Impulsive differential equations are useful for modelling certain biological events. We present three biological applications showing the use of impulsive differential equations in real-world problems. We also look at the effects of stability on a reduced two-dimensional impulsive HIV system. The first application is a system describing HIV induction-maintenance therapy, which shows how the solution to an impulsive system is used in order to find biological results (adherence, etc). A second application is an HIV system describing the interaction between T-cells, virus and drugs. Stability of the system is determined for a fixed drug level in three specific regions: low, intermediate and high drug levels. Numerical simulations show the effects of varying drug levels on the stability of a system by including an impulse. We reduce these two models to a two-dimensional impulsive model. We show analytically the existence and uniqueness of T-periodic solutions, and show how stability changes when varying the immune response rate, the impulses and a certain nonlinear infection term. The third application shows how seasonal changes can be incorporated into an impulsive differential system of Rift Valley Fever, and looks at how stability may differ when impulses are included. The analysis of impulsive differential systems is crucial in developing more realistic mathematical models for infectious diseases.

La fièvre Q se traduit par de graves conséquences obstétricales chez la femme enceinte. La voie principale de la contamination humaine par Coxiella burnetii, l’agent de la fièvre Q, est constituée des aérosols provenant des placentas d’animaux infectés. La nature des cellules placentaires cibles de C. burnetii reste totalement inconnue. J’ai montré que C. burnetii infecte les trophoblastes des lignées BeWo et JEG et que les bactéries se répliquent fortement dans les cellules BeWo et survivent dans les cellules JEG. Une analyse par microarray montre que C. burnetii induit une réponse inflammatoire dans les cellules BeWo qui lui est spécifique. Ces résultats suggèrent que les trophoblastes pourraient constituer une niche pour C. burnetii. Les macrophages placentaires pourraient également servir de réservoir pour C. burnetii. J’ai montré que les macrophages placentaires CD14+ sont des macrophages qui présentent des caractéristiques phénotypiques, transcriptionnelles et fonctionnelles différentes de celles des monocytes circulants et des macrophages dérivés de monocytes. Ils forment en outre des cellules géantes multinucléées qui pourraient réguler l’activité cytolytique des macrophages dans le contexte placentaire puisque les macrophages placentaires CD14+ ne sont ni de type M1 ni de type M2. / In pregnant women Q fever presents obstetrical complications. The principal way of human contamination by Coxiella burnetii, the agent of Q fever, is due to aerosols from placentas of infected animals. The nature of placenta cells that are targeted by C. burnetii remains unknown. I showed that C. burnetii infects BeWo and JEG trophoblastic cells and that organisms intensively replicated in BeWo cells and survived in JEG cells. A microarray analysis showed that C. burnetii induced a specific inflammatory response in BeWo cells. These results suggest that trophoblasts may serve as a reservoir for C. burnetii. Placenta macrophages placentaires may also targeted by C. burnetii. I showed that placenta CD14+ macrophages were characterized by phenotypic, transcriptional and functional properties different from those of circulating monocytes and monocyte-derived macrophages. In addition, placenta CD14+ macrophages differentiate into multinucleated giant cells that may regulate the cytolytic activity of macrophages in the placenta context since placenta CD14+ macrophages were not polarized in M1 or M2 macrophages. While M1/M2 polarization of macrophages is well established, that of monocytes remains an important question. We activated monocytes with canonical agonists of M1 and M2 profiles in macrophages using microarrays. The early response, 6 hours, of monocytes corresponded to a type M1/M2 response but the delayed response, 18 hours, did not correspond to the M1/M2 dichotomy, demonstrating a new level of heterogeneity of myeloid cells.

