Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Background The ability of T cells, acting independently of antibodies, to control malaria parasite growth in people has not been defined. If such cell-mediated immunity was shown to be effective, an additional vaccine strategy could be pursued. Our aim was to ascertain whether or not development of cell-mediated immunity to Plasmodium falciparum blood-stage infection could be induced in human beings by exposure to malaria parasites in very low density. Methods We enrolled five volunteers from the staff at our research institute who had never had malaria. We used a cryopreserved inoculum of red cells infected with P falciparum strain 3D7 to give them repeated subclinical infections of malaria that we then cured early with drugs, to induce cell-mediated immune responses. We tested for development of immunity by measurement of parasite concentrations in the blood of volunteers by PCR of the multicopy gene STEVOR and by following up the volunteers clinically, and by measuring antibody and cellular immune responses to the parasite. Findings After challenge and a extended period without drug cure, volunteers were protected against malaria as indicated by absence of parasites or parasite DNA in the blood, and absence of clinical symptoms. Immunity was characterised by absence of detectable antibodies that bind the parasite or infected red cells, but by the presence of a proliferative T-cell response, involving CD4+ and CD8+ T cells, a cytokine response, consisting of interferon gamma but not interleukin 4 or interleukin 10, induction of high concentrations of nitric oxide synthase activity in peripheral blood mononuclear cells, and a drop in the number of peripheral natural killer T cells. Interpretation People can be protected against the erythrocytic stage of malaria by a strong cell-mediated immune response, in the absence of detectable parasite-specific antibodies, suggesting an additional strategy for development of a malaria vaccine.

O papel do/a educador/a de infância na integração de uma criança cujo português é língua não materna

Relatório apresentado à Escola Superior de Educação de Lisboa para obtenção de grau de mestre em Educação Pré-Escolar

O impacto da auditoria interna no desempenho organizacional – estudo de caso das 65 maiores empresas a atuarem em Portugal

Dissertação de Mestrado apresentado ao Instituto Superior de Contabilidade e Administração do Porto para a obtenção do grau de Mestre em Auditoria, sob orientação das docentes Doutora Alcina Dias e Doutora Ana Paula Lopes

Atteintes cardiaques dans les connectivites: l'exemple du lupus érythémateux systémique [Cardiac involvement in connective tissue disease: the example of systemic lupus erythematosus]

When we think of cardiac affection in the context of systemic lupus erythematosus (SLE), we usually refer to pericarditis first. As frequent as this affection is, it is actually not the only cardio-vascular problem that occurs with this systemic inflammatory disease. Are the cardiac events--ranging from multiple heart valve involvements to increased cardiovascular risks--clinically significant? And are they involving a specific follow-up, treatment or support? We are therefore trying to evaluate these questions in order to give some recommendations to any practitioners following up a lupus patient, or a patient suffering from any other inflammatory systemic disease.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻&supl;³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Les symbioses agro-industrielles en Afrique de l'Ouest : évaluation du potentiel d'une nouvelle stratégie pour un développement durable

