How did varying levels of intensity of the 2005 Pakistan earthquake differentially affect women’s fertility decisions and children’s health outcomes?

This paper uses a difference in difference model to investigate the impact of a large scale and high mortality 2005 earthquake in Pakistan on women’s fertility decisions and children’s health outcomes. Using a nationally representative, cross sectional DHS data from 2006 and geographical data from USGS, this paper investigates how variation in earthquake intensity levels can differentially impact total fertility for women and the likelihood of children suffering from diseases such as diarrhea, Acute Respiratory Infections (ARI) and fever. The post-earthquake results demonstrate a statistically significant increase in total fertility for areas closer to the epicenter of the earthquake, within a 100km radius of the rupture surface and at higher altitudes. Similarly, for children who were in-utero at the time of the earthquake, the probability of having early symptoms of ARI or fever was much smaller in lower earthquake intensity zones compared to the highest intensity zone.

Investigating the developmental and behavioral consequences of maternal immune activation on affected offspring

Maternal infection during pregnancy increases the risk of several neuropsychiatric disorders later in life, many of which have a component of dopaminergic (DA) dysfunction, including schizophrenia, autism spectrum disorders (ASD), and attention deficit hyperactivity disorder (ADHD). The majority of DA neurons are found in the adult midbrain; as such the midbrain is a key region of interest regarding these disorders. The literature is conflicting regarding the behavioral alterations following maternal immune activation (MIA) exposure, and the cellular and molecular consequences of MIA on the developing midbrain remain to be fully elucidated. Thus, this thesis aimed to establish the consequences of acute and mild MIA on offspring dopamine-related behaviors, as well as the associated cellular and molecular disturbances of MIA on offspring midbrains. We utilized a rat model of MIA using low dose (50μg/kg, I.P.) of LPS administered at different gestational ages. Our first study indicated that MIA at later gestational ages significantly increased pro-inflammatory IL-1β expression, and reduced HSD11B2 expression in the placenta, which is an important regulator of fetal development. In utero LPS exposure at later gestational ages also impaired the growth of neurons from affected offspring. This study identified key gestational stages during which MIA resulted in differential effects. We utilized these time points in subsequent studies, the next of which investigated neurobehavioral outcomes following MIA. Our results from that study showed that motor differences occurred in juvenile offspring following MIA at E16 only, and these differences were compensated for in adolescence. Then, there was a decline in motor behavior capabilities in adulthood, again only for animals exposed to MIA on E16 (and not E12). Furthermore, our results also demonstrated adolescent and adult offspring that were exposed to MIA at E12 had diminished responses to amphetamine in reward seeking behaviors. In our final study, we aimed to investigate the molecular and cellular changes following MIA which might explain these behavioral alterations. This final study showed a differential inflammatory response in fetal midbrains depending on gestational age of exposure as well as differential developmental alterations. For example, LPS exposure at E16 resulted in decreased VM neurosphere size after 7DIV and this was associated with an increased susceptibility to neurotoxic effects of pro-inflammatory cytokines for VM neurospheres and VM DA neurons treated in culture. In utero LPS exposure at E16 also reduced DA neuron count of fetal VM, measured by TH staining. However, there were no differences in DA neuron number in juvenile, adolescent, or adult offspring. Similarly, LPS exposure did not alter cell number or morphology of glial cells in the midbrains of affected offspring. In conclusion, this thesis indicated later rat pregnancy (E16) as vulnerable time for MIA to affect the development of the nigrostriatal pathway and subsequent behavioral outcomes, possibly implicating a role for MIA in increased risk for disorders associated with motor behavior, like PD. These effects may be mediated through alterations in the placenta and altered inflammatory mediators in the offspring brain. This thesis has also shown that MIA in earlier rat pregnancy (E12) results in altered mesocorticolimbic function, and in particular MIA on E12 resulted in a differential response to amphetamine in affected offspring, which may implicate a role for MIA in increasing the risk for disorders associated with this pathway, including drug tolerance and addiction.