Les granulomes signent une réponse immune efficace dans de nombreuses maladies infectieuses. C’est le cas de la fièvre Q où ils sont présents dans la forme aiguë de la maladie spontanément résolutive mais où ils sont absents dans sa forme chronique. J’ai mis au point une méthode permettant d’étudier la formation in vitro des granulomes à partir de cellules mononucléées du sang périphérique incubées en présence de billes de Sepharose recouvertes d’extraits de C. burnetii, l’agent de la fièvre Q. Ces granulomes apparaissent en quelques jours avant de disparaître au bout d’une vingtaine de jours. Ils sont composés essentiellement de macrophages et de lymphocytes et, à un moindre degré, de cellules épithélioïdes, de cellules géantes multinucléées et de cellules dendritiques. La méthode d’obtention in vitro des granulomes a permis également d’étudier les premiers stades de leur formation grâce à la mise au point d’une technique en live imaging d’observation en lumière transmise des cellules. J’ai montré que les monocytes, les premières cellules à migrer vers les billes et à entièrement les recouvrir, initient le recrutement des lymphocytes. J’ai également montré que le défaut de formation des granulomes observés chez des patients atteints d’une fièvre Q chronique pourrait être lié à un défaut de migration de leurs monocytes circulants. / Granulomas indicate effective immune response in a large number of infectious diseases. The primo-infection by Coxiella burnetii, the agent of Q fever, is spontaneously resolutive and is characterized by the presence of granulomas, whereas granulomas are absent in the chronic form of the disease. I developed a new method to study in vitro the formation of granulomas using peripheral blood mononuclear cells incubated in the presence of Sepharose beads coated with C. burnetii extracts. Granulomas appeared in few days before disappearing at day 20. They were essentially composed of macrophages and lymphocytes and, in a lesser extent, of epithelioid cells, multinucleated giant cells and dendritic cells. The method to obtain in vitro granulomas allowed the study of the first events of granuloma formation in live imaging microscopy. Monocytes migrated toward Sepharose beads and entirely covered these beads, and initiated the recruitment of lymphocytes. Finally, mononuclear cells from patients with Q fever were unable to generate granulomas due to defective migration of monocytes. We hypothesize that defective migration of monocytes may be responsible for the defective formation of granulomas in Q fever.

Circulation des Phlébovirus en Turquie, l'Iran et l'Algérie a été étudiée. L'isolement, la caractérisation génomique, les relations phylogénétiques de six virus ont été présentées: le virus Adana (ADAV), deux souches de virus Toros (TORV), le virus Zerdali (ZERV) de la Turquie; le virus Dashli (DASHV) de l'Iran; le virus Toscana (TOSV) d'Algérie. Cette étude a commencé avec la collection de 38,131 phlébotomes de la nature. La méthode de séquençage de nouvelle génération (NGS) à haut débit nous à été utilisée pour l’analyse des génomes complet des virus isoles. En conclusion, cette étude a d'importantes contributions sur phlébovirus négligées. Voici quelques-unes des contributions significatives; (i) ZERV et TORV qui sont étroitement apparentés au virus Tehran (THEV) et le virus Corfou (CFUV), respectivement, ont été isolés depuis 56 et 30 ans des premiers isolements de THEV et CFUV, respectivement, (ii) Détection du virus ADAV un animal domestique et sur quelques sérums humain par test de neutralisation. Ce virus ADAV constitue avec le virus le virus (SALV), le virus Arbia (ARBV), et le virus (ADRV) le groupe Salehabad. Seul le virus ADRV a été détectée dans le liquide cérébro-spinal auparavant landais que avec les autres, aucune preuve pathogène n’a été détectée, (iii) Nous avons découvert la plus récente circulation phlébovirus en Iran après 56 années, (iv) TOSV a été isolé en Algérie pour la première fois et la circulation a été confirmée par séropositivités dans le sérum humain. / Sandfly-borne phlebovirus circulation in Turkey, Iran, and Algeria was investigated. The isolation, genomic characterization, phylogenetic relationships of 6 viruses was presented: Adana virus (ADAV), two strains of Toros virus (TORV), Zerdali virus (ZERV) from Turkey; Dashli virus (DASHV) from Iran; Toscana virus (TOSV) from Algeria. This study has begun with the collection of 38,131 sandflies from nature. The well established, high-throughput methodology was applied for the discovery of viruses including PCR tools and cell culture methods. Next generation sequencing (NGS) technology facilitated to perform complete genome analysis of the isolated viruses. In conclusion, this study has contributions to the neglected sandfly-borne phlebovirus group and filled some gaps about the circulation of these agents in Turkey, Iran, and Algeria. Following are some significant contributions; (i) ZERV and TORV which are closely related to Tehran virus (THEV) and Corfou virus (CFUV), respectively were isolated after 56 and 30 years of the first isolations of THEV and CFUV, respectively, (ii) There was no evidence of the pathogenicity of Salehabad virus (SALV) and Arbia virus (ARBV) except the detection of Adria virus (ADRV) in CSF until ADAV which belongs to the Salehabad serocomplex was detected in domestic animal and very few human sera by neutralization assay, (iii) We have discovered the most recent sandfly-borne phlebovirus circulation in Iran after 56 years, (iv) TOSV was isolated in Algeria for the first time and circulation was confirmed by seropositivities in human sera.