RésuméCette thèse traite de l'utilisation des concepts de Symbiose Industrielle dans les pays en développement et étudie le potentiel de cette stratégie pour stimuler un développement régional durable dans les zones rurales d'Afrique de l'Ouest. En particulier, lorsqu'une Symbiose Industrielle est instaurée entre une usine et sa population alentour, des outils d'évaluation sont nécessaires pour garantir que le projet permette d'atteindre un réel développement durable. Les outils existants, développés dans les pays industrialisés, ne sont cependant pas complètement adaptés pour l'évaluation de projets dans les pays en développement. En effet, les outils sont porteurs d'hypothèses implicites propres au contexte socio-économique dans lequel ils ont été conçus.L'objectif de cette thèse est de développer un cadre méthodologique pour l'évaluation de la durabilité de projets de Symbiose Industrielle dans les pays en développement.Pour ce faire, je m'appuie sur une étude de cas de la mise en place d'une Symbiose Industrielle au nord du Nigéria, à laquelle j'ai participé en tant qu'observatrice dès 2007. AshakaCem, une usine productrice de ciment du groupe Lafarge, doit faire face à de nombreuses tensions avec la population rurale alentour. L'entreprise a donc décidé d'adopter une nouvelle méthode inspirée des concepts de Symbiose Industrielle. Le projet consiste à remplacer jusqu'à 10% du carburant fossile utilisé pour la cuisson de la matière crue (calcaire et additifs) par de la biomasse produite par les paysans locaux. Pour ne pas compromettre la fragile sécurité alimentaire régionale, des techniques de lutte contre l'érosion et de fertilisation naturelle des sols sont enseignées aux paysans, qui peuvent ainsi utiliser la culture de biomasse pour améliorer leurs cultures vivrières. A travers cette Symbiose Industrielle, l'entreprise poursuit des objectifs sociaux (poser les bases nécessaires à un développement régional), mais également environnementaux (réduire ses émissions de CO2 globales) et économiques (réduire ses coûts énergétiques). Elle s'ancre ainsi dans une perspective de développement durable qui est conditionnelle à la réalisation du projet.A travers l'observation de cette Symbiose et par la connaissance des outils existants je constate qu'une évaluation de la durabilité de projets dans les pays en développement nécessite l'utilisation de critères d'évaluation propres à chaque projet. En effet, dans ce contexte, l'emploi de critères génériques apporte une évaluation trop éloignée des besoins et de la réalité locale. C'est pourquoi, en m'inspirant des outils internationalement reconnus comme l'Analyse du Cycle de Vie ou la Global Reporting Initiative, je définis dans cette thèse un cadre méthodologique qui peut, lui, être identique pour tous les projets. Cette stratégie suit six étapes, qui se réalisent de manière itérative pour permettre une auto¬amélioration de la méthodologie d'évaluation et du projet lui-même. Au cours de ces étapes, les besoins et objectifs en termes sociaux, économiques et environnementaux des différents acteurs sont déterminés, puis regroupés, hiérarchisés et formulés sous forme de critères à évaluer. Des indicateurs quantitatifs ou qualitatifs sont ensuite définis pour chacun de ces critères. Une des spécificités de cette stratégie est de définir une échelle d'évaluation en cinq graduations, identique pour chaque indicateur, témoignant d'un objectif totalement atteint (++) ou pas du tout atteint (--).L'application de ce cadre méthodologique à la Symbiose nigériane a permis de déterminer quatre critères économiques, quatre critères socio-économiques et six critères environnementaux à évaluer. Pour les caractériser, 22 indicateurs ont été définis. L'évaluation de ces indicateurs a permis de montrer que le projet élaboré atteint les objectifs de durabilité fixés pour la majorité des critères. Quatre indicateurs ont un résultat neutre (0), et un cinquième montre qu'un critère n'est pas atteint (--). Ces résultats s'expliquent par le fait que le projet n'en est encore qu'à sa phase pilote et n'a donc pas encore atteint la taille et la diffusion optimales. Un suivi sur plusieurs années permettra de garantir que ces manques seront comblés.Le cadre méthodologique que j'ai développé dans cette thèse est un outil d'évaluation participatif qui pourra être utilisé dans un contexte plus large que celui des pays en développement. Son caractère générique en fait un très bon outil pour la définition de critères et indicateurs de suivi de projet en terme de développement durable.SummaryThis thesis examines the use of industrial symbiosis in developing countries and studies its potential to stimulate sustainable regional development in rural areas across Western Africa. In particular, when industrial symbiosis is instituted between a factory and the surrounding population, evaluation tools are required to ensure the project achieves truly sustainable development. Existing tools developed in industrialized countries are not entirely suited to assessing projects in developing countries. Indeed, the implicit hypotheses behind such tools reflect the socioeconomic context in which they were designed. The goal of this thesis is to develop a methodological framework for evaluating the sustainability of industrial symbiosis projects in developing countries.To accomplish this, I followed a case study about the implementation of industrial symbiosis in northern Nigeria by participating as an observer since 2007. AshakaCem, a cement works of Lafarge group, must confront many issues associated with violence committed by the local rural population. Thus, the company decided to adopt a new approach inspired by the concepts of industrial symbiosis.The project involves replacing up to 10% of the fossil fuel used to heat limestone with biomass produced by local farmers. To avoid jeopardizing the fragile security of regional food supplies, farmers are taught ways to combat erosion and naturally fertilize the soil. They can then use biomass cultivation to improve their subsistence crops. Through this industrial symbiosis, AshakaCem follows social objectives (to lay the necessary foundations for regional development), but also environmental ones (to reduce its overall CO2 emissions) and economical ones (to reduce its energy costs). The company is firmly rooted in a view of sustainable development that is conditional upon the project's execution.By observing this symbiosis and by being familiar with existing tools, I note that assessing the sustainability of projects in developing countries requires using evaluation criteria that are specific to each project. Indeed, using generic criteria results in an assessment that is too far removed from what is needed and from the local reality. Thus, by drawing inspiration from such internationally known tools as Life Cycle Analysis and the Global Reporting Initiative, I define a generic methodological framework for the participative establishment of an evaluation methodology specific to each project.The strategy follows six phases that are fulfilled iteratively so as to improve the evaluation methodology and the project itself as it moves forward. During these phases, the social, economic, and environmental needs and objectives of the stakeholders are identified, grouped, ranked, and expressed as criteria for evaluation. Quantitative or qualitative indicators are then defined for each of these criteria. One of the characteristics of this strategy is to define a five-point evaluation scale, the same for each indicator, to reflect a goal that was completely reached (++) or not reached at all (--).Applying the methodological framework to the Nigerian symbiosis yielded four economic criteria, four socioeconomic criteria, and six environmental criteria to assess. A total of 22 indicators were defined to characterize the criteria. Evaluating these indicators made it possible to show that the project meets the sustainability goals set for the majority of criteria. Four indicators had a neutral result (0); a fifth showed that one criterion had not been met (--). These results can be explained by the fact that the project is still only in its pilot phase and, therefore, still has not reached its optimum size and scope. Following up over several years will make it possible to ensure these gaps will be filled.The methodological framework presented in this thesis is a highly effective tool that can be used in a broader context than developing countries. Its generic nature makes it a very good tool for defining criteria and follow-up indicators for sustainable development.

