Introduction Maternal obesity (defined as a body mass index (BMI) ≥30kg/m2) and overweight (defined as BMI 25-29.9kg/m2) have adverse implications for both the mother and the baby, including an increased risk of caesarean section. The prevalence of caesarean section among the UK obstetric population has been increasing in recent years. Evidence suggests that caesarean section in obese women may carry a higher risk of postoperative complications, such as haemorrhage, wound infection and delayed healing. These complications may result in a longer length of stay in hospital after caesarean delivery. To date, UK evidence on the association between maternal BMI and caesarean section has been limited. Aim The overall aim of my PhD was to investigate the association between maternal BMI and caesarean section within the North East of England. Methods and Results My PhD consists of three phases: Phase one: a review of the available published literature that investigated the association between maternal BMI and caesarean section rate. The review found that most studies been carried out in the US with only six from the UK. The review highlighted the need for further research in the UK. Phase two: an investigation of the association between maternal early pregnancy BMI and caesarean section using an existing dataset of 42,362 deliveries in five hospitals in the North East of England. The objectives of this phase were; to identify the caesarean section rate among five hospitals in the North East of England; to describe the caesarean section rate by booking BMI; and to examine the independent impact of BMI on caesarean section, adjusting for potentially confounding variables including maternal age, gestational age, birth weight, ethnicity and socio-economic status in overweight and obese pregnant women compared to pregnant women with recommended BMI. In phase two, the overall caesarean section rate was 20.6%; 28.4% of obese and 21.9% of overweight women delivered by caesarean section, compared to 17.8% of women with recommended BMI. After adjusting for available confounding factors, the adjusted odds ratio (aOR) for caesarean section among obese women was 1.81 (95%CI: 1.67-1.97; p<0.0005) and 1.29 (95%CI: 1.20-1.39; p<0.0005) among overweight women compared to women with recommended BMI. Thus, there was an almost two-fold increased risk of delivery by caesarean section among women who were obese at the start of pregnancy and an increased risk for women who were overweight. Phase three: a case note review of 205 women with a singleton pregnancy in 2008, aged ≥16 years and delivered by caesarean section in a district general hospital in the North East of England. The study hypothesis was that overweight and obese pregnant women have more post-caesarean section complications than pregnant women with recommended BMI, resulting in a longer length of stay in hospital. The results of this study showed that from 205 cases (28% of all caesarean section deliveries in 2008), 86 (42.0%) were to women with recommended BMI, 54 (26.3%) to overweight and 65 (31.7%) to obese women. The median length of maternal stay in hospital was three days, with an inter quartile range (IQR) of 2-3. Twelve (18.5%) obese women stayed in hospital after caesarean section for four days compared to five (9.3%) overweight and eight (9.4%) women with recommended BMI, (p=0.44) but this was not significant. There were no significant differences in postoperative complications or length of stay in hospital between overweight and obese pregnant women compared to women with recommended BMI. Conclusion Overall, my study confirms that obese and overweight women in the North East of England are at increased risk of caesarean section. Among women delivered by caesarean section, however, there was no association between maternal BMI and post-operative complications or length of stay in hospital.

Background. Caesarean sections are critical interventions in obstetric care. The unmet need for caesareans is an important indicator for monitoring emergency obstetric care coverage: several methods have been proposed, however there is no consensus on how to measure the unmet need for caesareans in sub-Saharan Africa and South Asia. Methods. First, trends in the caesarean rate by wealth were analysed in 26 countries in sub-Saharan Africa and South Asia using Demographic and Health Surveys, in order to identify groups with rates below 1% and 2%. Second, a global online survey was conducted on obstetricians’ opinions of the optimal caesarean rate. Third, linked hospital and population-based data were used to validate the Unmet Obstetric Need (UON) indicator in central Ghana, which measures the unmet need for surgery for absolute maternal indications (AMIs), and to investigate novel approaches using hospital data. Results. The caesarean rate was extremely low among poor women in most sub-Saharan African and South Asian countries. The median optimal caesarean rate reported by obstetricians worldwide was 20%, and there was a large variation in responses (IQR: 15-30%). The 1.4% threshold for the UON indicator was found not to be valid in Ghana. For most complications – including AMIs, among which caesarean rates were close to 100% – women were equally likely to have their need for caesareans met regardless of their educational level. Conclusion. The optimal caesarean rate remains unknown, and thus cannot be used as a benchmark for measuring the unmet need. The UON indicator does not produce valid estimates of AMI-related mortality avertable with caesareans, however caesarean rates below 1% probably indicate a critical unmet need for life-saving surgery. Comparing caesarean rates in hospitals by education is useful for determining whether population-based differences in the caesarean rate are partly explained by differential access to care within facilities.

