The production of viable germ cells during human embryonic development determines adult reproductive success. This is particularly true for females, as development of germ cells (GCs) into primordial follicles before birth is imperative for future fertility. During fetal development GCs migrate to the genital ridge to form the gonad, after which several tightly regulated events, including proliferation, differentiation, and association with somatic cells, must occur to form a functional gonad. In the ovary these processes also include the initiation and subsequent arrest of meiosis. These developmental processes are orchestrated by local autocrine and paracrine factors, many of which remain to be identified in the human. In order to decipher further the pathways by which the gonad and GCs develop, potential regulators including prostaglandin (PG) E2, the interleukin (IL)6-type cytokines, and the prokinetecins (PROKs), were examined in the human fetal ovary and PROKs in the human fetal testis. Patterns of gene expression, protein localisation, function, and interaction of the potential mediators throughout human development (8-20 weeks gestation) were determined. Primary fetal tissue was investigated, in addition to immortalized GCs (T-Cam2 cells) and a murine model of fetal ovarian development. PGE2 interacts with known regulators of GC development in non-reproductive organs. It was postulated PGE2 may regulate GC progression by modulating these factors. Examination of PGE2 receptors and precursor enzymes in the fetal ovary revealed that all were present and some were developmentally regulated, with mRNA expression increasing with gestation. These developmentally regulated components were localised to the GCs. The PGE2 receptors were among those differentially expressed, with one localised solely to mature GCs. Culture of human fetal ovary confirmed that PGE2 regulates known regulators of GC development, increasing expression of survival and anti-apoptotic factors. To test the hypothesis that PGE2 is necessary for female GC development, paracetamol, an inhibitor of PGE2 precursor enzymes, was utilised in a murine model of fetal exposure. Fetal ovaries from this experiment displayed disruption of normal development. The IL6-type cytokines are also postulated to be involved in early gonad development, and are known to regulate proliferation and differentiation of mouse embryonic stem and GCs in vitro. A significant increase in transcript levels of the shared receptor components was determined in second trimester human ovaries, as well as developmental increases of several of the IL6-type ligands. Both common receptor components were located specifically in the GCs identifying them as the target of IL6 action in the human fetal ovary. The PROKs regulate cell migration, proliferation and differentiation, and modulate secretion of PGE2 and expression of some IL6-type cytokines. To-date, PROKs have not been examined in the human fetal gonad. Transcript levels were higher in the fetal testis compared to the ovary, with receptor and ligand components increasing with gestation. Most components also increased with gestation in the ovary. However, location of PROK components was strikingly different between the two tissues, with GCs being the primary target of PROK action in the fetal ovary, and Leydig and interstitial cells being the target in the testis. PROKs interaction with other regulators of gonad development was examined utilising a GC line in the case of the ovary and primary interstitial cell cultures in the case of the testis. These studies have identified new factors involved in human fetal gonad development, and how they interact with known regulatory pathways of development.

Exposure to ethanol (ETOH) during fetal development results in a range of cognitive/behavioral deficits. There are differences in sensitivity to the effects of ETOH that could be explained by other factors, such as hypoxia. Similar mechanisms of damage underlie both ETOH, more specifically ETOH withdrawal, and hypoxia. Based on this overlap, it was hypothesized that sub threshold levels of these insults may interact to produce increased damage in sensitive brain regions. This study used a rodent organotypic hippocampal slice culture model to investigate the interaction of hypoxia and ETOH withdrawal and to determine possible developmental differences in the sensitivity to these insults. The combination of ETOH and hypoxia produced greater damage in the CA1 and CA3 hippocampal regions, as measured by propidium iodide uptake. Differences in outcome were noted between on postnatal (PND) 2 and PND 8 tissue. ETOH alone caused damage as measured by the neuronal marker NeuN, suggesting the ETOH/hypoxia interaction involves different cell types and that caution should be taken when determining appropriate levels of exposure. This data could explain why some offspring appear more sensitive to ETOH and/or hypoxic challenges during early life.