Incremento de la participación de Atención Primaria en la asistencia al virus de la inmunodeficiencia humana: opinan los profesionales de las unidades hospitalarias.

AIM To determine the opinions of infectious diseases professionals on the possibilities of monitoring patients with HIV in Primary Care. DESIGN Qualitative study using in-depth interviews. LOCATION Infectious Diseases Unit in the University Hospital "Virgen de la Victoria" in Málaga. PARTICIPANTS Health professionals with more than one year experience working in infectious diseases. A total of 25 respondents: 5 doctors, 15 nurses and 5 nursing assistants. METHOD Convenience sample. Semi-structured interviews were used that were later transcribed verbatim. Content analysis was performed according to the Taylor and Bogdan approach with computer support. Validation of information was made through additional analysis, expert participation, and feedback of part of the results to the participants. RESULTS Hospital care professionals considered the disease-related complexity of HIV, treatment and social aspects that may have an effect on the organizational level of care. Professionals highlighted the benefits of specialized care, although opinions differed between doctors and nurses as regards follow up in Primary Care. Some concerns emerged about the level of training, confidentiality and workload in Primary Care, although they mentioned potential advantages related to accessibility of patients. CONCLUSIONS Physicians perceive difficulties in following up HIV patients in Primary Care, even for those patients with a good control of their disease. Nurses and nursing assistants are more open to this possibility due to the proximity to home and health promotion in Primary Care.

