Objective: Describe the prevalence of Bordetella pertussis via PCR in children under 5 years old hospitalized as probable cases of pertussis and report the most common clinical features among them. Results: A positive PCR result for B. pertussis was observed in 20.5% of our samples (18/88), one-third of them were from infants between 2 and 3 months old. The most common symptoms were paroxysms of coughing (88.9%), difficulty breathing (72.2%), cyanosis (77.8%) and fever (50%). The mother was the most common symptomatic carrier (27.8%), followed by uncles/aunts (22.2%) among children with pertussis. / This work was supported by fourth research incentive of the Universidad Peruana de Ciencias Aplicadas (UPC), Lima‑Peru. / Revisión por pares

Orientador: Maria Marluce dos Santos Vilela / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T01:20:12Z (GMT). No. of bitstreams: 1 Zorzeto_TatianeQueiroz_M.pdf: 1695884 bytes, checksum: 267f0534bc256440762ad9d78bc6402d (MD5) Previous issue date: 2008 / Resumo: A associação temporal de eventos adversos de variada gravidade à imunização com pertussis celular total (DTP) tem estimulado o desenvolvimento de vacinas antipertussis menos reatogênicas. Este ensaio clínico fase I visou à avaliação da imunogenicidade da vacina pertussis celular modificada pela extração do lipopolissacarídeo (DTPm) em comparação com a vacina convencional (DTP). Um total de 234 lactentes foi imunizado aos dois, quatro e seis meses de idade com DTPm ou DTP. Os títulos de anticorpos para os componentes pertussis, tétano, difteria e hepatite B foram determinados um mês após a terceira dose de vacina. A proliferação de células T CD3+ foi avaliada por citometria de fluxo após seis dias de cultivo de células mononucleares de sangue periférico estimuladas com células inativadas de B. pertussis ou com fitohemaglutinina (PHA). Células CD4+, CD8+ e TCR ?d+ foram identificadas no gate de blastos. Os níveis de IFN-?, TNF-a, IL-4 e IL-10 no sobrenadante de cultura foram quantificados por ensaio imunoenzimático (ELISA). A vacina modificada DTPm mostrou-se inferior à DTP quanto ao título de anticorpos antipertussis, mas não houve diferença de resposta aos outros componentes vacinais avaliados. A porcentagem líquida de blastos sob estímulo da B. pertussis foi menor no grupo que recebeu três doses de DTPm (mediana de 3,9% para DTPm e 6,2% para DTP, p=0,029), mas as freqüências de células CD4+, CD8+ e ?d+ em proliferação e as concentrações de citocinas não diferiram entre os grupos. A vacina DTPm não apresentou, portanto, imunogenicidade similar à da vacina DTP convencional nos ensaios laboratoriais / Abstract: Concerns about systemic reactions after immunization with whole-cell pertussis (wP) have stimulated efforts to produce less reactogenic vaccines. This phase I comparative trial aimed the efficacy evaluation of a cellular pertussis vaccine with low lipopolysaccharide (LPS) content (wPlow) in comparison to conventional wP vaccine. A total of 234 infants was vaccinated at 2, 4, and 6 months with conventional wP or wPlow. Serum antibody titers to pertussis, diphtheria, tetanus and hepatitis B were measured 1 month after the third dose of vaccine. Proliferation of CD3+ T cells was evaluated by flow cytometry after 6 days of peripheral blood mononuclear cells culture, with heat-killed B. pertussis or phytohemagglutinin (PHA) stimulation. CD4+, CD8+ and TCR ?d+ cells were identified in the gate of blast lymphocytes. IFN-?, TNF-a, IL-4 and IL-10 levels in supernatants were determined by ELISA. wPlow was inferior to wP in terms of anti-pertussis titers, but there was no diference in other serum antibody evaluations. Net percent blasts in cultures with B. pertussis was lower in the group vaccinated with wPlow (medians of 3.9% and for wPlow and 6.2% for wP; p=0.029), but the frequency of proliferating CD4+, CD8+ and ?d+ cells and the cytokine concentrations in supernatants were similar between vaccination groups. Therefore, wPlow wasn't as imunogenic as conventional wP in experimental evaluations / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