The maturation of the public sphere in Argentina during the late nineteenth and early twentiethcenturies was a critical element in the nation-building process and the overall development ofthe modern state. Within the context of this evolution, the discourse of disease generatedintense debates that subsequently influenced policies that transformed the public spaces ofBuenos Aires and facilitated state intervention within the private domains of the city’sinhabitants. Under the banner of hygiene and public health, municipal officials thusEuropeanized the nation’s capital through the construction of parks and plazas and likewiseutilized the press to garner support for the initiatives that would remedy the unsanitaryconditions and practices of the city. Despite promises to the contrary, the improvements to thepublic spaces of Buenos Aires primarily benefited the porteño elite while the efforts to rootout disease often targeted working-class neighborhoods. The model that reformed the publicspace of Buenos Aires, including its socially differentiated application of aesthetic order andpublic health policies, was ultimately employed throughout the Argentine Republic as theconsolidated political elite rolled out its national program of material and social development.

Casos fatais de Febre Maculosa são registrados no estado do Rio de Janeiro. Avaliou-se o status epidemiológico de riquétsias Grupo Febre Maculosa em cães e ectoparasitas de seis municípios usando métodos imunológico (Reação de Imunofluorescência Indireta) e moleculares (Reação em Cadeia pela Polimerase convencional e em Tempo Real e Análise de Sequências). Avaliou-se a funcionalidade de iniciadores para a região VNTR (Número Variável de Repetições Sequenciais) de Rickettsia rickettsii, para genotipagem de amostras brasileiras. Registraram-se cães sorologicamente positivos em todos os municípios e gene riquetsial (gltA) foi detectado em seus soros, indicando sua importância na epidemiologia de riquétsias na região Metropolitana. R. rickettsii foi diagnosticada em Amblyomma cajennense sugerindo o envolvimento deste no surto com casos fatais do município de Petrópolis. Os iniciadores VNTRB mostraram-se limitados para genotipagem das cepas de R. rickettsii. O estudo evidenciou a necessidade de um sistema de vigilância ambiental contínuo para prevenção de casos fatais. / Spotted Fever fatal cases are reported in Rio de Janeiro state. We evaluated the epidemiological status of Spotted Fever Group Rickettsiae in dogs and ectoparasites of six municipalities using immunological methods (Indirect Immunofluorescence Assay) and molecular (Conventional and Real-Time Polymerase Chain Reaction and Sequence Analysis). We evaluated the functionality of primers for the VNTR region (Variable Number Tandem Repeat) of Rickettsia rickettsii, for brazilian samples genotyping. Dogs serologically positive were registered in all municipalities and riquetsial gene (gltA) was detected in their serum, indicating its importance in rickettsiae epidemiology in Metropolitan region. R. rickettsii was diagnosed in Amblyomma cajennense suggesting an involvement of this species in an outbreak with fatal cases in Petrópolis city. Primers VNTRB proved limited for genotyping R. rickettsii strains. This study highlighted the need for a continuous environmental monitoring system to prevent fatal cases.