Die vorliegende Arbeit untersucht die Steroidogenese und die Expression Leydig-Zellspezifischer Gene in Kulturen postnataler fetaler Leydig-Zellen (PFLC). Die Stimulation von PFLC mit hCG und (Bu)2cAMP bewirkt eine Steigerung der Testosteronproduktion in vitro. Es wurde eine zeitabhängige Abschwächung der Testosteronproduktion durch (Bu)2cAMPstimulierte PFLC beobachtet. Diese war begleitet von einer Akkumulation von Progesteron im Kulturmedium und einer Suppression der Expression von P450c17 auf dem translatorischen Level. Während der Kultivierung verloren PFLC ihre Fähigkeit der Expression Leydig-Zell-spezifischer Gene (z.B. 3βHSD, P450c17, Insl3). Dieses Phänomen konnte durch Stimulation mit (Bu)2cAMP rückgängig gemacht werden. Außerdem zeigte sich, dass PDGFα allein und in Kombination mit (Bu)2cAMP signifikant die Proliferation der PFLC in vitro stimulierte. Die vorliegende Arbeit deutet darauf hin, dass cAMP-aktivierte Signalkaskaden eine wichtige Rolle in der Regulation von Differenzierung und Funktion von PFLC spielen.

Alkoholinio vaisiaus sindromo sąvoka yra labai plati, ja apibūdinamas kūdikio ar vaiko negrįžtamų anomalijų rinkinys (Lombard et al., 2007). Sindromas pasireiškia motorinio, socialinio, pažintinio ir kalbos vystymosi sutrikimais (Steinhausen et al., 2003), todėl AVS sergantiems asmenims taikomas kompleksinis gydymas (Burd et al., 2003). Tyrimo objektas – alkoholiniu vaisiaus sindromu sergančių vaikų stambioji ir smulkioji motorika. Tyrimo problema – nėra aišku, kokia kineziterapijos ar fizinio aktyvumo forma tinkamiausia alkoholinį vaisiaus sindromą turintiems vaikams, kad gerėtų stambioji ir smulkioji motorika. Darbo tikslas – nustatyti kineziterapijos poveikį vaikų stambiajai ir smulkiajai motorikai esant alkoholiniam vaisiaus sindromui. Šiam tikslui pasiekti iškelti uždaviniai: 1) Įvertinti stambiosios motorikos rodiklius vaikams, turintiems alkoholinį vaisiaus sindromą, taikant bendralavinančius pratimus (kontrolinė grupė) ir judriuosius žaidimus (tiriamoji grupė) prieš ir po kineziterapijos. 2) Įvertinti smulkiosios motorikos rodiklius vaikams, turintiems alkoholinį vaisiaus sindromą, taikant bendralavinančius pratimus (kontrolinė grupė) ir judriuosius žaidimus (tiriamoji grupė) prieš ir po kineziterapijos; 3) palyginti stambiosios ir smulkiosios motorikos rezultatus tarp vaikų, kuriems taikyti bendralavinantys pratimai ir judrieji žaidimai; 4) palyginti bendrą standartinį motorikos rodiklį tarp vaikų, kuriems taikyti bendralavinantys pratimai ir vaikų, kuriems taikyti... [toliau žr. visą tekstą] / Fetal alcohol syndrome is an umbrella term used to describe the irreversible array of anomalies associated with in utero alcohol exposure (Lombard et al, 2007). Fetal alcohol syndrome manifestes by developmental perturbation in motor, social, cognitive and language domain (Steinhaussen et al, 2003). Appropriate management nearly always involves a multidisciplinary team effort with ongoing programming (Burd et al, 2003). Subject: gross and fine motor in children with fetal alcohol syndrome. Problem: there is no clear evidence about the most proper form of physiotherapy or physical activity on purpose to improve gross and fine motor functions in children with fetal alcohol syndrome. Objective: to determine the effectiveness of physiotherapy on gross and fine motor in children with fetal alcohol syndrome. There are four tasks to reach an objective: 1) to determine gross motor indexes for children with fetal alcohol syndrome in casual physiotherapy group (control) and active playing group (investigative) before and after physiotherapy; 2) to determine fine motor indexes for children with fetal alcohol syndrome in casual physiotherapy group (control) and active playing group (investigative) before and after physiotherapy; 3) to compare fine and gross motor indexes between the casual physiotherapy group and active playing group; 4) to compare standard motor score between the casual physiotherapy group (control) and active playing group (investigative); The fine and gross motor... [to full text]

