Introdução: A infecção genital pelo papilomavírus humano (HPV) é um fator necessário para o desenvolvimento do câncer cervical. Vacinas para prevenir a infecção pelos tipos de alto risco HPV 16 e 18 foram desenvolvidas e idealmente devem ser administradas antes da exposição ao HPV através do contato sexual. As variações na prevalência do HPV e na de seus tipos específicos em diferentes populações podem influenciar as recomendações da vacina contra o HPV em diferentes locais. A vacinação após o primeiro parto poderia ser uma estratégia em potencial para atingir mulheres jovens e saudáveis, dependendo da proporção de mulheres desse grupo ainda não infectadas pelos tipos de alto risco, HPV 16 e 18. Objetivos: O objetivo principal deste estudo foi determinar a prevalência genital do DNA de tipos específicos do HPV e avaliar a associação dessa infecção com fatores de risco selecionados em mulheres após o primeiro parto, usuárias de uma maternidade pública. Métodos: Esse estudo transversal foi realizado no Hospital Maternidade Leonor Mendes de Barros (HMLMB), uma das maiores maternidades públicas da cidade de São Paulo. Durante junho de 2006 até fevereiro de 2007, 301 primíparas de 15-24 anos, cujos partos ocorreram no referido Hospital, foram incluídas no estudo entre 43 e 60 dias após o parto. Na detecção de DNA do HPV extraído das células cervicais esfoliadas foi utilizado protocolo padrão da Reação em Cadeia por Polimerase (PCR), utilizando primers PGMY09/11. Para estimar a associação da infecção por HPV com fatores de risco selecionados, foi calculada a Razão de Prevalência (RP) e o intervalo de 95% de confiança [IC]; o ajuste foi realizado utilizando-se o Modelo Linear Generalizado (MLG) com distribuição binomial e função de ligação logarítmica. Resultados: O DNA do HPV foi detectado em 58,5% (IC 95% 52,7%-64,0%) das jovens mulheres. Os tipos de HPV mais comumente encontrados foram: HPV 16, HPV 51, HPV 52, HPV 58 e HPV 71. A prevalência dos tipos de HPV incluídos nas vacinas profiláticas foi: HPV 16 - 12,0%, HPV 18 - 2,3% e HPV 6+11 - 4,3%. Os tipos de alto risco de HPV foram encontrados em 133 (44,2%) mulheres, enquanto 43 delas (14,3%) apresentaram somente tipos de HPV de baixo risco. Cento e duas mulheres (33,9%) foram positivas para apenas um tipo de HPV; entretanto, 43 (14,3%) apresentaram dois tipos, e 31 (10,3%) apresentaram três ou mais tipos virais. A análise multivariada revelou que somente a idade (p=0,020) e o hábito de fumar (p <0,001) foram fatores de risco independentemente associados com a infecção por HPV. Conclusões: Essas adolescentes e jovens primíparas apresentaram elevada prevalência de infecção genital por tipos de alto risco do HPV, mostrando que constituem um grupo de risco para o desenvolvimento de câncer cervical. Contudo, apenas 17,3% apresentaram pelo menos um dos quatro tipos virais presentes na vacina quadrivalente (HPV 6, 11, 16 ou 18), 13,3% apresentaram infecção pelos tipos HPV 16 ou 18, e somente 1,0% apresentou concomitantemente infecção por esses dois tipos virais de alto risco presentes nas vacinas. Portanto, esse estudo indica que a grande maioria dessas jovens primíparas poderia ainda se beneficiar da imunização (catch-up) contra o HPV e constitui um grupo que deve ser alvo de programas efetivos de prevenção primária e secundária para o câncer cervical / Introdution: Genital infection by human papillomavirus (HPV) is a necessary factor in the development of cervical cancer. Vaccines to prevent infection by high risk HPV genotypes 16 and 18 were developed and ideally should be administered before exposure to HPV through sexual contact. Variations in HPV prevalence in different populations and of specific HPV types could affect vaccine recommendations in different settings. Vaccination after first delivery could be a potential strategy for reaching healthy young women depending on the baseline prevalence of high risk genotypes 16 and 18 in this target group. Objectives: The main objective of this study was to determine genital type specific HPV DNA prevalence and selected risk factors associated with HPV infection after the delivery of the first child among young women in a public maternity. Methods: This cross-sectional study was carried out at Hospital Maternidade Leonor Mendes de Barros (HMLMB), one of the largest public maternity hospitals in Sao Paulo. During June 2006 to February 2007, 301 primiparous women aged 15-24 years, who gave birth at that hospital, were included in the study between 43 and 60 days after delivery. Detection of HPV DNA in cervical specimens was performed using a standardized polymerase chain reaction (PCR) protocol with PGMY09/11 primers. To