Orientador: Isabel Cristina Cherici Camargo / Banca: Regildo Márcio Gonçalves da Silva / Banca: Eneri Vieira de Souza Leite Mello / Resumo: A Agave sisalana (sisal) é amplamente cultivada em território brasileiro. Foi constatada a presença de cinco saponinas esteroidais nessa planta, responsáveis por várias atividades farmacológicas, destacando-se as atividades antifúngica e anti-inflamatória. Popularmente, o sisal ainda é utilizado para o tratamento de doenças hepáticas, tuberculose e sífilis. Devido à sua ação detergente, as saponinas são dotadas de efeito tóxico em função de sua propriedade de causar ruptura em eritrócitos, liberando hemoglobina, além de outros efeitos ainda relacionados à lise celular como as ações inseticida, anti-helmíntica e ictiotóxica. Considerando-se as diversas ações farmacológicas da A. sisalana e seu amplo uso na medicina popular, torna-se necessário investigar seus possíveis efeitos colaterais na reprodução feminina, os quais ainda não foram relatados na literatura / Abstract: The Agave sisalana (sisal) is largely cultivated in Brazil. It was found the presence of five steroidal saponins that plant, responsible for various pharmacological activities, especially the anti-fungal and anti-inflammatory activities. Popularly, sisal is also used for the treatment of liver diseases, tuberculosis and syphilis. Due to its detergent action, saponins are equipped with toxic effect due to its property to cause disruption in erythrocytes, releasing hemoglobin, and other effects still related to cell lysis as the actions insecticide, anthelmintic and ichthyotoxic. Considering the various pharmacological actions of A. sisalana and its widespread use in folk medicine, it is necessary to investigate their possible side effects on female reproduction, which have not yet been reported in the literature / Mestre

Orientadores: Carlos A. M. Guerreiro, Iscia T. Lopes-Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T14:30:31Z (GMT). No. of bitstreams: 1 Costa_AlbertoLuizCunhada_D.pdf: 10395581 bytes, checksum: a6d86ff240a4e83b2dc8cdef41ca4db7 (MD5) Previous issue date: 2007 / Resumo: A maioria das gestações em mulheres com epilepsia não apresenta complicações, porém a persistência de crises e efeitos das drogas antiepilépticas (DAE) podem afetar o feto causando retardo do crescimento intra-uterino, dismorfismos, atraso do desenvolvimento neuro-psicomotor e malformações fetais, com aumento no risco estimado em 2 a 3 vezes em fetos expostos intrautero. Os objetivos foram identificar a ocorrência de malformações fetais em filhos de mães com epilepsia; determinar a ocorrência de atraso de desenvolvimento intra-uterino; investigar o crescimento e desenvolvimento de filhos de mães com epilepsia e descrever os achados e complicações materno-fetais nos grupos de gestantes com epilepsia. Entre maio de 2003 a maio de 2007, foram avaliadas 67 gestantes com epilepsia (GE) com um total de 69 gestações, com idades entre 17 e 37 anos, média 26,9 anos, e 66 gestantes não epilépticas (grupo controle - GC) com um total de 68 gestações, com idades entre 15 e 44 anos, média 26,9 anos, nos ambulatórios de Epilepsia e Genética Clínica do HC ¿ Unicamp. Duas pacientes do GE abandonaram o estudo, sendo recuperados os dados de uma paciente. Quarenta gestantes do GC abandonaram o seguimento. De 42 gestações, em 21 os dados foram recuperados para informações do parto e malformações fetais. Em vinte e uma não foi possível a recuperação. O seguimento longitudinal foi composto por 52 gestações de mulheres com epilepsia e vinte e seis gestantes não epilépticas. Quarenta e cinco pacientes estavam sob monoterapia, 13 com duas DAE e duas com três DAE. Carbamazepina foi usada por 38 gestantes, 26 em monoterapia e 12 em politerapia. Fenobarbital foi a segunda DAE mais usada, sob monoterapia em 07 e politerapia em 05. Três pacientes foram mantidas sem DAE. Todas as pacientes foram atendidas mensalmente pelo mesmo neurologista durante a gestação e puerpério conforme protocolo pré-estabelecido. Estudo antropométrico e neurológico dos neonatos foram realizados por geneticista no nascimento, aos 06 meses, 01 ano, 02, 05 e 07 anos de idade. Filhos de mães com epilepsia (FME) apresentaram menor peso ao nascer, porém índice de Apgar no 1º e 5º minutos não diferiu entre GE e GC. Malformações fetais maiores foram observadas em 16,39% das pacientes do GE (defeitos urogenitais ¿ 2, fenda labial + palatina ¿ 1, defeitos gastrointestinais ¿ 1, anormalidades esqueléticas ¿ 1, hérnias ¿ 2 e deficiência auditiva profunda ¿ 3) e 3,92% no GC (malformações cardiovasculares ¿ 2). Entre os sinais dismórficos estudados, anomalias de orelhas (28,85%), hipertelorismo (62,96%) e diminuição do perímetro cefálico (14,29%) foram mais freqüentes em FME expostos a crises parciais complexas e fenobarbital. Três mulheres do GE apresentaram partos com complicações: Uma criança