Background: After hypoxia-ischaemia and successful resuscitation, cerebral energy metabolism transiently recovers to the normal level (latent phase); after a variable period of time this phase is followed by secondary energy failure (SEF) in those subjects with an adverse outcome. A better understanding of the regional evolution of SEF may enhance the application of future neuroprotective strategies. Aims: The aim of this thesis was to determine associations between the insult severity, regional SEF evolution, and subsequent histo-pathological brain injury using magnetic resonance biomarkers. Methods: An established piglet model of neonatal encephalopathy was used. 1. Twenty-nine piglets were studied either normothermic or hypothermic (35°C or 33°C during 2-26 hours after hypoxia-ischaemia). 31-phosphorus magnetic resonance spectroscopy (31P MRS) was serially acquired; the brain was assessed histo-pathologically after 48 hours. 2. Global 31P MRS, and maps of apparent diffusion coefficient (ADC) and transverse relaxation time (T2) were serially obtained in 3 control and 18 asphyxiated piglets. Histo-pathological brain injury and MR biomarkers were compared at time periods of 16-48 hours after hypoxia-ischaemia. Results: 1. Severe acute insult, short latent phase, severe SEF and profound histo-pathological brain injury were associated between each other. 2. Transient recovery in phosphocreatine (PCr) higher than its baseline was indicative of absent subsequent evolution of SEF, whereas sub-baseline PCr recovery was suggestive of severe SEF. 3. Global 31P MRS biomarkers and regional ADC obtained just prior to termination and up to 18-24 hours before termination predicted histo-pathological brain injury; the predictive value was optimal for global PCr/ inorganic phosphate (Pi), followed by global PCr/exchangeable high-energy phosphate pool (EPP), Pi/EPP and regional ADC. Conclusions: Although 31P MRS was more accurate, regional ADC predicted subsequent brain injury up to 18 hours in advance of termination. Regional ADC can be used as a sensitive early marker for subsequent tissue injury when 31P MRS is not available.

Background: Therapeutic hypothermia following perinatal hypoxia-ischaemia improves survival and neurological functioning at 18 months of age. Precise brain temperature control commenced shortly after birth may improve the benefit. Aims: The aim of this thesis was (i) to clarify associations between regional brain temperatures, body weight, ambient temperature, cerebral perfusion and oxygen metabolism under normothermia/hypothermia; and (ii) to develop safe/reliable cooling device for pre-hospital cooling. Methods: 1. Brain temperatures were monitored in 14 anaesthetised newborn piglets with normothermia, whole-body cooling and selective-head cooling. 2. The rectal temperature (Trectal), non-invasive (zero-heat-flux) brain temperatures, relative superior vena-cava (rSVC) flow (echocardiography) to the brain weight, and the cerebral metabolic rate of oxygen (near-infrared spectroscopy) relative to rSVC flow (CMRO2 index), were obtained in 32 newborn infants. 3. Eleven anaesthetised newborn piglets were cooled to 33-34ºC 2-26h after hypoxia-ischaemia using either water bottles or phase-changing material (PCM; a heat buffer at 32ºC). Results: 1. In piglet models, brain temperatures were positively correlated with the body weight under normothermia, whole-body cooling and selective-head cooling, the influence of which was prominent under selective-head cooling. 2. In normothermic infants, rSVC flow was positively correlated with CMRO2 index. The rSVC flow, but not CMRO2 index, was positively associated with superficial brain temperatures. Ambient temperatures were negatively associated with temperature gradients between the scalp surface and body core. 3. In piglet models, therapeutic hypothermia was induced and maintained with both water bottles and PCM; the latter provided more stable cooling within the target range. Conclusions: Brain cooling was more efficient with lower body weight due to greater surface-to-volume ratios; body-size adjustment may be required to accomplish consistent regional temperatures. In healthy newborn infants, cerebral perfusion and ambient temperature, but not cerebral metabolism, were associated with brain temperatures. PCM provided stable hypothermia, which may substitute for electronic cooling devices during transportation.

In this thesis, numerical and statistical time series analysis techniques have been applied for the purpose of objective quantitative analysis of fetal heart rate (FHR) recording from the antepartum period (period of pregnancy before labour). Currently FHR is routinely analyzed visually and the form of medical interpretations that medics make are simply binary. Medical literature on fetal monitoring, based on FHR, has been extensively searched and the current status of FHR and its components of interest to the medics for screening purposes have been presented coherently. Ambiguities and false expectations have been clarified. All the FHR components of interest used by the medics during the antepartum period have been addressed and analyzed numerically. Prior to any successful analysis of non-stationary FHR, its baseline or trend (an important screening variable by itself) had to be estimated and removed from the original data in a statistically unbiased manner. This has been achieved via a first order bi-directional autoregressive filtering technique. Non-stationarities in both first and second moments had to be taken into account. The detrimental effects of the baseline when analyzing FHR variability through one-dimensional scalar statistic namely the standard deviation have been studied and the need to use detrended data for this purpose has been emphasized. A new non-parametric approach to analyze the development of the FHR variability based on relative frequency histogram analysis has also been proposed. A rule based routine has been devised which makes use of the rate of change of the unbiased estimated baseline and the original antepartum recorded FHR to numerically detect FHR accelerations. The accelerations are a very important screening component of FHR which are usually scanned for visually. This visual scanning technique is inefficient and inaccurate.