estimate the association of HPV infection with selected risk factors, prevalence ratios (PR) and 95% confidence interval [CI] were estimated using a Generalized Linear Model (GLM) with binomial distribution and log link function. Results: Any HPV DNA was detected in 58.5% (95% CI 52.7%-64.0%) of the enrolled young women. Most common types of HPV found were: HPV16, HPV51, HPV52, HPV58 and HPV71. The overall prevalence of HPV types targeted by the HPV prophylactic vaccines was: HPV16 - 12.0%, HPV18 -2.3% and HPV 6+11- 4.3%. High-risk HPV types were found in 133 (44.2%) women, whereas 43 women (14.3%) had only low-risk HPV types. One hundred and two women (33.9%) were positive for one HPV type only; however, 43 (14.3%) had two types, and 31 (10.3%) had three or more types detected. The multivariate analysis revealed that only age (p for trend =0.020) and smoking habits (p <0.001) were risk factors independently associated with HPV infection. Conclusions: These adolescents and young primiparous women had high cervical HPV prevalence, suggesting that this is a high risk group for cervical cancer development. Nevertheless, 17.3% were positive to any of the four HPV types included in HPV vaccines (HPV6, 11, 16 or 18), with 13.3% positive for HPV 16 or 18, and only 1.0% of them had both vaccine related oncogenic HPV types. Thus, this study supports that the most part of young primiparous women could benefit from catch-up HPV vaccination, and represents a target group for effective primary and secondary cervical cancer prevention programs

Objetivo: Avaliar a citologia cérvico-vaginal em adolescentes com lúpus eritematoso sistêmico juvenil (LESJ) e comparar com controles. Material e métodos: Cinqüenta e duas adolescentes com LESJ (critérios do American College of Rheumatology) foram comparadas com 52 controles saudáveis. Todos os esfregaços de Papanicolaou foram avaliados por uma mesma citopatologista, que desconhecia o exame ginecológico, e foram classificados de acordo com o Sistema de Bethesda, 2001. Resultados: As médias das idades das pacientes com LESJ e controles foram similares (16,17 ± 1,94 versus 16,13 ± 2,16 anos, p=0,92). A citologia cérvico-vaginal foi similar em ambos os grupos, embora as relações sexuais no último mês tenham sido menos freqüentes nas pacientes com LESJ em relação aos controles (23% versus 59,6%, p=0,0003). Apenas uma paciente (2%) com LESJ e duas controles (4%) tinham displasia cervical (LIE-BG) e papilomavírus humano (HPV) (p=1,0). Citologia cérvico-vaginal inflamatória foi observada em 21 (60%) das pacientes com SLEDAI maior ou igual a 4 e em apenas 4 (23%) daqueles com SLEDAI < 4 (p=0,001). Assim como, uma maior freqüência de achados inflamatórios também foi observada em adolescentes virgens com LESJ (57% versus 8%, p=0,005). Vaginite por Candida spp foi observada em 7 pacientes com LESJ (14%) e em nenhuma dos controles (p=0,012), e foi associada com uso de drogas imunossupressoras (p=0,01) e dose alta de prednisona (p=0,002). Conclusão: Nossos achados indicam que o trato genital feminino é um órgão alvo no LESJ, pois inflamação cérvico-vaginal está associada com atividade da doença independentemente da atividade sexual. / Objective: To evaluate cervicovaginal cytology in adolescents with juvenile systemic lupus erythematosus (JSLE) and to compare them to controls. Material and methods: Fifty-two female adolescents with JSLE (American College of Rheumatology criteria) were compared to 52 age-matched healthy controls. All Pap smears were evaluated by the same cytopathologist blinded to gynecology examination, and performed according to the Bethesda Classification System 2001. Results: The mean age of JSLE patients and controls were similar (16.17 ± 1.94 vs. 16.13 ± 2.16 years, p=0.92). The cervicovaginal cytology was found to be similar in both groups, although sexual intercourses in the last month were less frequent in JSLE than controls (23% vs. 59.6%, p=0.0003). Only one patient (2%) with JSLE versus two controls (4%) had cervical dysplasia (LGSIL) and human papilomavirus (p=1.0). Inflammatory cervicovaginal cytology was observed in 21 (60%) of patients with SLEDAI ? 4 and only 4(23%) of those with SLEDAI<4 (p=0.001). Likewise, a higher frequency of inflammatory changes were also observed in virgin JSLE (57% vs. 8%, p=0.005). Candida spp vaginitis was observed in 7 JSLE (14%) versus none in controls (p=0.012) and was associated to immunosuppressive drugs (p=0.01) and high dose of prednisone (p=0.002). Conclusion: Our findings supports the notion that female genital tract is a target organ in SLE since cervical inflammation is associated to disease activity independently of sexual activity.