Cortisol salivaire chez des mères adolescentes et leur nourrisson : exploration de quelques corrélats psychopathologiques et comportementaux

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Immunologically silent cancer clone transmission from mother to offspring

Rare cases of possible materno-fetal transmission of cancer have been recorded over the past 100 years but evidence for a shared cancer clone has been very limited. We provide genetic evidence for mother to offspring transmission, in utero, of a leukemic cell clone. Maternal and infant cancer clones shared the same unique BCR-ABL1 genomic fusion sequence, indicating a shared, single-cell origin. Microsatellite markers in the infant cancer were all of maternal origin. Additionally, the infant, maternally- derived cancer cells had a major deletion on one copy of chromosome 6p that included deletion of HLA alleles that were not inherited by the infant (i.e., foreign to the infant), suggesting a possible mechanism for immune evasion.

Fetal Movements in late Pregnancy : Categorization, Self-assessment, and Prenatal Attachment in relation to women’s experiences

Aim: To explore how pregnant women experience fetal movements in late pregnancy. Specific aims were:  to study women’s experiences during the time prior to receiving news that their unborn baby had died in utero (I), to investigate women’s descriptions of fetal movements (II), investigate the association between the magnitude of fetal movements and level of prenatal attachment (III), and to study women’s experiences using two different self-assessment methods (IV). Methods: Interviews, questionnaires, and observations were used. Results: Premonition that something had happened to their unborn baby, based on a lack of fetal movements, was experienced by the participants. The overall theme “something is wrong” describes the women’s insight that the baby’s life was threatened (I). Fetal movements that were sorted into the domain “powerful movements” were perceived in late pregnancy by 96 % of the participants (II). Perceiving frequent fetal movements on at least three occasions per 24 hours was associated with higher scores of prenatal attachment in all the three subscales on PAI-R. The majority (55%) of the 456 participants reported average occasions of frequent fetal movements, 26% several occasions and 18% reported few occasions of frequent fetal movements, during the current gestational week.  (III). Only one of the 40 participants did not find at least one method for monitoring fetal movements suitable. Fifteen of the 39 participants reported a preference for the mindfetalness method and five for the count-to-ten method. The women described the observation of the movements as a safe and reassuring moment for communication with their unborn baby (IV). Conclusion:  In full-term and uncomplicated pregnancies, women usually perceive fetal movements as powerful. Furthermore, women in late pregnancy who reported frequent fetal movements on several occasions during a 24-hour period seem to have a high level of prenatal attachment. Women who used self-assessment methods for monitoring fetal movements felt calm and relaxed when observing the movements of their babies. They had a high compliance for both self-assessment methods. Women that had experienced a stillbirth in late pregnancy described that they had a premonition before they were told that their baby had died in utero. 

Functional analysis of the 5′ flanking region of the human G6PC3 gene: regulation of promoter activity by glucose, pyruvate, AMP kinase and the pentose phosphate pathway

G6PC3 is a widely expressed isoform of glucose-6-phosphatase, found in many foetal and adult tissues. Mutations in this gene cause developmental abnormalities and severe neutropenia due to abolition of glucose recycling between the cytoplasm and endoplasmic reticulum. Low G6PC3 expression as a result of promoter polymorphisms or dysregulation could produce similar outcomes. Here we investigated the regulation of human G6PC3 promoter activity. HeLa and H4IIE cells were transiently transfected with G6PC3 promoter coupled to the firefly luciferase gene, and promoter activity was measured by dual luciferase assay. Activity was highest in a 453 bp segment of the G6PC3 promoter, from − 455 to − 3 relative to the transcriptional start site. This promoter was unresponsive to glucostatic hormones. Its activity increased significantly between 1 and 5.5 mM glucose, and was not elevated further by glucose concentrations up to 25 mM. Pyruvate increased its activity, but β-hydroxybutyrate and sodium acetate did not. Promoter activity was reduced by inhibitors of hexokinase, glyceraldehyde phosphate dehydrogenase and the oxidative branch of the pentose phosphate pathway, but not by a transketolase inhibitor. Deletion of two adjacent Enhancer-boxes (− 274 to − 279 and − 299 to − 304) reduced promoter activity and abolished the glucose effect, suggesting they could function as a glucose response element. Deletion of an additional downstream 140 bp (− 140 to − 306) restored activity, but not the glucose response, suggesting the presence of repressor elements in this region. 5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) reduced promoter activity, showing dependence on AMP-kinase. Regulation of the G6PC3 promoter is thus radically different to that of the hepatic isoform, G6PC. It is sensitive to carbohydrate, but not to fatty acid metabolites, and at much lower physiological concentrations. Based on these findings, we speculate that reduced G6PC3 expression could occur during hypoglycemic episodes in vivo, which are common in utero and in the postnatal period. If such episodes lower G6PC3 expression they could place the foetus or infant at risk of impaired immune function and development, and this possibility requires further examination both in vitro and in vivo.