No description available.

No description available.

No description available.

No description available.

Childhood feminising surgery remains standard clinical practice for those born with ambiguous genitalia, such as women with Congenital Adrenal Hyperplasia (CAH). The aims of such an intervention are to promote "normal" female appearance, allow comfortable penetrative intercourse with unimpaired sensation, avoid increased psychological sequelae and prevent urinary difficulties due to anatomical variations. However, these aims remain largely unevaluated. Little is known about the range of normal female genital appearance with few objective measurements in the literature. Scanty long-term data is available regarding sexual function and sensation following childhood feminising surgery. To date there is no evidence to suggest that childhood surgery reduces psychological distress compared with those who did not have operations. Finally, no studies are available assessing urinary outcomes following surgery. These areas are assessed in turn, starting with a study to ascertain normal female appearance of the genital area, and to illustrate the variations of normality. Genital sensation is next considered, with a study of 28 women with CAH who underwent objective sensation testing to the clitoris, where surgery had taken place, and to the upper vagina, where no operations had been performed. This data was compared with 9 normal subjects who had no history of sexual function difficulties or previous operations to the genital area. Clitoral sensation was significantly impaired in those who had undergone surgery, but not vaginal sensation. Sexual function and subjective views regarding surgery were assessed, with 32 women with CAH recruited to complete a detailed questionnaire assessing various aspects of anatomical and psychosexual function. This was then compared with data from 10 normal controls, showing women with a history of surgery had increased sexual function difficulties. Finally, a further study assessed the degree of lower urinary tract symptoms in those who had undergone surgery, and compared this with a normal control group. This showed increased urinary tract symptomatology in the group who had undergone childhood surgery. The results of these studies are discussed and considered in the context of current knowledge of intersex research. Recommendations for clinical practice and future research are given.

Reduced cerebral blood flow (CBF) has been reported in patients with Alzheimer's disease (AD), with increasing evidence to suggest that the hypoperfusion contributes to decline in cognitive function and possibly to progression of the neurodegeneration. Key proteins that are upregulated under conditions of cerebral hypoxia are the hypoxia inducible factor-ia (HIFia) and neuroglobin (NGB) which both induce the transcription of mUltiple genes, including some involved in the production of amyloid-β (Aβ) and the angiogenic growth factor, vascular endothelia growth factor (VEGF). This thesis describes a series of studies to investigate the molecular evidence of hypoxia in post-mortem brain tissue from patients with AD, vascular dementia (VaD), dementia with Lewy bodies (DLB; all cases with little or no cerebrovascular disease) and non-demented controls. qRT-PCR and ELISA were used to investigate the mRNA and protein expression of HIFla, NGB and VEGF. Hypoxia was also indirectly assessed by the measurement of myelinassociated glycoprotein (MAG), which is more sensitive to ischaemia than other myelin proteins, and comparing it to the relatively stable proteolipid protein-1 (PLP). The relationship to the severity of the two main structural abnormalities of the microvasculature, arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), both of which can cause cerebral ischaemia and cognitive impairment; the levels of total Aβ, Aβ1-40 and Aβ1.42 and severity of AD pathology as determined by Braak tangle stage; and the level and activity of angiotensin-converting enzyme (ACE), which catalyses the production of a powerful vasoconstrictor angiotensin II, and the level ofthe vasoconstrictor, endothelin-1 (ET-1) were also assessed. NGB protein level did not differ significantly in AD or VaD compared to controls but MAG protein level was reduced in both disease groups, consistent with what was previously demonstrated in the white matter, and was found to decrease with increasing severity of SVD. In contrast, VEGF protein was elevated in both disease groups but particularly AD; it correlated with the level of insoluble Aβ, Aβ1-42 and the Aβ1-42:Aβ1-40 ratio and to a lesser extent with the Braak tangle stage and ACE activity. There was no relationship between the level of ET-1 and VEGF. There was also only a weak relationship between VEGF or NGB and the severity of SVD or CAA. It seems likely that the increase in VEGF protein in AD is largely related to the accumulation of A~ rather than to SVD or to vasoconstriction mediated by ET-1 or angiotensin II. In DLB, NGB protein level was significantly increased in the cingulate cortex and MAG protein level reduced, although not significantly. There was no significant change in VEGF level. The mechanism of hypoperfusion seems likely to differ from that in AD. Together these findings suggest that the molecular assessment of hypoxia may provide a useful means to investigate different mechanisms of reduced CBF in various forms of dementia.