O câncer cervical é o segundo câncer mais comum entre mulheres no mundo. A maioria dos casos (83%) ocorre em países em desenvolvimento, onde são encontrados em estágios relativamente avançados e, conseqüentemente, a sobrevida média é de cerca de 49% após cinco anos. Portanto, uma vacina eficaz contra as infecções pelo HPV pode levar ao controle do câncer do colo do útero. Apesar de prevenir, a vacina profilática não é acessível em função do alto custo, além de não eliminar o vírus em mulheres já infectadas pelo HPV. Assim, propusemos o desenvolvimento de uma vacina terapêutica eficaz utilizando duas abordagens: VLPs (virus-like particles) quiméricas, que poderiam apresentar propriedades profiláticas e terapêuticas, obtidas da fusão das proteína L1 e E7; proteínas quiméricas obtidas a partir da fusão de epítopos das proteínas E6 e E7 do HPV16, com e sem ubiquitina. Após subclonagens, com a obtenção dos vetores pPICHOLI-L1&#916;CE71-50 e pPICHOLI-L1&#916;CE743-77, partiu-se para a indução da expressão das VLPs quiméricas em Pichia pastoris, das quais não foram detectadas expressão protéica. Realizaram-se inúmeras modificações no protocolo de indução. Mesmo após essas alterações não foi detectada nenhuma expressão das fusões L1&#916;CE71-50 ou L1&#916;CE743-77. Como alternativa de uma vacina terapêutica, nos propusemos a expressar em E. coli proteínas sintéticas originadas da fusão entre epítopos das proteínas E6 e E7 do HPV16, com ou sem Ubiquitina, visando aumentar a apresentação de peptídeos via MHC de classe I de modo a estimular a eliminação de células infectadas com HPV16, evitando e regredindo o desenvolvimento dessas células cancerosas. Com a proteína E6E7 solúvel e purificada, realizou-se um ensaio de imunização. Nesse experimento, 20% dos animais imunizados com a proteína E6E7 não apresentaram desenvolvimento de tumor após a inoculação de células TC1. Assim isso nos leva a crer que com o aumento da concentração de proteína e utilização de adjuvantes seria possível aumentar o número de animais resistentes ao desenvolvimento do tumor. Em um segundo experimento de imunização, comparamos as proteínas E6E7 e E6E7Ub, em duas concentrações, 15 e 40 &#181;g, e também com ou sem o adjuvante whole cell pertussis (WCP). Independentemente da concentração e presença ou ausência de WCP, os grupos imunizados com E6E7Ub apresentaram proteção contra o tumor entre 80% e 100% dos camundongos, enquanto os grupos imunizados com E6E7 apresentaram proteção entre 0% e 25%. Esses resultados são promissores, ainda que preliminares, indicando um potencial de uso da proteína E6E7Ub como imunógeno para vacina terapêutica contra o câncer cervical induzido por HPV16 / Cervical cancer is the second most common cancer among women worldwide. Most cases (83%) occur in developing countries, where they are found in relatively advanced stages and, consequently, the median survival is about 49% after five years. Therefore, an effective vaccine against HPV infections can lead to control of cancer of the cervix. Although preventable, the prophylactic HPV vaccine is not accessible to all due to their high cost and in addition the vaccine does not eliminate the HPV in infected women. We have therefore proposed the development of effective therapeutic vaccines using two approaches: chimeric VLPs (virus-like particles), endowed with prophylactic and therapeutic properties, obtained from the fusion protein L1 and E7; chimeric proteins derived from the fusion of epitopes of proteins E6 and E7 of HPV16 with and without ubiquitin. After subcloning, we obtained the vectors pPICHOLI-L1&#916;CE71-50 and L1 pPICHOLI- L1&#916;CE743-77. After transformation of yeast Pichia pastoris with these constructions, the cells were induced, but it was not possible to detect any recombinant protein expression. As an alternative, we proposed the expression of synthetic proteins in E. coli derived from the fusion between epitopes of E6 and E7 proteins of HPV16 with or without Ubiquitin, in order to enhance the presentation of peptides through MHC class I to stimulate the elimination of HPV16-infected cells, preventing and regressing the development of cancer cells. Soluble E6E7 protein was purified and, 20% of the animals immunized with this protein did not develop tumor after inoculation of TC1 cells. In a second immunization experiment we compared the proteins E6E7 and E6E7Ub, in two concentrations, 15 and 40&#181;g, with or without the adjuvant whole cell pertussis (WCP). Regardless of concentration and presence or absence of WCP, all the groups immunized with E6E7Ub showed protection against tumor between 80% and 100%, while the groups immunized with E6E7 showed protection from 0% to 25%. These results are promising and although preliminary, indicate the potential of E6E7Ub protein as an immunogen, for a therapeutic vaccine against cervical cancer induced by HPV16