Cecal volvulus during pregnancy. Case report

Introduction. Acute intestinal obstruction in pregnancy is a rare, but life-threatening complication associated with high fetal and maternal mortality. Case report. A 20-year old gravida presented with a 24 hour history of several episodes of vomiting, complete constipation and severe crampy abdominal pain. The patient was admitted with the diagnosis of acute abdomen associated with septic shock. On examination echography showed distended intestinal loops and presence of free peritoneal fluid. Abdominal X-ray with shielding of the fetus revealed colonic air-fluid levels. The obstetrician consult diagnosed dead fetus in utero and was decided to operate immediately. On laparotomy was found complete cecal volvulus with gangrene of cecum, part of ascending colon and terminal ileum. A right hemicolectomy was performed with side to side ileotransverse anastomosis. Afterwards a lower segment cesarean section was made and a stillborn fetus was delivered. The patient made an uneventful recovery and was discharged on 9th postoperative day. Conclusion. Cecal volvulus during pregnancy is a rare, but serious surgical problem. Correct diagnosis may be difficult until exploratory laparotomy is performed. Undue delay in diagnosis and surgical treatment can increase the maternal and fetal mortality.

Prevalencia de acortamiento y embudización del cérvix, y factores asociados a parto prematuro en mujeres atendidas en el Hospital Vicente Corral Moscoso 2012. Cuenca

Objetivo: Determinar la prevalencia del acortamiento del cérvix más embudización y otros factores asociados al parto prematuro, en mujeres de 20 a 34 semanas de gestación que acuden al hospital Vicente Corral Moscoso 2012. Materiales y Métodos: Se realizó un estudio transversal en mujeres embarazadas entre 20 y 34 semanas de gestación, durante el año 2012. Las pacientes fueron asignadas en forma secuencial cumpliendo los criterios de inclusión y exclusión. La longitud cervical y la presencia o no de embudización fueron medidas con Ecografía Transvaginal y los demás datos se obtuvieron de la ficha clínica y por entrevista directa siendo trascritas a un cuestionario; mismos que fueron procesados con software Microsoft Exel y SPSS. Resultados obtenidos: La prevalencia de partos prematuros fue del 12,06%. La prevalencia de acortamiento cervical fue del 14%, la de embudización del 4,5%. Dentro de los factores de riesgo asociados al parto prematuro con significancia estadística se muestran: acortamiento del cérvix, embudización del cérvix, la escolaridad y el antecedente de parto prematuro. Conclusiones: Seestudió un grupo de 506 mujeres cuya edad gestacional mínima fue de 20 semanas la máxima de 34,6 con una media de 30,14. La edad inferior fue de 16 años y la superior de 42, con una media de 24,18. La prevalencia de partos prematuros fue del 12,06%. La prevalencia de acortamiento cervical fue del 14% y la de embudización del 4,5%. Dentro de los factores de riesgo asociados al parto prematuro con significancia estadística se muestran: acortamiento del cérvix, embudización del cérvix, la escolaridad y el antecedente de parto prematuro.

Is the legal protection for the foetus adequate in clinical trials?

In 2009 and 2010, the major drug regulatory bodies, the European Medicines Agency and the Food and Drug Administration in the USA, issued requests for the generation of information relating to the absorption, distribution, metabolism, excretion, efficacy and safety of investigational drugs in pregnant women prior to approval. In the wake of thalidomide, research involving pregnant women other than for obstetric or gynaecologic purposes became rare, and studies of investigational drugs practically unknown. Consequently, none of the legislation applicable in the UK and few of the guidelines introduced in the last 40 years properly addresses the conduct of clinical trials of investigational drugs in this population. This thesis questions whether the legal protection for the foetus is adequate in clinical trials. The answer appears to be a qualified “no”. Arguments persist regarding the moral standing of the foetus, particularly regarding abortion. That will not be the intent of such trials, and a moral case is made for the conduct of clinical trials in this population by analogy with the neonate, and the pregnant woman’s autonomy. Legally, we already recognise the foetus has ‘interests’ which crystallise upon live birth, and that compensation is recoverable for harm inflicted in utero manifesting as congenital injury. The essence of research is quite different from medical practice, and the extent to which this is understood by trial participants is unclear. The approvals processes contain a number of inadequacies which have the potential to expose the foetus to harm and affect the consent of the pregnant woman. The recovery of compensation in the event of children born injured following clinical trials during pregnancy in many ways may be more complex than other personal injury cases.. The conclusions of this thesis are that the existence of a foetus does merit recognition by the law in this setting and that morally such studies are justifiable. However, the present legislation and approval processes potentially expose the foetus to avoidable risk and may not be appropriate to enable the recovery of compensation, thereby creating potential to deter future trial participants. A proposal is made regarding an approach to simplify the process for recovery of compensation, and thereby strengthen the approval and consent processes.