La pratique régulière d’une activité physique (AP) est un important message de santé publique. L’AP améliore non seulement la santé cardiovasculaire via l’augmentation de la production de NO (nitric oxide) par l’endothélium vasculaire mais aussi la santé cérébrale via l’augmentation des taux de BDNF (brain-derived neurotrophic factor) dans le cerveau. Comme la synthèse et la sécrétion de BDNF sont proportionnelles à l’activité neuronale, il est généralement admis que l’élévation des taux cérébraux de BDNF induite par l’AP est à relier à l’hyperactivité neuronale. Nous avons testé l’hypothèse selon laquelle l’élévation du flux sanguin dans les vaisseaux de la circulation cérébrale pendant la réalisation de l’AP contribue à augmenter les taux cérébraux de BDNF. Les expériences ont été menées chez des rats soumis ou non à l’AP (tapis roulant). Nos résultats montrent : 1) que l’augmentation des taux de BDNF induite par l’AP (tapis roulant, 18m/min, 30 min/j, 7j consécutifs) est moindre lorsque l’augmentation du flux sanguin pendant la réalisation de l’AP, est prévenue par un clampage mono- ou bi- carotidien, 2) que l’effet de l’AP sur les taux de BDNF dépend de l’intensité de l’AP ( tapis horizontal versus déclive descendant), 3) que la dysfonction endothéliale (modèle de rat spontanément hypertendu) et le traitement par un inhibiteur de NO synthase diminuent les effets de l’AP sur les taux cérébraux de BDNF et 4) qu’il existe une association positive entre les taux cérébraux de BDNF et la production de NO par l’endothélium vasculaire.L’ensemble de nos résultats suggère que l’augmentation des taux cérébraux de BDNF induite par l’AP met en jeu l’augmentation du flux sanguin dans les vaisseaux de la circulation cérébrale et, plus précisément, l’augmentation de la production endothéliale de NO qui en résulte. Ils fournissent de nouvelles données pour comprendre le lien existant entre fonction endothéliale et performances cognitives, soulevant l’idée selon laquelle les modalités d’AP pour améliorer la santé cérébrale doivent être différentes en cas de pathologies associées à une dysfonction endothéliale. / The regular practice of physical activity (PA) is an important public health message. PA not only improves cardiovascular health through the increase in NO (nitric oxide) production by the vascular endothelium but also through the increase levels in brain BDNF (brain-derived neurotrophic factor) levels. As the synthesis and secretion of BDNF are proportional to neuronal activity, it is generally accepted that PA-induced brain BDNF levels elevation is linked to neuronal hyperactivity. We tested the hypothesis that the increase in blood flow in cerebrovasculature during PA contributes to increase brain BDNF levels. The experiments were carried out in sedentary and trained rats (treadmill). Our results show that: 1) brain BDNF levels elevation induced by PA (treadmill, 18m /min, 30 min /day, 7 consecutive days) is lower when the normal rise of cerebral blood flow during the PA is prevented by occluding one or both common carotid arteries, 2) the effect of PA on brain BDNF levels is dependent on PA intensity (horizontal versus downhill), 3) the presence of endothelial dysfunction (spontaneously hypertensive rat model) as well as NO synthase inhibition decrease the effects of PA on brain BDNF levels and 4) there is a positive association between brain BDNF levels and vascular endothelium NO production .Collectively, our results suggest that increase in brain BDNF levels, induced by PA, involves increase in cerebrovasculature blood flow and more precisely elevation in endothelium NO production. They provide new data for understanding the relationship between endothelial function and cognitive performance, raising the idea that PA modalities to improve brain health might be different in pathologies diseases with endothelial dysfunction.