Introdução: O câncer do colo do útero é um problema de saúde publica, é uma importante causa de morbidade e mortalidade em mulheres de todo mundo. O rastreamento com a citologia de Papanicolaou, quando realizado periodicamente demonstrou ser eficaz na redução de incidência e mortalidade em países desenvolvidos. O rastreamento com unidade móvel de prevenção é uma estratégia para o diagnóstico precoce do câncer do colo do útero. Objetivo: Avaliar os resultados do programa de rastreamento com busca ativa e unidade móvel na detecção precoce do câncer do colo do útero na população das zonas urbana e rural de Barretos. Casuística e Métodos: Estudo retrospectivo, descritivo, com 16.849 mulheres na zona urbana e 1.055 na zona rural de Barretos. O projeto inclui visitas domiciliares repetidas de um profissional de saúde da unidade móvel do Hospital de Câncer de Barretos (HCB), entrevista e coleta de Papanicolaou. Mulheres com diagnóstico citológico de ASC-US, ASC-H, lesões intraepiteliais e carcinoma invasivo, foram convocadas para colposcopia e todas as mulheres com histopatológico de carcinoma foram tratadas e permanecem em seguimento no HCB. Os resultados deste programa foram comparados com dados do registro sobre câncer do colo do útero do Departamento Regional de Saúde V (DRS-V) e da Fundação Oncocentro de São Paulo (FOSP), do mesmo período. Resultados: Na zona urbana 10.350 (61,4%) mulheres foram examinadas e realizaram o exame de Papanicolaou, com taxa de cobertura de 62,9% nas mulheres em idade alvo (25 a 60 anos) do programa brasileiro. Foram identificados 35 casos de carcinoma, sendo 77,1% de carcinoma espinocelular in situ. A idade média foi 41,9 anos, 81,4% das mulheres examinadas eram das classes socioeconômicas D e E, e 88,6% apresentavam exame prévio de Papanicolaou. Na zona rural, 1.055 (100%) mulheres foram entrevistadas, examinadas e realizaram o exame de Papanicolaou, com taxa de cobertura de 74,4% na idade alvo. Foram identificados 6 casos de carcinoma, sendo 83,3% de carcinoma espinocelular in situ. A idade média foi de 39,8 anos, 86,7% nas classes socioeconômicas D e E, e 81,0% das mulheres apresentavam exame de Papanicolaou prévio. Analisamos os dados do programa de rastreamento do HCB e comparamos com os dados, em relação ao estadiamento, da DRS-V e FOSP, no mesmo período. Está análise mostrou que houve uma prevalência de lesões in situ em relação às invasivas no programa de rastreamento do HCB quando comparado à DRS-V (p=0,005) e à FOSP (p<0,001). Conclusões: O rastreamento com busca ativa e unidade móvel é um método efetivo no diagnóstico precoce do câncer do colo do útero / Introduction: Uterine cervical cancer is a public health problem and an important cause of morbidity and mortality among women worldwide. Screening using the Papanicolaou cytological test, when done repeatedly, has been shown to be effective for reducing the incidence and mortality of this disease in developed countries. Screening with an active search using a mobile unit is a strategy for early diagnosis of uterine cervical cancer. Objective: To evaluate the results from a screening program with an active search using a mobile unit for early detection of uterine cervical cancer among the populations in the urban and rural zones of Barretos. Sample and Methods: This was a retrospective descriptive study on 16,849 women in the urban zone and 1,055 in the rural zone of Barretos. The project included repeated home visits by a healthcare professional from the mobile unit of Barretos Cancer Hospital (HCB), interviews and collection of Papanicolaou smears. Women with a cytological diagnosis of ASC-US, ASC-H, intraepithelial lesions and invasive carcinoma were called in for colposcopy examinations. All the women with a histopathological diagnosis of carcinoma were treated and remained under follow-up by HCB. The results were compared with data from the uterine cervical cancer records of the Fifth Regional Health Department (DRS-V) and the Oncocenter Foundation of São Paulo (FOSP), covering the same period. Results: From the urban zone, 10,350 Papanicolaou smears (61.4%) were collected, with a coverage rate of 62.9% of the women at the target age for the Brazilian program. There were 35 cases of carcinoma, of which 77.1% were in situ squamous cell carcinoma. The womens mean age was 41.9 years; 81.4% were in socioeconomic classes D and E; and 88.6% had had a previous Papanicolaou examination. In the rural zone, 1,055 Papanicolaou smears (100.0%) were collected, with a coverage rate of 74.4% of the women at the target age. There were six cases of carcinoma, of which 83.3% were in situ squamous cell carcinoma. The womens mean age was 39.8 years; 86.7% were in socioeconomic classes D and E; and 81.0% had had a previous Papanicolaou examination. We analyzed the data from the HCB screening program in comparison with the staging data from DRS-V and FOSP, over the same period. There were statistically significant differences in the proportions of in situ and invasive carcinoma found in the HCB screening program in relation to DRS-V (p = 0.0046) and in relation to FOSP (p < 0.001). This analysis showed that there was higher prevalence of in situ lesions than of invasive lesions in the HCB screening program. Conclusions: Screening with an active search using a mobile unit is an effective method for early diagnosis of uterine cervical cancer