nasceu com encefalopatia hipóxico-isquêmica, uma apresentou pneumotórax e um parto evoluiu com placenta prévia. Abortos (1), óbitos perinatais (1) e infantis (2) ocorreram apenas em FME. Concluímos que malformações fetais maiores são mais freqüentes em FME comparados com controles. Crises parciais complexas e fenobarbital estão associados com anomalias de orelhas, hipertelorismo e redução do perímetro craniano no seguimento longitudinal. Abortos, óbitos perinatais e infantis ocorreram apenas em FME / Abstract: Rationale: The majority of women with epilepsy do not experience significant changes during pregnancy; however the persistence of seizures and the effect of antiepileptic drugs (AED) may affect the fetus. These effects include lower intrauterine growth, dysmorphisms, fetal malformation and neuropsicomotor developmental delay. Most studies report that the risk of fetal malformation is two to three times higher in fetus exposed to AED. Objectives: The goals of our study were: to identify the occurrence of fetal malformation in children of woman with epilepsy (WWE); to determine the occurrence of intrauterine developmental delay; to investigate the growth and development of these children; to describe labor complications; and to assess birth and child outcome. Methods: From May 2003 to May 2007 we evaluated 67 WWE in 69 gestations, ages ranging from 17 to 37 years, average 26.9 years. Those patients were compared with 66 non-epileptic pregnant women (control group) with 68 gestations, ages ranging from 15 to 44 years, average 26.9 years. Patients were referred from the Epilepsy Unit and Medical Genetics section of Hospital das Clínicas ¿ Unicamp. Results: Two WWE abandoned the study, although the data of one of them were recover. Forty women of the non-epileptic group quitted the study but we were able to recovered the data of 21 of these women reporting on the delivery and fetal malformations. Twenty-one women had their information lost. Follow-up was obtained in 52 WWE and 26 control women. Forty-five women were on one AED, 13 were on two AED and two were on three. Carbamazepine was used by 38 pregnant women, 26 were in monotherapy and 12 were in polytheraphy. Phenobarbital was the second most used AED, seven in monotherapy and five in polytheraphy. Three patients were on no medication. All patients were seen by the same neurologist, monthly during pregnancy and the post gestation period. In addition, anthropometric and neurological evaluation were performed by a geneticist at birth period, six month, 1, 2, 5 and 7 years of age. Three children of WWE presented complications: hypoxic ischemic encephalopathy (1), abruptio placentae (1) and pneumothorax (1). Low birth weight was identified in children of WWE. There was no difference in the Apgar scores in the first and fifth minutes, and head circunference in the two groups. Ten (16.39%) children from WWE (urogenital anomalies ¿ 2, cleft lip+cleft palate ¿ 1, gastrointestinal defects ¿ 1, skeletal defects ¿ 1, hernia ¿ 2, congenital deafness ¿ 3) and two (3.92%) of the control group (cardiac defects ¿ 2) showed major fetal malformations. Dysmorphic signs such as ear anomalies (28.85%), hypertelorism (62.96%), and small head circumference, were more frequent in children of epileptic mother, particularly associated with use of phenobarbital and complex partial seizures. Conclusions: We conclude that major fetal malformations were more frequent in children of WWE (16.39%) compared to controls (3.92%). Children of mothers with complex partial seizures, using phenobarbital presented more ear anomalies (28.85%), increased intercantal distance (62.96%) and smaller head circunference (14.29%) in longitudinal follow-up. Furthermore, abortions (1), perinatal (1) and infantile death (2) occurred only in children of WWE / Doutorado / Neurologia

A Distrofia Muscular de Duchenne (DMD) é uma doença genética neuromuscular hereditária, ligada ao cromossomo X, sendo encontrada em humanos do sexo masculino. Esta doença muscular é descrita em outras espécies. O modelo de estudo pré-clínico GRMD (Golden Retrievier Muscular Dystrophy) apresenta sintomas clínicos fenotipicamente característicos da DMD em humanos e, por esta razão, tem sido amplamente utilizado como modelo de estudos pré-clínicos. O objetivo da presente pesquisa foi avaliar o tecido muscular, no modelo canino distrófico, ao longo da gestação. Quatro fêmeas, portadoras do gene distrófico, foram inseminadas com sêmen fresco de cães distróficos. No 25º dia, pós-inseminação, as fêmeas foram submetidas a exames de ultrassonografia para confirmar a gestação. As fêmeas gestantes passaram por uma ovariosalpingohisterectomia (OSH) para a retirada dos embriões e fetos nos seguintes períodos gestacionais: 28º , 33º , 38º e 42º dias. Em seguida fragmentos de tecido muscular foram analisados macroscopicamente e microscopicamente. Para