The cognitive and/or behavioural problems associated with Fetal Alcohol Spectrum Disorder (FASD) place this population at increased risk of involvement in the justice system. Although FASD poses challenges at each stage of the justice system, legal discussion and commentary have pinpointed the sentencing stage as the phase in which the issue of FASD is most commonly raised and considered. The purpose of this study is to examine if (and how) FASD is being taking into consideration at sentencing. To this end, a comparative analysis of 87 sentencing judgments (42 FASD offenders and 45 non-FASD offenders) reported in Quicklaw was conducted. Cases were matched on most serious offence (assault, robbery and sexual assault) and jurisdiction (Yukon, British Columbia and Ontario). Descriptions of FASD and non-FASD offenders as reported by judges were found to differ in a number of significant ways. Similarly, sentencing purposes applied to each offender group emerged as distinct. Despite these distinctions, no differences were found in the type and length of sentence handed down (even after controlling for criminal record and breaches). These findings indicate a need for further research and possible policy changes.

Objective: Fetal alcohol spectrum disorder (FASD) is a permanent developmental disorder that can occur if women drink alcohol while pregnant. Despite substantial variability in FASD as a population, anecdotal evidence and clinical reports suggest that affected individuals have difficulty learning from experience and generalizing information from one situation to another, and tend to make the same mistakes over and over. Consistent with research in cognitive and educational psychology, these difficulties were conceptualized as impairments in “transfer of learning.” This dissertation sought to measure transfer of learning using three experimental transfer measures and an exploratory parental transfer questionnaire. In addition, performance on the experimental transfer measures was investigated in relation to aspects of executive functioning, because abilities thought to underlie successful transfer bear much resemblance to aspects of executive functioning. Participants and Methods: The sample included 16 children diagnosed with FASD and 16 age- and gender-matched control children. Children were screened for intelligence and excluded if their performance on both Vocabulary and Matrix Reasoning from the WISC-IV fell below the 9th percentile. Children completed three transfer tasks: (1) a novel, experimental modification of the Tower of Hanoi involving nested plastic cups and Tupperware containers; (2) a variation of Chen’s (1996) Bead Retrieval Problem; and (3) the Purdue Pegboard. Participants also completed three executive functioning tasks that were selected to measure concept formation and flexibility: (1) Picture Concepts from the WISC-IV; (2) the D-KEFS Color-Word Interference Test; and (3) the Visual-Verbal Test. In addition, parents or caregivers completed an exploratory questionnaire designed to assess children’s transfer of learning abilities in everyday life, along with the ABAS-II, a standardized measure of adaptive functioning. Results: Children with FASD displayed significantly weaker performance on the Transfer Condition of the Tower of Hanoi, even after controlling for intelligence. Group differences were not observed on the Bead Retrieval Problem or on the Purdue Pegboard. On the measures of executive functioning, control children outperformed those with FASD on all measures before controlling for intelligence. In addition, there was a significant relationship between the Tower of Hanoi and the Visual-Verbal Test; the latter was the only executive functioning task related to transfer of learning. This finding, however, did not persist when intelligence was accounted for. After controlling for intelligence, significant group differences also were found on parental ratings of everyday transfer ability and on more complex aspects of adaptive functioning. Conclusions: Two out of four newly created measures in this exploratory dissertation provided partial support for weak transfer of learning in FASD. This was observed on the modified Tower of Hanoi, which shared an identical structure between conditions but differed in surface appearance. Parental ratings also indicated weak transfer of learning, although in children with FASD, these reports did not correlate with transfer abilities on the Tower of Hanoi. Children with FASD also demonstrated weak executive functioning, but this weakness was moderated significantly by intelligence. The relationship between transfer of learning and executive functioning appeared to be driven primarily by cognitive flexibility, although this relationship also was moderated by intelligence.