Prenatal appetitive learning about ethanol in the rat: possible reinforcers.

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Modificaciones de cuello uterino detectadas por examen de papanicolaou en mujeres beneficiarias del programa de detección oportuna del cáncer (DOC) Hospital Vicente Corral Moscoso durante el año 2003, Cuenca 2005

Estudio descriptivo en el que se incluyeron 3953 papanicolaou, con la nomenclatura del Sistema Bethesda. Justificación: proque se cree necesario conocer la realidad del medio sobre patología cervical. Resultados: dentro de límites normales 7, cambios celulares benignos 76.5, células escamosas atípicas de significancia indeterminada ASCUS 12.2neoplasia intraepitelial de bajo grado LIE BG 1.7, neoplasia intraepitelial de alto grado LIEAG 0, 7, carcinoma de células escamosas 0,6, células glandulares atípicas de significancia indeterminada AGUS

Balance ability in 7- and 10-year-old children:associations with prenatal lead and cadmium exposure and with blood lead levels in childhood in a prospective birth cohort study

OBJECTIVES: Most studies reporting evidence of adverse effects of lead and cadmium on the ability to balance have been conducted in high-exposure groups or have included adults. The effects of prenatal exposure have not been well studied, nor have the effects in children been directly studied. The aim of the study was to identify the associations of lead (in utero and in childhood) and cadmium (in utero) exposure with the ability to balance in children aged 7 and 10 years. DESIGN: Prospective birth cohort study. PARTICIPANTS: Maternal blood lead (n=4285) and cadmium (n=4286) levels were measured by inductively coupled plasma mass spectrometry in women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) during pregnancy. Child lead levels were measured in a subsample of 582 of ALSPAC children at age 30 months. MAIN OUTCOME MEASURES: Children completed a heel-to-toe walking test at 7 years. At 10 years, the children underwent clinical tests of static and dynamic balance. Statistical analysis using SPSS V.19 included logistic regression modelling, comparing categories of ≥ 5 vs <5 µg/dL for lead, and ≥ 1 vs <1 µg/L for cadmium. RESULTS: Balance at age 7 years was not associated with elevated in utero lead or cadmium exposure (adjusted OR for balance dysfunction: Pb 1.01 (95% CI 0.95 to 1.01), n=1732; Cd 0.95 (0.77 to 1.20), n=1734), or with elevated child blood lead level at age 30 months (adjusted OR 0.98 (0.92 to 1.05), n=354). Similarly, neither measures of static nor dynamic balance at age 10 years were associated with in utero lead or cadmium exposure, or child lead level. CONCLUSIONS: These findings do not provide any evidence of an association of prenatal exposure to lead or cadmium, or lead levels in childhood, on balance ability in children. Confirmation in other cohorts is needed.