La fièvre est la première cause de consultation et d’exposition médicamenteuse chez l’enfant. Les principales molécules utilisées dans cette indication sont le paracétamol et un anti-inflammatoire non stéroïdien (AINS), l’ibuprofène. L’objectif général de cette thèse était de produire des connaissances nouvelles sur les pratiques des parents et des professionnels de santé pour la prise en charge symptomatique, notamment médicamenteuse, de la fièvre chez l’enfant. Les données étaient issues d’une étude transversale nationale menée entre 2007 et 2008, où 1534 médecins généralistes, pédiatres et pharmaciens (taux de participation 13%) ont inclus 6596 enfants avec une fièvre < 48h. Les analyses ont notamment utilisé des modèles multi-niveau multivariés. Les connaissances et les pratiques des parents et des professionnels étaient fréquemment discordantes par rapport aux recommandations, notamment pour la mise en œuvre des mesures antipyrétiques. Les principaux déterminants de pratiques non concordantes aux recommandations étaient un faible niveau d’études des parents, un âge élevé de l’enfant et la formation initiale de généraliste du professionnel consulté. Pour les enfants ayant reçu du paracétamol, un recours important aux suppositoires a été observé, y compris chez les enfants âgés et sans vomissement. Les parents utilisaient beaucoup plus d’AINS que les professionnels de santé et ce gradient augmentait dans des situations potentiellement à risque d’effet indésirable. Nos résultats montrent la nécessité d’actions d’éducation à la santé et de formation médicale continue pour la prise en charge de la fièvre de l’enfant et permettent de cerner les messages prioritaires. / Fever is the first reason for consultation and drug treatment in children in primary care. Main drugs used in this indication are acetaminophen and a non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen. The objective of this thesis was to produce new knowledge on parents’ and healthcare professionals' (HPs) practices for the symptomatic treatment of fever in children with a focus on drug treatments. We used data from an observational, cross-sectional, national study performed from October 2007 to June 2008, where 1,534 general practitioners, primary care pediatricians, and pharmacists (participation rate 13%) included 6,596 children with fever < 48 hr. Analyses used notably multivariate multilevel models.Knowledge and practices of parents and HPs were frequently discordant with recommendations, notably for antipyretic measures. The main determinants of discordant practices were a low parental educational level, an older child’s age and the healthcare professional being a general practitioner. Among children who received acetaminophen, a large use of suppositories has been observed, including for non-vomiting and/or older children. Parents used more NSAIDs than HPs, and this gradient increased in clinical conditions potentially at risk of adverse effect. Our results highlight the need for health education interventions and continuing medical training on fever management in children, and enable to identify priority messages.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22327号 / 医博第4568号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 江藤 浩之, 教授 生田 宏一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Les nourrissons âgés de moins de trois mois ont la particularité d’être à relativement haut risque d’infections bactériennes sévères (IBS), majoritairement représentées par les infections urinaires et en particulier celles plus invasives (IBI) que sont les méningites et les bactériémies. On ne dispose actuellement pas d’outil suffisamment fiable et d’un rapport coût-bénéfice bien évalué pour différencier les nourrissons fébriles porteurs d’une affection virale banale de ceux porteurs d’une infection bactérienne.Le travail doctoral avait pour objectifs d’évaluer l’épidémiologie et les pratiques de prise en charge françaises des infections bactériennes de l’enfant fébrile âgé de moins de trois mois admis aux urgences pédiatriques ainsi que des outils diagnostiques, tels que la bandelette urinaire et la procalcitonine dans cette population. Plus de 2000 nourrissons ont été inclus dans une étude prospective observationnelle multicentrique (PRONOUR) sur une période de trente mois d’octobre 2008 à Mars 2011.Nous avons dans un premier temps décrit les modalités de prise en charge de ces jeunes nourrissons fébriles et montré que les pratiques étaient hétérogènes entre les centres participants et variaient par rapport aux recommandations existantes.Nous avons dans un second temps, étudié les pratiques de dépistage des infections urinaires, IBS la plus fréquente dans cette tranche d’âge, et en particulier les performances de la bandelette urinaire. La majorité des urines étaient prélevées par poche collectrice et la bandelette urinaire avait une sensibilité pour la détection d’infection urinaire comparable à celle de l’analyse par microscopie