Eine Dysbalance zwischen Sauerstoffradikalen und der plasmatischen antioxidativen Kapazität sowie eine gesteigerte Aktivität der neutrophilen Granulozyten werden als mögliche pathophysiologische Faktoren der Schwangerschaftserkrankungen Präeklampsie (PE) und intrauterine Wachstumsretardierung (IUGR) diskutiert. Das Ziel der Studie war, zu prüfen, ob der plasmatische antioxidative Status und die Plasmaspiegel der neutrophilen Granulozyten Myeloperoxidase und PMN Elastase bei Schwangerschaften mit uteriner Perfusionsstörung, die ein Hochrisikokollektiv für die oben genannten Schwangerschaftskomplikationen darstellen, verändert sind. Die Messungen mit dem immundiagnostischen ELISA zur Bestimmung der antioxidativen Kapazität (ImAnOx) ergaben, dass eine signifikante Erniedrigung der Totalen Antioxidativen Kapazität im Hochrisikokollektiv vorlag. Eine Verbesserung der Risikobeurteilung war durch den ImAnOx-Test nicht möglich. Die Berechnung des Antioxidativen Quotienten durch die zusätzliche Bestimmung des Harnsäurespiegels konnte die Voraussage nicht verbessern. Zur inflammatorischen Komponente mit Hilfe der Enzymspiegelmessungen zeigten die Ergebnisse weder einen Zusammenhang mit der uterinen Perfusionsstörung noch verbesserten sie die Einschätzung des Risikos. Anhand der Ergebnisse wird deutlich, dass mit der uterinen Dopplersonographie insbesondere für das fetale Geburtsgewicht eine Kalkulation möglich ist.

La grossesse est un état physiologique particulier où de nombreux changements fonctionnels et structuraux surviennent. Chez la rate, pour répondre aux besoins grandissants du fœtus, l’artère utérine se développe pour atteindre le double de son diamètre original avant parturition. Par conséquent, le débit sanguin utérin augmente d’environ vingt fois. Pour ce faire, les vaisseaux utérins sont l’objet d’un remodelage caractérisé par une hypertrophie et une hyperplasie des différentes composantes de la paroi. De plus, ce remodelage est complètement réversible après la parturition, par opposition au remodelage vasculaire « pathologique » qui affecte les artères systémiques, dans l’hypertension chronique, par exemple. La grossesse s’accompagne aussi de modifications hormonales importantes, comme les œstrogènes dont la concentration s’accroît progressivement au cours de cette période. Elle atteindra une concentration trois cents fois plus élevée avant terme que chez une femme non gravide. Cette hormone possède de multiples fonctions, ainsi qu’un mode d’action à la fois génomique et non génomique. Considérant l’ensemble de ces éléments, nous avons formulé l’hypothèse que l’œstradiol serait responsable de modifier la circulation utérine durant la grossesse, par son action vasorelaxante, mais aussi en influençant le remodelage de la vasculature utérine. Nous avons montré que le 17β-Estradiol (17β-E2) produit une relaxation due à un effet non génomique des artères utérines en agissant directement sur le muscle lisse par un mécanisme indépendant du monoxyde d’azote et des récepteurs classiques aux œstrogènes (ERα, ERβ). De plus, la relaxation induite par le 17β-E2 dans l’artère utérine durant la gestation est réduite par rapport à celle des artères des rates non gestantes. Ceci serait attribuable à une diminution de monoxyde d’azote provenant de la synthase de NO neuronale dans les muscles lisses des artères utérines. Nos résultats démontrent que le récepteur à l’œstrogène couplé aux protéines G (GPER), la protéine kinase A (PKA) et la protéine kinase G (PKG) ne sont pas impliqués dans la signalisation intracellulaire associée à l’effet vasorelaxant induit par le 17β-E2. Cependant, nous avons montré une implication probable des canaux potassiques sensibles au voltage, ainsi qu’un rôle possible des canaux potassiques de grande conductance activés par le potentiel et le calcium (BKCa). En effet, le penitrem A, un antagoniste présumé des canaux potassiques à grande conductance, réduit la réponse vasoralaxante du 17β-E2. Toutefois, une autre action du penitrem A n’est pas exclue, car l’ibériotoxine, reconnue pour inhiber les mêmes canaux, n’a pas d’effet sur cette relaxation. Quoi qu’il en soit, d’autres études sont nécessaires pour obtenir une