The impact and control of malignant catarrhal fever in Tanzania

Malignant Catarrhal Fever (MCF), an often-lethal infectious disease, presents as a variable complex of lesions in susceptible ungulate species. The disease is caused by a -herpesvirus following transmission from an inapparent carrier host. Two major epidemiological forms exist: wildebeest-associated MCF (WA-MCF), in which the virus is transmitted to susceptible species by wildebeest calves less than approximately four months of age, and sheepassociated MCF (SA-MCF) in which the virus is spread by sheep (primarily adolescents). Due to the lack of an in-vitro propagation system for the causative agent of the more economically significant SA-MCF, and with the expectation that cross-protective immunity may be provided, vaccine development has focused on the more easily propagated alcelaphine herpesvirus-1 (AlHV-1) that causes WA-MCF. In 2008 a direct viral challenge trial showed that a novel vaccine, employing an attenuated AlHV-1 (atAlHV-1) `C5000 virus strain, protected British Friesian-Holstein (FH) cattle against an intranasal challenge with virulent AlHV-1 `C5000 virus. For cattle keeping people living near wildebeest calving areas in sub-Saharan Africa an effective vaccine would have value as it would release them from the costly annual disease avoidance strategy of having to move their herds away from the oncoming wildebeest. On the other hand, an effective vaccine will release herd owners from the need to avoid MCF, allowing them to graze their cattle alongside wildebeest on the highly nutritious pastures of the calving areas. As such conservationists have raised concerns that the development of a vaccine might lead to detrimental grazing competition. The principle objective of this study was to test the novel vaccine on Tanzanian shorthorn zebu cross cattle (SZC).We did this firstly using a natural challenge field trial (Chapter Two) which demonstrated that immunisation with the atAlHV-1 vaccine was well tolerated and induced an oro-nasopharyngeal AlHV-1-specific and -neutralising antibody response. This resulted in an immunity in SZC cattle that was partially protective and reduced naturally transmitted infection by 56%. We also demonstrated that non-fatal infections occurred with a much higher frequency than previously thought. Because the calculated efficacy of the vaccine was less than that seen in British FH cattle we wanted to determine whether host factors, particular to SZC cattle, had impacted the outcomes of the field trial. To do this we repeated the 2008 direct viral challenge trial using SZC cattle (Chapter Four). During this trial we also investigated whether the recombinant bacterial flagellin monomer (FliC), when used as an adjuvant, might improve the vaccine’s efficacy. The findings from this trial indicated that direct challenge with pathogenic AlHV-1 is effective at inducing MCF in SZC cattle and that FliC is not an appropriate adjuvant for this vaccine. Furthermore, with less control group cattle dying of MCF than expected we speculate that SZC cattle may have a degree of resistance to MCF that affords them protection from infection and developing fatal disease. In Chapter Three we investigated aspects of the epidemiology of MCF, specifically whether wildebeest placenta, long implicated by Maasai cattle owners as a source of MCF, might play a role in viral transmission. Additionally, through comparative sequence analysis, at two specific genes (A9.5 and ORF50) of wild-type and atAlHV-1, we investigated whether the `C5000 strain, the source of which was taken from Africa more than 40 years ago, was appropriate for vaccine development. The detection of AlHV-1 virus in approximately 50% of placentae indicated that infection can occur in-utero and that this tissue might play a role in disease transmission. And, despite describing three new alleles of the A9.5 gene (supporting previous evidence that this gene is polymorphic and encodes a secretory protein with interleukin-4 as the major homologue), the observation that the most frequently detected haplotypes, in both wild-type and attenuated AlHV-1, were identical suggests that AlHV-1 has a slow molecular clock and that the attenuated strain was appropriate for vaccine development. In Chapter Five we present the first quantitative assessment of the annual MCF avoidance costs that Maasai pastoralists incur. In particular we estimated that as a result of MCF avoidance 64% of the total daily milk yield during the MCF season was not available to be used by the 81% of the family unit remaining at the permanent boma. This represents an upper-bound loss of approximately 8% of a household0s annual income. Despite these considerable losses we concluded that, given an incidence of fatal MCF in cattle living in wildebeest calving areas of 5% to 10%, if herd owners were to stop trying to avoid MCF by allowing their cattle to graze alongside wildebeest, any gains made through increased availability of milk, improved body condition and reduced energy demands would be offset by an increase in MCF-incidence. With the development of an effective vaccine, however, this alternative strategy might become optimal. The overall conclusion we draw therefore is that, despite the substantial costs incurred each year avoiding MCF, the partial protection afforded by the novel vaccine strategy is not sufficient to warrant a wholesale change in disease avoidance strategy. Nonetheless, even the partial protection provided by this vaccine could be of value to protect animals that cannot be moved, for example where some of the herd remain at the boma to provide milk or where land-use changes make traditional disease avoidance difficult. Furthermore, the vaccine may offer a feasible solution to some of the current land-use challenges and conflicts, providing a degree of protection to valuable livestock where avoidance strategies are not possible, but with less risk of precipitating the potentially damaging environmental consequences, such as overgrazing of highly nutritious seasonal pastures, that might result if herd owners decide they no longer need to avoid wildebeest.