Cost-effectiveness analysis of the first-line therapies for nicotine dependence.

BACKGROUND: Nicotine dependence is the major obstacle for smokers who want to quit. Guidelines have identified five effective first-line therapies, four nicotine replacement therapies (NRTs)--gum, patch, nasal spray and inhaler--and bupropion. Studying the extent to which these various treatments are cost-effective requires additional research. OBJECTIVES: To determine cost-effectiveness (CE) ratios of pharmacotherapies for nicotine dependence provided by general practitioners (GPs) during routine visits as an adjunct to cessation counselling. METHODS: We used a Markov model to generate two cohorts of one-pack-a-day smokers: (1) the reference cohort received only cessation counselling from a GP during routine office visits; (2) the second cohort received the same counselling plus an offer to use a pharmacological treatment to help them quit smoking. The effectiveness of adjunctive therapy was expressed in terms of the resultant differential in mortality rate between the two cohorts. Data on the effectiveness of therapies came from meta-analyses, and we used odds ratio for quitting as the measure of effectiveness. The costs of pharmacotherapies were based on the cost of the additional time spent by GPs offering, prescribing and following-up treatment, and on the retail prices of the therapies. We used the third-party-payer perspective. Results are expressed as the incremental cost per life-year saved. RESULTS: The cost per life-year saved for only counselling ranged from Euro 385 to Euro 622 for men and from Euro 468 to Euro 796 for women. The CE ratios for the five pharmacological treatments varied from Euro 1768 to Euro 6879 for men, and from Euro 2146 to Euro 8799 for women. Significant variations in CE ratios among the five treatments were primarily due to differences in retail prices. The most cost-effective treatments were bupropion and the patch, and, then, in descending order, the spray, the inhaler and, lastly, gum. Differences in CE between men and women across treatments were due to the shape of their respective mortality curve. The lowest CE ratio in men was for the 45- to 49-year-old group and for women in the 50- to 54-year-old group. Sensitivity analysis showed that changes in treatment efficacy produced effects only for less-well proven treatments (spray, inhaler, and bupropion) and revealed a strong influence of the discount rate and natural quit rate on the CE of pharmacological treatments. CONCLUSION: The CE of first-line treatments for nicotine dependence varied widely with age and sex and was sensitive to the assumption for the natural quit rate. Bupropion and the nicotine patch were the two most cost-effective treatments.

Définir le risque du carcinome spinocellulaire: rôle de la clinique et du rapport anatomopathologique [Risk of cutaneous squamous cell carcinomas: the role of clinical and pathological reports].

The history of most cutaneous squamous cell carcinomas (CSCC) is limited to the skin. However, about 4% of these malignancies are at risk of metastasis and can be life-threatening. This risk is determined by clinical and histological elements which are individually recognized, but so far staging systems allow us neither to assess a risk score, nor to adopt a standardized therapeutical approach. This article reviews prognostic factors for CSCC, and underlines the need for the clinician to have all clinical and histological elements available, in order to try to define the best therapeutical strategy for each case, following up-to-date recommendations.

Puheenaiheiden esittely ja jatkaminen lääkärin vastaanotolla

Summary: Iniating and following up topics in doctor-patient interaction

Teoría de la comunicación y paisaje. Las geografías del sujeto y la perspectiva interpretativa de la comunicación