meilleure compréhension des mécanismes impliqués dans la relaxation non génomique sur le muscle lisse des artères utérines. Quant à l’implication de l’œstrogène sur le remodelage des artères utérines durant la gestation, nous avons tenté d’inhiber la synthèse d’œstrogènes durant la gestation en utilisant un inhibiteur de l’aromatase. Plusieurs paramètres ont été évalués (paramètres sanguins, réactivité vasculaire, pression artérielle) sans changements significatifs entre le groupe contrôle et celui traité avec l’inhibiteur. Le même constat a été fait pour le dosage plasmatique de l’œstradiol, ce qui suggère l’inefficacité du blocage de l’aromatase dans ces expériences. Ainsi, notre protocole expérimental n’a pas réussi à inhiber la synthèse d’œstrogène durant la grossesse chez le rat et, ce faisant, nous n’avons pas pu vérifier notre hypothèse. En conclusion, nous avons démontré que le 17β-E2 agit de façon non génomique sur les muscles lisses des artères utérines qui implique une action sur les canaux potassiques de la membrane cellulaire. Toutefois, notre protocole expérimental n’a pas été en mesure d’évaluer les effets génomiques associés au remodelage vasculaire utérin durant la gestation et d’autres études devront être effectuées. / Pregnancy is a peculiar physiological state in which many structural and functional changes occur. In rats, to meet the growing needs of the fetus, uterine artery expands to reach twice its original diameter before parturition. Therefore, uterine blood flow increases by about twenty times. To do this, the uterine vessels undergo substantial remodelling characterized by hypertrophy and hyperplasia of the various components of the wall. Furthermore, this remodelling is completely reversible after parturition, as opposed to “pathological vascular remodelling” that affects systemic arteries in chronic hypertension, for instance. Pregnancy is also accompanied by significant hormonal changes, such as estrogens whose concentration in the blood increases progressively during this period. It reaches concentrations three hundred times higher before term than in non-pregnant women. This hormone has multiple functions and mediates its effects by genomic and non-genomic pathways. Considering these elements, we hypothesized that estradiol would be responsible for remodeling the uterine circulation during pregnancy, by its vasorelaxant action, but also by influencing the remodeling of the uterine vasculature. We have shown that 17β-Estradiol (17β-E2) produced non-genomic relaxation of uterine arteries by acting directly on smooth muscle using a mechanism independent of nitric oxide and classical estrogen receptors (ERα, ERβ). Moreover, the relaxation induced by 17β-E2 in the uterine artery during pregnancy is reduced compared to that of arteries from non-pregnant animals. This is the result of decrease of nitric oxide derived from neuronal NO synthase in smooth muscle of uterine arteries. Our results also show that the estrogen receptor coupled to G proteins (GPER), protein kinase A (PKA) and protein kinase G (PKG) are NOT involved in intracellular signaling associated with the vasorelaxant effect induced by the 17β-E2. Moreover, we have shown a possible involvement of potassium channels sensitive to voltage and a possible involvement of large conductance calcium-activated potassium channels (BKCa). Indeed, the penitrem A, a suspected antagonist of BKCa, reduced the vasoralaxant responses of 17β-E2. However, some other actions of penitrem A are not excluded because iberiotoxin, known to inhibit the same channels, had no effect on this relaxation. However, further studies are needed to obtain a better understanding of the mechanisms involved in the relaxation non-genomics on the smooth muscle of uterine arteries. As for the involvement of estrogen on the remodeling of uterine arteries during pregnancy, we attempted to inhibit the synthesis of estrogen during pregnancy using an aromatase inhibitor. Several parameters were evaluated (plasma values, vascular reactivity, blood pressure) without significant changes between the control group and those treated with the inhibitor. The same observation was made for the determination of plasma estradiol, suggesting the uneffectiveness of aromatase blocking in these experiments. Thus, our experimental protocol failed to inhibit the synthesis of estrogen in rats during pregnancy and, in so doing, we cannot confirm or refute our hypothesis. In conclusion, we demonstrated that 17β-E2 acts on smooth muscle of the uterine arteries by a non-genomic pathway by apparently acting on potassium channels. However, our experimental protocol was not able to assess the genomic effects associated with uterine vascular remodeling during pregnancy and further studies are required to ascertain this aspect of our work.