This thesis is concerned with quantifying the dynamical role of stochasticity in models of recurrent epidemics. Although the simulation of stochastic models can accurately capture the qualitative epidemic patterns of childhood diseases, there is still considerable discussion concerning the basic mechanisms generating these patterns. The novel aspect of this thesis is the use of analytic methods to quantify the results from simulations. All the models are formulated as continuous time Markov processes, the temporal evolutions of which is described by a master equation. This is expanded in the inverse system size, which decomposes the full stochastic dynamics into a macroscopic part, described by deterministic equations, plus a stochastic fluctuating part. The first part examines the inclusion of non-exponential latent and infectious periods into the the standard susceptible-infectious-recovered model. The method of stages is used to formulate the problem as a Markov process and thus derive a power spectrum for the stochastic oscillations. This model is used to understand the dynamics of whooping cough, which we show to be the mixture of an annual limit cycle plus resonant stochastic oscillations. This limit cycle is generated by the time-dependent external forcing, but we show that the spectrum is close to that predicted by the unforced model. It is demonstrated that adding distributed infectious periods only changes the frequency and amplitude of the stochastic oscillations---the basic mechanisms remain the same. In the final part of this thesis, the effect of seasonal forcing is studied with an analysis of the full time-dependent master equation. The comprehensive nature of this approach allows us to give a coherent picture of the dynamics which unifies past work, but which also provides a systematic method for predicting the periods of oscillations seen in measles epidemics. In the pre-vaccination regime the dynamics are dominated by a period doubling bifurcation, which leads to large biennial oscillations in the deterministic dynamics. Vaccination is shown to move the system away from the biennial limit cycle and into a region where there is an annual limit cycle and stochastic oscillations, similar to whooping cough. Finite size effects are investigated and found to be of considerable importance for measles dynamics, especially in the biennial regime.

Background: Little is known about whether there are any longer-term adverse health effects in children following Tdap (tetanus, diphtheria, and acellular pertussis) vaccination during pregnancy. Objective: To assess the association between maternal Tdap vaccination during pregnancy and risk of the following early childhood adverse health outcomes: (1) infections (upper and lower respiratory tract infections, gastrointestinal infections, and otitis media), (2) pediatric asthma, (3) neoplasm, (4) vision or hearing loss, and (5) urgent and in-patient health services utilization. Methods: This retrospective cohort study used multiple linked health administrative databases in the province of Ontario, Canada containing vaccine information in mothers and information on health outcomes in their children up to age 6 years. Infants exposed to prenatal Tdap were matched 1:5 with unexposed infants and outcomes were compared using hazard ratios and incidence rate ratios. Results: No significant adverse associations between prenatal Tdap and our study outcomes were observed. Inverse associations were found with upper respiratory infections (adjusted incidence rate ratio [aIRR]: 0.96, 95% CI: 0.93-0.99), lower respiratory infections (aIRR: 0.93, 95% CI: 0.89-0.98), gastrointestinal infections (aIRR: 0.88, 95% CI: 0.82-0.94), and urgent and in-patient health service utilization (aIRR: 0.95, 95% CI: 0.94-0.97). Conclusions: Our findings support the long-term safety of Tdap administration in pregnancy.

Vaccine-preventable infectious diseases are still prevalent today. Hence, accurate data and techniques such as mathematical modelling are required to better understand their impact on a population level. This is especially the case for measles, as it has been identified to cause immune amnesia (IA): the loss of pre-existing immunological memory for other diseases after a measles infection. First, spectral analysis was used to describe the recurrent patterns of measles and whooping cough (WC) using weekly London mortality data between 1750–1900. Then, stochastic simulations of a model incorporating IA were performed to understand the effect of IA on the recurrent patterns of WC. The periodograms of the simulated model revealed that increasing IA strength and duration caused the longer periodicities of WC to resemble those of measles. This shift was seen for different population sizes, seasonal forcing amplitudes, and mean transmission rates, suggesting this trend can be observed in different ecological or social contexts. When the birth and death rates of London were used in the model with IA duration of less than a year, the WC periodogram of the simulations resembled that of the London mortality data between 1842–1900. Overall, the simulations demonstrate that IA may have contributed to the longer period spectral structure of WC that was found in the real data. Additionally, the mortality, birth rate, and death rate data presented in this thesis provide new tools for future studies in mathematical epidemiology. / Thesis / Master of Science (MSc) / This thesis presents the weekly mortality time series of measles and whooping cough between 1750 and 1900, and describes their epidemic patterns over time. We also model the phenomenon of measles-induced immune amnesia (reduced pre-existing immunity after a measles infection), and examine how it alters the recurrent patterns of whooping cough at a population level. Additionally, we construct a plausible time series of the birth and all-cause mortality rate over the same 150 years. Overall, our analysis suggests immune amnesia alters the longer periodicities of whooping cough to resemble that of measles. Furthermore, we show that this longer periodic structure is similar to that of whooping cough in the late 19th century. Finally, the given mortality, birth rate, and all-cause mortality rate time series can serve as tools for other epidemiological studies, such as predicting long-term epidemic patterns of other diseases.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Virginia, 1997. / Spine title: Characterization of PT receptors. Includes bibliographical references (111-128). Also available online through Digital Dissertations.