Phase-contrast magnetic resonance imaging (PC-MRI) can provide a complement to echocardiography for the evaluation of the fetal heart. Cardiac imaging typically requires gating with peripheral hardware; however, a gating signal is not readily available in utero. In this thesis, I present a technique for reconstructing time-resolved fetal phase-contrast MRI in spite of this limitation. Metric Optimized Gating (MOG) involves acquiring data without gating and retrospectively determining the proper reconstruction by optimizing an image metric, and the research in this thesis describes the theory, implementation, and evaluation of this technique. In particular, results from an experiment with a pulsatile flow phantom, an adult volunteer study, in vivo application in the fetal population, and numerical simulations are presented for validation. MOG enables imaging with conventional PC-MRI sequences in the absence of a gating signal, permitting flow measurements in the great vessels in utero.

Preterm birth remains a major challenge in obstetrics. It complicates up to 13% of all pregnancies and accounts for approximately 80% of neonatal mortality and morbidity. Bacterial Vaginosis (BV) is associated with a 1.4-fold increased risk of preterm birth. Due to ineffectiveness of antibiotics in preventing preterm labour, probiotics have been proposed to serve as an alternative for treatment of BV and prevention of preterm birth. The objectives of this thesis were to determine 1) the effect of Lactobacillus rhamnosus GR-1 (L. rhamnosus GR-1) supernatant on cytokine profile and prostaglandin (PG)-regulating enzyme expression in lipopolysaccharide (LPS)-stimulated human chorion and placental trophoblast cells from human placentae, 2) the potential signaling pathways through which lactobacilli act and 3) the potential role of immune and placental trophoblast cells in initiating a response to LPS and L. rhamnosus GR-1 treatments. Primary cultures of human placental trophoblast cells were pre-treated with lactobacilli supernatant and then with LPS. In addition, immune cells were removed from cell suspensions using a magnetic purification technique to determine their role in modulating cytokine levels. The expression of pro- and anti-inflammatory cytokines and prostaglandin-regulating enzymes was then determined. We found sex-specific differences in the ability of LPS to increase the output of TNF-α, IL-10, and PTGS2. We also showed that L. rhamnosus GR-1 is able to act through the JAK/STAT and MAPK pathways to increase IL-10 and G-CSF, and independently down-regulates PTGS2 and TNF-α and up-regulates PGDH. The increase in G-CSF and PGDH were only observed in women carrying a female fetus. L. rhamnosus GR-1 may serve as an alternative to antibiotics in preventing some infection/inflammation-mediated cases of preterm birth.

Phase-contrast magnetic resonance imaging (PC-MRI) can provide a complement to echocardiography for the evaluation of the fetal heart. Cardiac imaging typically requires gating with peripheral hardware; however, a gating signal is not readily available in utero. In this thesis, I present a technique for reconstructing time-resolved fetal phase-contrast MRI in spite of this limitation. Metric Optimized Gating (MOG) involves acquiring data without gating and retrospectively determining the proper reconstruction by optimizing an image metric, and the research in this thesis describes the theory, implementation, and evaluation of this technique. In particular, results from an experiment with a pulsatile flow phantom, an adult volunteer study, in vivo application in the fetal population, and numerical simulations are presented for validation. MOG enables imaging with conventional PC-MRI sequences in the absence of a gating signal, permitting flow measurements in the great vessels in utero.