OBJECTIF: évaluer un modèle prédictif de prééclampsie associant des marqueurs cliniques, biologiques (Inhibine A, PP-13, hCG, ADAM12, PAPP-A et PlGF) et du Doppler des artères utérines (DAU) au 1er trimestre de la grossesse. METHODE : étude prospective de cohorte de 893 nullipares chez qui DAU et prélèvement sanguin étaient réalisés à 11-14 semaines. RESULTATS : 40 grossesses se sont compliquées de prééclampsie (4,5%) dont 9 de prééclampsie précoce (1,0%) et 16 de prééclampsie sévère (1,8%). Le meilleur modèle prédictif de la prééclampsie sévère associait les marqueurs cliniques, PAPP-A et PlGF (taux de détection 87,5% pour 10% de faux positif). Le DAU étant corrélé à la concentration de PAPP-A (r=-0,117 ; p<0,001), il n’améliorait pas la modélisation. CONCLUSION : la combinaison de marqueurs cliniques et biologiques (PlGF et PAPP-A) au 1er trimestre permet un dépistage performant de la prééclampsie sévère. Le DAU n’est pas un instrument efficace de dépistage au 1er trimestre dans cette population. / OBJECTIVE: To determine the value of combined screening for pregnancy hypertensive disorders by maternal characteristics, first trimester uterine artery Doppler (UAD) and serum biomarkers (Inhibine A, PP-13, hCG, ADAM12, PAPP-A et PlGF). STUDY DESIGN: In this prospective cohort study, 893 nulliparous women had UAD evaluation and collection of serum sample at 11-14 weeks. RESULTS: 40 women developed preeclampsia (4.5%) of which 9 early-onset preeclampsia (1.0%), and 16 severe preeclampsia (1.8%). The best model to predict preeclampsia associated maternal charateristics, PAPP-A and PlGF (detection rate 87.5% for 10% of false positive). UAD was correlated to PAPP-A concentration (r=-0.117 ; p<0.001), and so did not add to predictive accuracy. CONCLUSION: Combination of maternal characteristics and first trimester PlGF and PAPP-A provides a useful screening for severe preeclampsia. First trimester UAD was not an efficient screening tool in this population.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Incidences of uterine infections in dairy cattle are high between parturition and Day 21 postpartum. Dairy cows with uterine infections are at risk for prolonged periods of days open and multiple services before becoming pregnant. Neutrophils are the first wave of immune system defense against uterine contamination. Neutrophil function seems to be mediated by reproductive hormones and good uterine health is related to properly functioning neutrophils. To elucidate the interaction between reproductive hormones, neutrophils and uterine health in dairy cows the objectives of this research were to evaluate: 1) changes in circulating white blood cell populations during the estrous cycle, 2) the effects of prostaglandin F₂[subscript α](PGF₂[subscript α]) on circulating white blood cell populations and 3) the effects of a two-injection PGF₂[subscript α] regimen on uterine neutrophil and bacterial populations and numbers of days open and services per conception. In the first experiment, the effect of stage of the estrous cycle on plasma neutrophil numbers was evaluated. Neutrophils were observed throughout the entire estrous cycle and numbers were greatest (P<0.05) on Day 14 (mid-cycle), when the corpus luteum was the dominant ovarian structure and plasma progesterone was at its acme. In the second experiment, plasma neutrophil numbers were examined in cows after injections of saline or the PGF₂[subscript α] pharmaceutical product, Lutalyse. Compared to saline, numbers of neutrophils were greater (P<0.05) 4 and 8 hr after Lutalyse injection. In the third experiment, neutrophil numbers were examined after injections of saline, Lutalyse or the PGF₂[subscript α] analog, Estrumate. Compared to saline, numbers of neutrophils did not differ (P>0.10) from cows injected with Lutalyse or Estrumate. In the fourth experiment, uterine bacterial populations and numbers of neutrophils were quantified in cows treated with Lutalyse or saline on Days 0 and 14 or 14 and 28 postpartum. Compared to saline, Lutalyse treatment decreased (P<0.05) total bacteria present in the uterus and increased (P<0.05) the number of uterine neutrophils. In experiment five, numbers of days open and services per conception were evaluated in cows treated with Lutalyse or saline on Days 0 and 14 or 14 and 28 postpartum. Compared to saline, Lutalyse decreased days open (154.7 ± 14.1 vs. 120.1 ± 7.9 days, respectively; P<0.05) and services per conception (3.0 ± 0.4 vs. 2.3 ± 0.2 services, respectively; P=0.09). These results suggest PGF₂[subscript α] treatment can increase neutrophil and depress bacterial cell populations in favor of the dairy cow's uterine health and may explain why fertility is improved when PGF₂α is administered early in the postpartum period. / Graduation date: 2012