El estudio de las implicaciones comunicativas presentes en el paisaje tangible e intangible circundante abre un amplio abanico de posibilidades para el tratamiento de la denominada comunicación en el paisaje. El análisis de los efectos que el entorno genera en los procesos de comunicación humana, el seguimiento de los procesos comunicativos mediante los cuales se mercadea con el paisaje, la construcción de imaginarios individuales y colectivos a partir de la interacción ciudadanía-territorio, el tránsito de espacio a lugar y, más recientemente, la habilitación de identidades territoriales a partir de la construcción de una imagen de marca de ciudad o de país –léase promoción turística, citymarketing y/o branding, entre otros– presentan, en todos los casos, amplias connotaciones de alcance comunicativo. La búsqueda del mensaje presente en el paisaje plantea, en este mismo sentido, el tratamiento del espacio a modo de sistema de comunicación. En cualquier caso, parece claro que, en los últimos tiempos, asistimos a una cierta eclosión de procesos de comunicación concebidos desde la realidad existente en el espacio y más aún, en el paisaje, por lo que se hace necesario avanzar hacia un tratado comunicativo del paisaje.

Forensic processing of false identity and travel documents to produce intelligence: a novel approach to assist in fighting organized crime

The production and use of false identity and travel documents in organized crime represent a serious and evolving threat. However, a case-by-case perspective, thus suffering from linkage blindness and a limited analysis capacity, essentially drives the present-day fight against this criminal problem. To assist in overcoming these limitations, a process model was developed using a forensic perspective. It guides the systematic analysis and management of seized false documents to generate forensic intelligence that supports strategic and tactical decision-making in an intelligence-led policing approach. The model is articulated on a three-level architecture that aims to assist in detecting and following-up on general trends, production methods and links between cases or series. Using analyses of a large dataset of counterfeit and forged identity and travel documents, it is possible to illustrate the model, its three levels and their contribution. Examples will point out how the proposed approach assists in detecting emerging trends, in evaluating the black market's degree of structure, in uncovering criminal networks, in monitoring the quality of false documents, and in identifying their weaknesses to orient the conception of more secured travel and identity documents. The process model proposed is thought to have a general application in forensic science and can readily be transposed to other fields of study.

Varastonhallintakäytäntöjen kehittäminen maahantuontia harjoittavalle pienyritykselle

Työn tavoitteet liittyivät varastonhallintakäytäntöjen kehittämiseen sekä tämän seurantaan ja ylläpitoon liittyvien työvälineiden luomiseen. Päätutkimuskysymyksenä oli: 'Miten varastonhallintakäytäntöä kannattaisi parantaa, niin että nykyisillä resursseilla saavutettaisiin kustannussäästöjä asiakkaan palvelutasoa alentamatta?' Keskeinen teoreettinen sisältö liittyy varastonhallintakäytäntöihin. Tämä käsitellään varastonhallinnan perusteiden, varastonohjauksen, suorituskyvyn arvioinnin sekä varastonhallintakäytännön muutosprosessin avulla. Empiirinen osuus suoritetaan kohdeyrityksen logistisen muutosprosessimallin läpiviemisen avulla sisältäen tunnuslukuja, täydennysmenetelmiä, tuoteluokittelua ja muita analyyseja. Muutosprosessin vaiheet ovat edellytysten selvittäminen, nykytilan kuvaus ja analysointi, vaihtoehtoisten ratkaisujen ehdottaminen, nykytilan vertailu ratkaisuehdotelmiin, yhden ratkaisun valitseminen, muutoksen läpivienti ja lopputulosten seuranta. Työn keskeiset tulokset ovat erilaisten varastonhallintaan liittyvien tunnuslukujen laskeminen, tuoteluokittelun suorittaminen, täydennysmenetelmiin kuuluvien kaavojen luominen, varastokartan laatiminen ja toimintavaihtoehtojen esittely. Viimeiseen sisältyy oman muokatun kohdeyritykselle soveltuvan ¿voi tilata¿ täydennysmenetelmän laatiminen, ehdotuksen tekeminen liikkumattomien nimikkeiden eroon pääsemisestä, nimikkeiden uudelleensijoittaminen varastoon laaditun varastokartan mukaisesti, uuden työjaonluominen, muutosehdotuksen säännöllinen seuranta ja uusien tavoitteiden asettaminen sekä koulutustarpeeseen ja tietojärjestelmän kehittämiseen liittyvien ehdotusten tekeminen emoyhtiölle.