OBJETIVOS: Comparar el valor predictivo de la monitorización antenatal de la F.C.F. respecto al bienestar fetal en función de la patología materna o fetal detectada durante el embarazo, y en función de la edad gestacional en que se realice dicha prueba.MATERIAL Y MÉTODOS: Para evaluar el valor predictivo de la monitoprización antenatal de la F.C.F. en función de la patología materna o fetal detectada durante el embarazo se relacionan de manera retrospectiva los resultados perinatales con el resultado de la prueba realizada la semana antes del parto en 1944 fetos de 1928 gestantes agrupadas según la patología materna o fetal presente. Para evaluar el valor predictivo de la monitorización antenatal en función de la edad gestacional se practican de manera prospectiva y con seguimiento lineal pruebas basales de una hora de duración semanal en 50 fetos desde las 28 a las 34 semanas. También se evaluan los resultados perinatales de 205 fetos, que nacieron entre las 28 y 36 semanas y de 1408 fetos nacidos entre las 37 y 41 semanas de gestación, con los resultados de la monitorización antenatal de la F.C.F. practicada la semana antes del parto. Los criterios de interpretación de la monitorización antenatal son la presencia de aceleraciones transitorias como indicativas de normalidad y la presencia de desaceleraciones o disminución de la variabilidad para la sospecha de pérdida de bienestar fetal. Se consideran como fetos con resultados perinatales desfavorables aquellos que presentan como mínimo una de las siguientes condiciones: Muerte perinatal, pH de arteria umbilical inferior a 7,2 o si la arteria se halla colapsada con un pH de vena umbilical inferior a 7,25, un índice de Apgar inferior a 7 a los 5 minutos de vida y/o presencia de retraso de crecimiento intrauterino y líquido amniótico meconial cuando se práctica cesárea electivaSe realizan estudios de sensibilidad, especificidad, valor predictivo positivo y negativo para los distintos grupos estudiados y análisis comparativos mediante test de Chi cuadrado y test exacto de Fischer.RESULTADOS: Al analizar el valor predictivo de la monitorización de la F.C.f. en todos los grupos estudiados se observa una buena sensibilidad y valor predictivo de un resultado normal con una especificidad y un valor predictivo de un resultado patológico relativamente bajos. Las patologías materno-fetales en que la monitorización de la F.C.F. es más útil son la isoimmunización Rh, la sospecha clínica o ecográfica de retraso de crecimiento, los malos antecedentes obstétricos, los estados hipertensivos del embarazo y en las gestantes diabéticas con hipertensión sobreañadida. Es de poca utilidad en gestantes diabéticas y en gestantes sin patología por su baja especificidad y valor predictivo de un resultado patológico. La monitorización antenatal en los fetos pretérmino, estableciendo unos nuevos criterios interpretativos en función de la edad gestacional, permite obtener una alta sensibilidad y valor predictivo de un resultado normal, con una especificidad y un valor predictivo de un resultado patológico relativamente reducidos. / Predictive value of antenatal fetal heart rate monitoring (AFHRM) related to pathology and gestational ageOBJECTIVE: To compare predictive value of AFHRM related to maternal or fetal pathology detected during pregnancy or to gestational age on which monitoring is done.MATERIAL AND METHODS: Perinatal results in 1944 fetuses out of 1928 pregnant women, grouped according to mother or fetal pathology, are retrospectively related with the result of AFHRM the week before delivery in order to evaluate its predictive value. Fifty fetuses are tested prospectively with AFHRM one hour long on a weekly basis from 28 and 34 weeks. Perinatal results of 205 fetuses born between 28 and 36 weeks gestation and 1408 fetuses born between 37 and 41 weeks gestation are also evaluated and related to AFHRM results within a week before delivery. AFHRM criteria of normality are the presence of transient accelerations and the presence of decelerations or a low variability suggests fetal distress. Perinatal morbidity criteria are: Perinatal death, umbilical arterial pH lower than 7.20, or if artery is collapsed an umbilical vein pH lower of 7.25, Apgar index below 7 at five minutes life and/or presence of intrauterine growth retardation and amniotic meconium staining in elective caesarean.Studies of sensitivity, specificity, positive and negative predictive value and comparative analysis by means of Chi-square and exact Fischer test are made for the different groups studied.RESULTS: A good sensitivity and negative predictive value and a low specificity and positive predictive value are observed on all studied groups. Rh isoimmunization, clinical or ecographical suspicion of fetal growth retardation, poor obstetric history, hypertensive diseases, diabetes plus hypertension are pathologies where AFHRM is most useful. AFHRM looks less useful in diabetes without hypertension and in low risk pregnancies because of its low specificity and positive predictive value. AFHRM before term shows a high sensitivity and negative predictive value, with a low specificity and positive predictive value, as long as new interpretative criteria based on gestational age are clearly set.