Made available in DSpace on 2015-07-22T20:50:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-25. Added 1 bitstream(s) on 2015-08-11T03:25:36Z : No. of bitstreams: 1 Publico-045.pdf: 1293717 bytes, checksum: aa77a18d9ad66fac463c08766304abf5 (MD5) / Objetivo: avaliar os resultados anatômicos, funcionais e complicações do tratamento do prolapso da parede vaginal anterior com tela de submucosa de intestino delgado suíno (SIS) e com colporrafia anterior. Pacientes e Métodos: estudo prospectivo e randomizado para comparação do uso de tela de SIS e de colporrafia tradicional. As mulheres foram avaliadas no pré-operatório e com seis meses após a cirurgia. Os parâmetros utilizados foram: sistema de quantificação do prolapso genital (POP-Q), questionário de qualidade de vida validado (P-QoL) e complicações. Os dados foram analisados pelo teste de Mann-Whitney e Qui-quadrado para avaliação da homogeneidade entre os grupos. A seguir, utilizamos o teste t-Student pareado ou teste t-Student de amostras independentes. O estudo foi aprovado pelo Comitê de Ética Local e registrado no ClinicalTrials com o número NCT00827528. Resultados: os resultados representam a análise de 29 pacientes no grupo com tela de SIS e 27 no grupo com colporrafia tradicional. Os grupos foram semelhantes consoante idade, índice de massa corpórea, paridade, estádio do prolapso, cirurgia prévia para prolapso, presença de incontinência urinária de esforço, pontuação no questionário de qualidade de vida e medidas dos pontos anatômicos no pré-operatório. Com seis meses de seguimento, a taxa de cura anatômica no grupo com tela foi de 86,2% comparada com 59,3% no grupo da colporrafia, pelo critério da Sociedade Internacional de Continência (ICS). Não houve diferença de sucesso anatômico entre as técnicas quando consideramos a subdivisão do estádio II. A média do ponto Ba, pré-operatória, no grupo com tela foi de +2,07 cm e +2,22 cm na colporrafia e, no pós-operatório, de -1,93 cm (p<0,001) e de -1,37 cm (p<0,001), respectivamente. O NNT (Número Necessário a Tratar) foi 4. Ambos os procedimentos melhoraram de forma significativa as medidas de qualidade de vida. Contudo, o grupo com tela não demonstrou diferença quando comparado ao da colporrafia tradicional. Houve 4 pacientes com sangramento excessivo no grupo SIS, embora nenhuma requereu hemotransfusão. Observamos maior número de complicações no grupo SIS (20 vs 9; p=0,01) e maior tempo cirúrgico (48,3 min ±16,1 vs 30,3min ±19,4; p=0,001). O tempo de internação hospitalar foi de 3,3 e 3,2 dias, respectivamente. Não houve casos de infecção ou de erosão da tela. Conclusão: As cirurgias para o prolapso genital resultam em melhora significativa da qualidade de vida. Observamos melhor cura anatômica do ponto Ba com tela, de acordo com o critério da ICS. Consoante os parâmetros de qualidade de vida não houve diferença entre as técnicas. Houve maior número de complicações no grupo com tela. / Objective: the aim of this study was to evaluate anatomical, functional results and complications of small intestine submucosa (SIS) graft compared to traditional anterior repair in surgical treatment of anterior vaginal wall prolapse. Methods: This is a randomized and prospective study to compare the SIS graft with traditional colporrhaphy (TC) in surgical treatment of anterior vaginal prolapse. Subjects were randomized to SIS (n=29) or to TC (n=27) and compared preoperatively and at 6 months postoperatively. We used pelvic organ quantification system (POP-Q), a validated prolapse quality of life questionnaire (P-QoL) and possible complications. Data were compared using the Mann–Whitney test or a chi-squared test to determine that there were no significant intergroup differences. This then enabled us to use the independent samples t-test or the paired Student’s t-test. This study was approved by Local Ethics Committee and register at ClinicalTrials NCT00827528. Results: the outcomes represent the analysis of 29 patients in SIS group and 27 in traditional repair. Both groups were paired by age, parity, body mass index, stage of anterior prolapse, previous surgery for prolapse, presence of incontinence, POP-Q measurements and quality of life preoperatively. At 6-month follow-up, SIS group have 86.2% anatomic cure comparing with 59.3% in traditional repair, using the International Continence Society (ICS) patterns. We did not report differences between the techniques when we divided the stage II. The mean point Ba preoperatively in SIS group was +2.07 cm and +2.22 cm in traditional repair and postoperatively -1.93 cm (p<0.001) and -1.37 cm (p<0.001), respectively. The NNT (Number Need to Treat) was 4. Both operations significantly improved prolapse quality-of-life severity measures. Although SIS group did not showed significant improvement in quality-of-life parameters measured in comparison to traditional repair. Excessive bleeding occurred in 4 patients in SIS group although none required blood transfusion. We reported more complications in SIS group (20 vs 9, p=0.01) and longer surgical time (48.3min ±16.1 vs 30.3min ±19.4; p=0.001). The average hospital length was 3.3 and 3.2 days, respectively. We did not reported infections or erosion of the mesh. Conclusions: Surgery for vaginal prolapse results in marked improvement in prolapse quality of life. We could see that SIS repair improved point Ba measurement significantly using the ICS patterns. Regarding quality-of-life parameters we did not observe significant differences in both techniques. / TEDE / BV UNIFESP: Teses e dissertações