With the advent of new fetal phonocardiographic transducers affording better signal qualities than hitherto possible, this non-invasive monitoring technique is explored with a view to long-term fetal heart rate (FHR) monitoring. The analysis of fetal heart phonocardiographic (phono) signals in spectral composition, stationarity and type of interference noise sets the basis for the development of FHR estimation algorithms. For repeatability purposes, the fetal heart signals are simulated at varying signal to noise ratios (SNR). This enables the controlled generation of simulated fetal phono time series which are then used to assess the performance of the investigated algorithms. The computation cost of each algorithm is extracted and given in processor independent format, thus giving an idea of the applicability to real-time FHR processing. A time domain beat-to-beat (BTB) FHR estimation algorithm, namely the 'Pseudo-Inverse Filter', is given, and its performance is subjectively compared to the pulse correlation approach. The pseudo-inverse filter is shown to offer increased accuracy in the detection of heart beat events. Contributions to block processing FHR estimation algorithms are also detailed in this work, notably the 'Comb Filter', 'Modified Block Autocorrelation' and the 'Iterative Block Clean-up'. The performances of fourteen FHR estimation algorithms are compared using varying SNR phono signals. Those algorithms based on block processing are further subjected to accelerating FHR signals to assess their tracking performances. Using pre-determined FHR inclusion bands, two measurable performance quantities are obtained: The outlier error rate (OER) and the in-band standard deviation (IBSD). Overnight recordings of phonocardiographic signals are processed in real-time using the 'Comb Filter' on a stand-alone, VME based, signal processing facility. FHR estimates obtained from two second blocks are then transmitted to the Mainframe computer for further processing and display.

No description available.

Studies in skeletal muscle following damage have demonstrated splicing of the insulin-like growth factor-1 gene to IGF-1Ea that is the source of mature IGF-I which is a main anabolic factor, IGF-1Eb,the function of which is not known and IGF-1Ec, known as Mechano Growth Factor (MGF). MGF increases the pool of muscle stem cells by activating them to proliferate. The aim of the thesis was to study expression of IGF-1 variants in female reproductive organs where cellular damage may lead to pathology: 1. The levator ani (LA) muscle: significant damage occurs following vaginal delivery and is a key element in pelvic floor physiology. LA samples from pre and post menopausal women were used as controls. 2. Ovarian tissue: repeated ovulations and failure of the epithelium to repair which may be a predisposing factor for ovarian cancer. 3. Myometrium: single monoclonal cellular damage may lead to abnormal proliferation of myometrium and may be a factor in the aetiology of uterine fibroids.