avec cette méthode de recueil.Puis, nous avons réévalué les performances des algorithmes décisionnels existants pour la détection des enfants à faible risque d’IBS dans une nouvelle population (PRONOUR). Nous avons montré qu’ils avaient une valeur prédictive négative satisfaisante comme précédemment décrit, mais une faible valeur prédictive positive pour la distinction des enfants porteurs ou non d’une IBS.Enfin, les performances de la procalcitonine (PCT) dans la détection des IBS et IBI ont été calculées et comparées avec celles d’autres marqueurs inflammatoires usuels. La capacité discriminative de la PCT était excellente pour le diagnostique d’IBI et meilleure que celles des autres marqueurs inflammatoires. Pour la détection d’une IBS, la PCT avait des performances similaires à celles de la C-réactive protein.La prise en charge des nourrissons fébriles âgés de moins de trois mois est hétérogène et pourrait être améliorée par de nouveaux outils prédictifs La prise en charge des nourrissons fébriles âgés de moins de trois mois est hétérogène et pourrait être améliorée par de nouveaux outils prédictifs tels que l’utilisation de la procalcitonine et de la bandelette urinaire dans cette tranche d’âge. / The prevalence of severe bacterial infections (SBI),mainly represented by urinary tract infections is relatively high in infants less than three months of age and particularly those more invasive (IBI) that are meningitis and bacteremia. Current strategies to distinguish young infants with SBIs from those with viral infections are not absolutely reliable and their cost-effectiveness and the associated iatrogenic morbidity have not been extensively evaluated.The purposes of the study were to characterize the spectrum of disease, clinical outcomes and management of febrile infants aged three months or younger admitted to pediatric emergency department in France and to evaluate the performances of diagnostics tests that are urinary dipstick test and procalcitonin assay in this population. A prospective multicenter cohort study was conducted in 15 French pediatric emergency departments over a period of 30 months between October 2008 and March 2011(PRONOUR). More than 2000 infants were enrolled.First, we have described the management of these young febrile infants. We have showed that practices were heterogeneous between the participating centers and varied from the current guidelines.We have analyzed screening strategies of urinary tract infection, the most common SBI in this age group, and in particular we aimed to assess the test performances of urine dipstick test. Most of urine specimens were collected by bag. Dipstick tests on bag urine samples detected urinary tract infections in infants aged 7 to 92 days similarly to microscopy.Then, we have re-evaluated the performances of current strategies for identifying infants at low risk for SBI in a new population (PRONOUR). We have showed that current protocols maintained their good previously reported negative predictive values but have low positive predictive values to detect young infants with SBIs.Finally, the performances parameters of procalcitonine (PCT) for detecting SBI and IBI in this population were calculated and compared with usual biomarkers. Procalcitonin has better diagnostic accuracy than CRP for detecting IBI. The two tests perform similarly for identifying SBI in febrile infants aged 7 to 91 days.The management of febrile infants less than three months of age varied between centers should be improved by new predictive tests. The performance of PCT testing should encourage the development of decision-making rules incorporating PCT and urinary dipstick test.

My diploma thesis deals with the legislation of veterinary care. In doing so, I tried to provide a clear and comprehensive overview of all the institutes and essentials that relate to it. Many uninformed people could mistakenly assume that this topic covers solely animal healthcare. Although it is also an integral part of the topic we do not find so much material here; the concept of veterinary work goes beyond that. Within 5 chapters we will learn not only historical contexts of development, but also international conventions or organizations. We will compare the Czech Leagl norms against the Slovak ones. An integral part of the thesis is a brief overview of sources of EU law, both primary and secondary, as well as their historical development. "Welfare", or ensuring animal welfare, is a rather new concept, but a highly important one. Thanks to animal welfare, we have begun to pay attention to animal health both physically and mentally. It was therefore obvious that this topic was briefly addressed, especially its development and implementation. The concept of "an animal" related to this topic has not been not neglected, especially in how the view of the animal has changed in recent years by amending the Civil Code. Since the topic of the diploma thesis is to concern mainly legal regulations, I...