finalement, une curiosité minéralogique est présentée dans le chapitre sept. L'assemblage de minéraux de magnésite et de calcite en équilibre apparent est observé. Il est bien connu que ces deux carbonates ne sont pas stables ensemble dans le système CaO-MgO-FeO-CO.,. En effet, la magnésite et la calcite devraient réagir et produire de la dolomite pendant le métamorphisme. L'explication présentée pour cet assemblage à priori « interdit » est que un liquide carbonaté provenant des roches adjacentes infiltre cette roche et est responsable pour cette microstructure. Une autre implication associée à la présence de carbonates fondus est que la roche encaissante montre une diminution drastique de sa résistance et que les propriétés physiques de cette roche deviennent comparables à celles de la roche intrusive. Cette modification des propriétés rhéologiques des roches encaissantes peut faciliter la mise en place des roches intrusives. Ces différentes études démontrent bien le processus itératif utilisé et l'intérêt d'étudier aussi bien les roches intrusives que les roches encaissantes pour la compréhension des mécanismes de mise en place des magmas au sein de la croûte terrestre.

Characterisation of heteromers and oligomers in the TNF family of ligands and receptors

TNF family ligands and receptors fulfill a number of functions, mainly in the immune system. For example, the ligands BAFF and APRIL control growth and survival of mature Β cells at various stages of differentiation. TNF family ligands usually form homotrimers, but heteromers have also been described for lymphotoxin α1β2 and for BAFF and APRIL. Interestingly, twenty BAFF homotrimers can assemble into virus-like particles coined BAFF 60-mer, which are superior to BAFF 3-mer regarding their ability to signal in primary Β cells. A screen was performed in 293T cells, by co-transfecting differently tagged ligands, to identify six novel heteromers. The specificity of these novel heteromers, however, did not correspond to that of orphan receptors in the TNFR family. Little is known about heteromers of BAFF and APRIL, in particular their receptor-binding specificity and their ability to signal. A method to produce and purify heteromers of defined stoechiometry was developed, and the resulting reagents were used to demonstrate that BAFF2APRIL, like BAFF, binds to all BAFF receptors - namely BAFFR, TACI and Β CM A -, while APRIL2BAFF and APRIL only binds to TACI and BCMA. Heteromers could signal via their cognate receptors, sometimes as potently and sometimes less potently than homomers, depending on the receptors. A promising system to measure the activity of single-chain homo- and heteromers in vivo was set up: it measures mature Β cell rescue upon administration of single-chain ligands into BAFF-ko mice. To tackle the question of the physiological importance of BAFF 60-mer, a point mutation that prevents assembly of mouse BAFF into 60-mer while retaining its ability to form trimers was identified. This mutation (E247K) was introduced by homologous recombination into mouse embryonic stem cells that are now being used to generate knock-in mice. Results obtained in this work will help to better understand the role of various BAFF and APRIL forms that are elevated in a several autoimmune diseases. - Les ligands et récepteurs de la famille du TNF joue un rôle prédominant dans le système immunitaire. Par exemple, les ligands BAFF et APRIL contrôlent la croissance et la survie des cellules Β matures à différents stades de différenciation. Ces ligands existent souvent sous forme d'homotrimères (3-mer), bien que des héteromères aient été décrits pour la lymphotoxine α1β2 et pour BAFF et APRIL. Dans le cas de BAFF, vingt trimères peuvent, telle une particule virale, s'assembler en 60-mer qui surpasse le 3-mer pour signaler dans des cellules Β primaires. Un crible effectué dans des cellules 293T, par co-transfection de ligands différemment marqués, a permis d'identifier six nouveaux heteromères dont la spécificité n'a, hélas, pas correspondu à celle d'un récepteur orphelin de la famille du TNFR. Les connaissances sur la spécificité de liaison aux récepteurs et la capacité à signaler des heteromères de BAFF et d'APRIL sont fragmentaires. Une méthode pour produire et purifier des heteromères "simple chaîne" de stoechiométrie déterminée a été mise au point, et les réactifs ainsi obtenus utilisés pour démontrer que BAFF2APRIL, comme BAFF, lie tous les récepteurs de BAFF - c'est-à-dire BAFFR, TACI et BCMA -, alors qu'APRIL2BAFF et APRIL ne lient que TACI et BCMA. Les héteromères peuvent transmettre des signaux, parfois aussi bien et parfois plus faiblement que les homomères, selon les récepteurs. Un système prometteur pour mesurer l'activité des ligands simple chaîne in vivo a été mis au point. Il mesure la réapparition de cellules Β matures dans des souris déficientes pour BAFF après administration des ligands. Pour s'attaquer à la question de l'importance physiologique du 60-mer de BAFF, ime mutation empêchant l'assemblage en 60-mer sans affecter la capacité à former des trimères a été identifiée. Cette mutation (E247K) a été introduite par recombinaison homologue dans des cellules souches embryonnaires de souris qui sont utilisées pour obtenir des souris déficientes en BAFF 60-mer. Les résultats de ces travaux contribueront à mieux cerner le rôle des différentes formes de BAFF et d'APRIL produites en excès dans plusieurs maladies auto-immunes.