Aim of this thesis is to study the changes in the maternal coagulation system during pregnancy and puerperium. The effect of labour and mode of delivery on the fetal coagulation system was also studies. A study of 191 women with inherited bleeding disorders showed a significant increase in mean FVIII (p <0.0001), VWF:Ag (p <0.0001) and VWF:CB (p <0.0001) levels in third trimester of pregnancy compared to mean pre pregnancy values, in women with von Willebrand disease (VWD). However, there was no increase in mean factor levels in those with severe VWD. A significant increase in mean FVIII levels (p <0.0001) in third trimester was also observed compared to mean pre pregnancy levels, in haemophilia A carriers, with FVIII level >50 IU dL-1 in 96% pregnancies. A significant increase in mean FIX levels in third trimester (p <0.0001) compared to mean pre pregnancy values was observed in carriers of haemophilia B. However, 29% pregnancies in carriers of haemophilia B had levels below 50 IU dL-1 at term. In women with FXI deficiency, there was only 19% increase in FXI level during third trimester over pre pregnancy level. Pregnancy associated rise in coagulation factors returns to pre pregnancy level after delivery. To assess the exact time when the factor levels start to decline in the immediate postnatal period, a study of FVIII, VWF:Ag and VWF:CB on days 1, 2 and 3 of the puerperium was conducted in 95 healthy pregnant women. There was no significant decrease in mean FVIII, VWF:Ag and VWF:CB levels on days 1 (p=0.17, p=0.36, p=0.21 respectively) and day 2 (p=0.064, p=0.97, p=0.46 respectively) of the puerperium compared to mean factor levels at the onset of labour or immediately prior to elective caesarean section (CS). A significant decrease in mean VWF:Ag and VWF:CB level (p=0.009 and p=0.04 respectively) was seen on day 3 postpartum. In another study, cord blood was obtained from 154 normal full term pregnancies, to study the level of coagulation factors and inhibitors of coagulation and to assess the effect of labour on these parameters. There was a significant difference in mean cord blood levels of FVIII:C (p<0.0001), VWF:Ag (p<0.0001), VWF:CB(p<0.0001), FIX(p=0.0002), FXI(p=0.0008), FXII(p<0.0001) and plasminogen (p=0.01) between cord blood of fetuses who went through labour, compared to those who were born by an elective caesarean section; levels being higher in those who laboured. Babies with meconium stained liquor, had significantly lower levels of FII (p=0.003), FV (p=0.009), FVII (p=0.0004) and FX (p=0.0009) in cord blood compared to those with clear liquor. In conclusion: This study has refined data on the changes of coagulation factor in pregnancy in women with inherited bleeding disorders. There was a significant increase in mean FVIII, FIX and VWF levels in third trimester compared to pre pregnancy level. All women with mild VWD and 96% of carriers of haemophilia A had factor normal (>50 IU dL-1) at term. However, 29% haemophilia B carriers, continue to have factor levels below 50 IU dL-1 at term, thus required prophylactic cover for labour/delivery as well as regional block. The changes in coagulation factors in first trimester in women with IBDs were also been defined in this study. 29% pregnancies with VWD and 24% pregnancies in carriers of haemophilia in this study, had factor levels below 50 IU dL-1 in the first trimester. They require haemostatic measures such as factor replacement, to reduce the risk of haemorrhagic complications in the event of miscarriage, termination of pregnancy and invasive prenatal diagnosis. Epidural catheters are generally removed within 12 h of delivery and it has been recommended that factor levels are reassessed before removal of the catheter. Study of postnatal changes in VWF and FVIII showed a significant drop in mean VWF level on day 3 compared to levels during early labour and FVIII:C levels did not show any statistically significant decrease on day 1, day 2 and day 3 after delivery. Thus, it seems unnecessary to repeatedly check coagulation profiles and factor levels prior to the removal of the epidural catheter, avoiding delay in removal of the catheter and mobilisation and limiting infection risk. The findings may provide an explanation for secondary PPH which most commonly occurs in the second week following delivery. Cord blood levels of FVIII:C, VWF:Ag, VWF:CB, FIX, FXI, FXII and plasminogen were significantly higher in women who laboured, compared to women who had elective caesarean section. Significantly lower values of FII, FV, FVII and FX were found in the cord blood of babies with meconium stained liquor compared to those with clear liquor. The current study provides valuable information on the effect of labour on the coagulation system of the fetus and indicates that, in cord blood, the results of coagulation parameters in the newborn baby should be considered in light of mode of delivery and events of labour.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders, affecting 5 % to 10 % of women of reproductive age. The Syndrome is associated with Type II diabetes and endometrial carcinoma but an association with epithelial ovarian cancer has also been suggested. The studies described in this thesis were designed to investigate this association at population, cellular and molecular levels. In the first study, a cross sectional questionnaire survey was conducted of 121 women aged between the ages of 20 and 40, with or without PCOS. Analysis of the replies from 52 women with PCOS and 82 controls, showed that women with PCOS were significantly more likely to give a positive family history of breast cancer and myocardial infarction (20% vs 5%, p<0.05 and 35% vs 15%, p, 0.05, respectively). The second study was performed on 102 formalin fixed, paraffin embedded ovarian biopsies. In this study the surface epithelium of PCOS ovaries was compared with controls. The results showed significant epithelial changes in the PCOS group, with a higher prevalence of Psammoma bodies and mitoses (p< 0.01 and p < 0.02, respectively). Expression of cell cycle and apoptotic (p53, Cyclin D, Ki67 and bcl2) proteins in the ovarian surface epithelium was assessed using immunohistochemistry in 15 PCOS subjects and 15 controls. P53 expression was significantly (p= 0.003) increased in the PCOS women compared with controls. The third project was performed to identify gene expression in ovaries from women with PCOS, ovarian cancer and healthy controls (three ovaries from each group were utilized). 34(2%) genes consistently varied in abundance between normal and PCOS samples, 12 genes were over expressed in PCOS and 22 under expressed. One of the over expressed genes identified is human alpha 2 smooth muscle actin. It was 15 fold higher in PCOS ovary, than in normal ovary p< 0.001. Conclusions: the results of these studies do not provide convincing evidence of a correlation between PCOS and ovarian cancer.

No description available.

The antiphospholipid syndrome (APS) is characterised by the presence of antiphospholipid antibodies (aPA) associated with thrombosis (arterial and venous) and pregnancy morbidity. This thesis has aimed to investigate the frequency of protein C pathway defects in patients with aPA and to study clinical correlates examine the mechanisms of antiphospholipid interference in the protein C pathway and to assess activated protein C (APC) resistance in patients with aPA in terms of thrombin generation. Although have I have discovered a high degree of heterogeneity in the phenotype of patients with APS, I have demonstrated APC resistance and increased thrombin generation in the majority of patients with APS. While in some cases, APC resistance is clearly immunoglobulin mediated, it is a multifactorial phenomenon with many confounding variables. My data suggest that immunoglobulin dependent APC resistance may occur through P2 glycoprotein-I dependent and independent mechanisms. In a detailed study of women with a history of pregnancy morbidity, I have found evidence for an underlying prothrombotic condition, which is due in part to a deficiency of tissue factor pathway inhibitor. This is associated with resistance to APC and increased thrombin generation, both of which may be attenuated through the restoration of normal TFPI levels by low molecular weight heparin.