La virulence de Bordetella pertussis, agent de la coqueluche, est liée à un arsenal de facteurs de virulence dont l’expression est régulée par le système à deux composants BvgAS. BvgA est le régulateur de réponse et BvgS le capteur du système, qui possède 3 domaines putatifs de perception de signaux. Il s’agit de 2 domaines périplasmiques « Venus FlyTrap » (VFT), reliés par un segment transmembranaire à un domaine PAS (Per-ARNT-Sim) cytoplasmique qui fait la jonction avec l’histidine-kinase. Les signaux perçus par ces domaines capteurs sont inconnus, mais une température de 37°C est suffisante pour maintenir le système actif en laboratoire. Cette activité peut être modulée négativement par des composés chimiques, comme le MgSO4 ou le nicotinate, qui à concentrations suffisantes entraînent le passage de la bactérie en phase avirulente.Nous nous sommes intéressés aux domaines VFT de BvgS. Ces domaines, ubiquitaires, sont composés de 2 lobes reliés par une charnière délimitant une cavité qui permet la fixation d’un ligand spécifique stabilisant le VFT sous une forme fermée.Les domaines VFT de BvgS ont pu être cristallisés et s’organisent en un dimère entrelacé définissant de larges interfaces entre les 4 VFTs. Les VFT2 sont fermés sans ligand et les VFT1 ouverts, et la fermeture artificielle de ces domaines par des ponts disulfure a montré qu’il s’agit de la conformation active de BvgS. L’importance des interfaces entre les domaines VFT pour la fonction de BvgS a été démontrée par mutagenèse dirigée. Un signal positif proviendrait du périplasme pour être transmis à travers la membrane par les interfaces entre les VFT et intégré via un couplage fonctionnel en trans entre ces domaines et les hélices pré-membranaires, dites H19.Ces hélices se prolongeraient à travers la membrane et dans le cytoplasme jusqu’au domaine PAS. Les domaines PAS sont ubiquitaires, avec une structure fortement conservée en feuillet  à 5 brins recouvert d’hélices  délimitant une cavité. Ils sont impliqués dans diverses fonctions biologiques, selon leur capacité de liaison d’un ligand. Certains domaines PAS fonctionneraient sans ligand et pourraient servir d’adaptateurs ou d’amplificateurs de signal.Nous avons pu mettre en évidence la capacité de dimérisation de PASBvg, confirmant la nature dimérique du capteur BvgS. Des substitutions de résidus de la cavité de PASBvg indiqueraient que l’intégrité de la cavité de PASBvg est nécessaire au passage de signaux positifs et négatifs provenant du périplasme. La fixation de ligand dans la cavité n’a pu être démontrée mais n’est pas exclue. D’autre part, certains résidus sont nécessaires au couplage du domaine PAS avec ses hélices flanquantes pour la transmission de signal. La perte de ces interactions déstabilise significativement PASBvg et rend BvgS inactif.Un message positif proviendrait du périplasme et serait maintenu par le domaine PAS, dans une conformation rigide, permettant aussi la transmission des signaux modulateurs. / Virulence of Bordetella pertussis, the whooping cough agent, is due to a plethora of virulence factors which expression is regulated by the two-component system BvgAS. BvgA is a classical response regulator and BvgS the sensor. BvgS contains 3 putative sensor domains, 2 periplasmic Venus FlyTrap (VFT), linked through a transmembrane segment to a cytoplasmic PAS domain preceding the histidine-kinase. Signals perceived by those sensor domains are still unknown, but a 37°C temperature is sufficient to maintain the system active under laboratory conditions. This activity can be down-modulated by chemical compounds, such as MgSO4 or nicotinate, which at sufficient concentration allows the bacteria to switch to avirulent phase.We investigated the role of BvgS VFT domains. VFTs are ubiquitous domains composed of 2 lobes linked by a hinge hence forming a cleft where a specific ligand can bind and stabilize the VFT in its closed conformation.BvgS VFT domains were crystalized and form an intricate dimer defining large interfaces between the 4 VFTs. VFT2s are closed without a ligand and VFT1s are opened, artificial closure of these domains via a disulfide bond indicates that this is the active conformation of BvgS. The role of the interfaces was probed by site-directed mutagenesis. A positive signal might originate from the periplasm to be transmitted through the membrane by the interfaces and integrated by a functional coupling between the VFT2s and the helices preceding the membrane, H19.These helices should be continued through the membrane and the cytoplasm to the PAS domain. Pas domains are ubiquitous with a highly conserved structure, a 5 stranded sheet surrounded by  helices defining a cavity. Pas domains are involved in a wide variety of physiological processes, depending on their ability to bind a ligand. Some PAS might function without a ligand and could then be signal adaptors or amplifiers.We demonstrated PASBvg was dimeric, confirming the dimeric nature of BvgS. Cavity residues were substituted indicating that integrity of the cavity is necessary to maintain activity and modulation capacity coming from the periplasmic moiety. Ligand binding wasn’t demonstrated but couldn’t be excluded. Some residues are needed for the correct coupling of the PAS domain to its flanking helices and hence signal transmission. Loss of these connections generates a strong destabilization of PASBvg and turns BvgS inactive.A positive signal might come from the periplasmic moiety and shoul be maintaines by the PAS domain, which is in a rigid conformation also allowing the transmission of negative signals.

Thesis (Ph. D.)--University of Virginia, 2001. / Includes bibliographical references (leaves 146-168). Also available online through Digital Dissertations.

Thesis (M.A.)--University of Missouri-Columbia, 2004. / Typescript. Includes bibliographical references (leaves 120-124). Also available on the Internet.