verificar expressões proteicas, amostras de tecido foram submetidas a técnicas imunológicas, e PCR para distrofina, miostatina, e utrofina. Aos, 33º e 38º dias de gestação, no grupo distrófico, foram observadas características teciduais que corroboram com desenvolvimento tardio do tecido muscular. Os resultados para detecção proteica sugerem que, a distrofina, miostatina e utrofina foram expressas igualmente nos grupos controle e distrófico, durante todos os períodos do desenvolvimento gestacional analisado. Por fim, os dados sugerem que animais distróficos apresentam músculo sadio durante a fase gestacional, o que pode ser benéfico para testes farmacológicos em idade precoce. / Duchenne Muscular Dystrophy (DMD) is a hereditary neuromuscular genetic disease linked to the X chromosome, being found in male humans. This muscle disease is described in other species. The pre-clinical GRMD (Golden Retrievier Muscular Dystrophy) study model presents phenotypically characteristic clinical symptoms of DMD in humans and,for this reason, has been widely used as a model for preclinical studies. The aim of the present study was to evaluate the muscular tissue, in the dystrophic canine model, throughout the gestation. Four females, carriers of the dystrophic gene, were inseminated with fresh semen from dystrophic dogs. On the 25th day, post-insemination, the females were submitted to ultrasonography to confirm the pregnancy. The pregnant females underwent an ovariosalpingohisterectomy (OSH) for the removal of the embryos and fetuses in the following gestational periods: 28º, 33º, 38º and 42º days. Then fragments of muscle tissue were analyzed macroscopically and microscopically. To verify protein expression, tissue samples were submitted to immunological techniques, and PCR for dystrophin, myostatin, and utrophin. At the 33 and 38th days of gestation, tissue characteristics were observed in the dystrophic group, which corroborate the late development of muscle tissue. The results for protein detection suggest that dystrophin, myostatin and utrophin were also expressed in the control and affected groups, during all periods of the gestational development analyzed. Lastly, the data suggest that dystrophic animals present healthy muscle during the gestational phase, which may be beneficial for pharmacological tests at an early age.

L-arginine is one of the most versatile amino acids due to the fact that it serves as a precursor for many molecules which have important roles in bodily functions including mammalian reproduction. The current studies sought to further examine the role that L-arginine has in mammalian reproduction utilizing both in vivo and in vitro approaches. In the first study, a novel bioluminescent murine pregnancy model was developed to monitor VEGFR2 transcription activity non-invasively in the fetoplacental unit. Secondly, the effect that dietary L-arginine supplementation has during mouse gestation was examined. L-arginine supplementation increased weight gain during the latter third of gestation, total litter size, number of implantation sites, and litter birth weight. Additionally, L-arginine supplementation increased VEGFR2 transcription activity in the fetoplacental unit which may create a more favorable environment for fetal survival. Moreover, the increased number of implantation sites observed suggests an effect of L-arginine at the level of the endometrium. To this end, the effect that L-arginine has on apoptosis and cell proliferation in an established endometrial cell line was examined. The addition of L-arginine at physiological (200 micromolar) and supra-physiological (800 micromolar) concentrations increased cell proliferation , and this effect was achieved through biosynthesis of polyamines and nitric oxide. L-arginine also decreased the proportion of cells that were experiencing mitochondrial mediated apoptosis, and it was observed that this decrease in mitochondrial mediated apoptosis was concurrent with increased phosphorylation of BAD protein, which induces apoptosis when not phosphorylated. The final study examined the ability of porcine uterine epithelial (PUE) cells to synthesize L-arginine from L-citrulline. L-citrulline was able to support PUE cell proliferation in the absence of L-arginine. Additionally, ASS-1 and ASL, L-arginine synthesizing enzymes, were expressed in PUE cells and were regulated by the presence of L-arginine and L-citrulline, respectively. This data would support the hypothesis that PUE cells may be able to convert L-citrulline to L-arginine. Together, the current findings along with the plethora of relevant literature provide further evidence for the role of L-arginine in mammalian reproduction and allow for new questions to be investigated regarding this particular amino acid’s role in mammalian reproduction.

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Master of Science