Si le rôle de la gustation sur le développement des préférences alimentaires a été étudié par le passé, il n’en ait pas de même du rôle de l’olfaction. Les objectifs de ce travail de thèse étaient d’étudier les réponses olfactives des nourrissons, leur dynamique au cours des deux premières années de vie, ainsi que leurs relations avec les expositions aromatiques précoces, l’appréciation alimentaire et le comportement néophobique des nourrissons. Ce travail, s’inscrivant dans le cadre de l’étude longitudinale OPALINE (Observatoire des Préférences ALImentaire du Nourrisson et de l’Enfant), a permis d’évaluer les réponses olfactives envers des odeurs alimentaires agréables, comme la vanille, et désagréables, comme le poisson, chez les nourrissons de 8, 12 et 22 mois. Les résultats révèlent que, dès 8 mois, les nourrissons sont capables de discriminer les odeurs agréables des odeurs désagréables. Toutefois, si des réponses d’évitement envers certaines odeurs désagréables sont observées, aucune réponse d’attraction n’est décrite au cours des deux premières années de la vie. De plus, nos résultats mettent également en évidence une certaine plasticité des réponses olfactives. Seules les réponses à quelques odeurs alimentaires désagréables sont stables entre deux âges consécutifs suggérant que les réponses hédoniques négatives vis-à-vis d’odeurs alimentaires apparaitraient plus précocement que les réponses hédoniques positives.Concernant les effets des expositions aromatiques précoces, il apparaît que plus un nourrisson a été exposé, in utero ou durant l’allaitement, aux notes aromatiques désagréables de certains aliments, moins il aura de réponses d’évitement face aux odeurs de ces aliments à 8 mois, mais pas au-delà.Lors de la diversification alimentaire (8 mois), la composante olfactive ne semble pas avoir d’impact sur l’appréciation des aliments nouvellement introduits. En revanche, à 12 mois, la composante olfactive pourrait jouer un rôle de modulateur dans l’appréciation des aliments à flaveur prononcée. Ce rôle n’est plus observé à 22 mois. Nos résultats mettent également en évidence que la réactivité différentielle à différentes odeurs, et non à différentes saveurs, est liée au degré de néophobie du nourrisson, suggérant que seules les odeurs contribuent à la méfiance envers les aliments nouveaux au cours de la seconde année de vie. Ce travail met en avant que les expositions aromatiques précoces peuvent influencer les réponses olfactives au début de la diversification alimentaire, période favorable à l’acceptation des aliments. Autour de l’âge d’un an, quand le répertoire alimentaire des nourrissons s’élargit et intègre des aliments dits « adultes », l’odorat jouerait un rôle clé dans l’appréciation des aliments en agissant comme un système d’alarme protégeant le nourrisson des aliments potentiellement dangereux / The role of taste on food preferences has already been investigated, however, little is known about the role of olfaction. The main objectives of this work were to assess infants’ olfactory responses, their dynamic during the first two years of life, and also their links with early food exposures, food liking and infants’ food neophobia. This work was conducted within a longitudinal study named OPALINE (Observatory of food preferences in infants and children). Olfactory responses were assessed, in 8-, 12- and 22-month-old infants, towards pleasant odours, such as vanilla, and unpleasant odours, such as fish. The results reveal that, from 8 months, infants can discriminate pleasant and unpleasant odours. However, only avoidance responses are observed towards some unpleasant odours; no attraction responses are highlighted during the first two years of life. Our results also suggest a plasticity of olfactory responses. Only responses towards some unpleasant odours are stable between two consecutive ages, suggesting that negative hedonic responses towards food odours would appear earlier than positive ones. Concerning the effects of early food exposure, it appears that the more an infant has been exposed, in utero or during breastfeeding, to some unpleasant food odours, the least s/he exhibits avoidance responses towards these food odours at 8 months, but not beyond. When complementary feeding has begun (8 months), olfaction does not seem to impact new food liking. However, at 12 months, olfaction can play a role of modulator in liking of the foods with strong flavour. This role is not observed anymore at 22 months. Our results also highlight that differential olfactory responses, and not gustatory ones, are linked to infants’ food neophobia suggesting that only odours contribute to the suspicion towards unfamiliar foods during the second year of life. This work stresses that early sensory exposures influence responses towards unpleasant odours at the onset of complementary feeding, which is a favourable period to food acceptance. Then, olfaction can play a role in food liking by acting as an alarm system protecting the infants against potentially harmful food