KUNNOSSAPIDON SUORITUSKYVYN SEURANTA JA KEHITTÄMINEN

Työn tavoitteena oli kehittää kunnossapitoyritykselle toiminnan tuottavuuden ja tehokkuuden mittausjärjestelmä. Ensin etsittiin teorian avulla ne sopivat suorituskykymittarit ja tekijät, joiden avulla yrityksen suorituskykyä voidaan luotettavasti ja ymmärrettävästi seurata. Apuna työnkulussa käytettiin kunnossapidon henkilökunnalle suunnattuja kirjallisia ja suullisia haastatteluja. Haastatteluiden avulla selvitettiin kunnossapidon suorituskyvyn mittauksen nykytila sekä mahdollisia kehityskohteita. Haastatteluihin ja kirjallisuuteen pohjautuen päätettiin yritykselle rakentaa suorituskykymittaristo. Mittaristoksi valittiin tuottavuus- eli tavoitematriisi, joka on toimiva työkalu mittareiden seurantaan. Se on helppokäyttöinen ja selkeä. Lisäksi matriisi antaa tulosindeksin avulla kokonaiskuvan kunnossapidon tasosta. Tavoitematriisi koostuu eri menestystekijöistä sekä näiden menestystekijöiden tunnusluvuista eli mittareista. Menestystekijöiksi valittiin: taloudellisuus, tuotantojärjestelmän tehokkuus, kustannusrakenne, kunnossapidon suunnittelu sekä häiriönkorjaus. Menestystekijöillä on jokaisella kolmesta kuuteen mittaria. Tavoitematriisin käyttö ja seuranta tapahtuu yksinkertaisen sovellusohjelman avulla. Mittariston kehittäminen on pitkä ja vaativa prosessi. Mittareita, niiden tavoitearvoja sekä menestystekijöitä tulee säännöllisin väliajoin tarkastaa, jotta kehitys on oikean suuntaista. Mittariston käyttöönotto ja käyttö edellyttävät kaikilta työntekijöiltä motivaatiota toiminnan kehitykseen sekä pitkäjänteisyyttä, sillä matriisin tarjoamat hyödyt ovat näkyvissä vasta kuukausien päästä.

Studies on 68Ga-Based Agents for PET Imaging of Cancer and Inflammation

Studies on up>68up>Ga-Based Agents for PET Imaging of Cancer and Inflammation Positron emission tomography (PET) is based on the use of radiolabeled agents and facilitates in vivo imaging of biological processes, such as cancer. Because the detection of cancer is demanding and is often obscured by inflammation, there is a demand for better PET imaging agents. The aim was to preliminarily evaluate new PET agents for imaging cancer and inflammation using experimental models. up>68up>Ga-chloride and peptides, up>68up>Ga-labeled through 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), targeting matrix metalloproteinase-9 (MMP-9) were tested for tumor imaging. In addition, a up>68up>Ga-DOTA-conjugated peptide targeting vascular adhesion protein-1 (VAP-1), was tested for inflammation imaging. The up>68up>Ga-based imaging agents described here showed potential features by passing the essential in vitro tests, proceeding further to preclinical in vivo evaluation and being able to visualize the target. The target uptake and target-to-background ratios of up>68up>Ga-based agents were, however, not optimal. up>68up>Ga-chloride showed slow clearance caused by its binding to blood transferrin. In the case of up>68up>Ga-DOTA-peptides low in vivo stability and/or low lipophilicity led to too rapid blood clearance and urinary excretion. The properties of up>68up>Ga-labeled peptides are modifiable, as shown with matrix metalloproteinase-9 targeting ligands. In the conclusion of this PhD thesis, up>68up>Ga-based agents for PET imaging of cancer and inflammation could be applied in the development of drugs, earlier diagnostics and following-up of the efficacy of therapies.