CARBON MONOXIDE AND PREGNANCY: A SEARCH FOR A POSSIBLE THERAPEUTIC IN THE TREATMENT OF PRE-ECLAMPSIA

Pre-eclampsia (PE) is a pregnancy disorder that affects roughly 5-7% of all pregnancies and is a leading cause of both maternal and fetal/neonatal morbidity and mortality. With no present cure for the disease, researchers are interested in the lower incidence of PE observed among the cigarette smoking pregnant population. However, women who use smokeless tobacco do not experience the same decreased incidence of PE, leading to hypothesis of protection against PE from the largest combustible product of cigarette smoke, carbon monoxide (CO). Studies evaluated levels of CO in PE women and found that they were statistically lower than those of healthy pregnancy. Researchers have found CO to possess many cytoprotective and regulatory properties and specifically within the placenta, it has been found to increase perfusion pressure, decrease oxidative stress, decreases ischemia/reperfusion induced apoptosis and maintain endothelial functioning. The idea for use of CO as a possible therapeutic for PE has thus become a real possibility. This study determined CO levels in pregnant women ± smoking as well as in PE women±smoking, as to discover a possible therapeutic range for future treatments. The best correlated automated CO measurement device with blood CO levels was determined, for use in future clinical studies. This thesis also sought a possible CO delivery concentration, in order to achieve the CO levels observed in the human correlation study. A threshold level of maternal CO exposure in a murine animal model was found, for which fetal and maternal negative toxicities were not observed. The results of this thesis lend a few more pieces to the complicated puzzle involving CO and PE and offer another step toward the possibility of a therapeutic treatment/prevention using this gaseous molecule.

Recombinant alpha 2(IV)NC1 domain of type IV collagen is an effective regulator of retinal capillary endothelial cell proliferation and inhibits pre-retinal neovascularisation

Background A recombinant form of the alpha 2(IV)NC1 domain of type IV collagen has been shown to have potent anti-angiogenic activity although this peptide has not been studied in the context of proliferative retinopathies. In the current investigation we examined the potential for alpha 2(IV) NC1 to regulate retinal microvascular endothelial cell function using a range of in vitro and in vivo assay systems.

Single-Element and Competitive Metal Mobility Measured with Column Infiltration and Batch Tests

The distribution coefficient, K-d, is often used to quantify heavy metal mobility in soils. Batch sorption or column infiltration tests may be used to measure K-d. The latter are closer to natural soil conditions, but are difficult to conduct in clays. This difficulty can be overcome by using a laboratory centrifuge. An acceleration of 2600 gravities was applied to columns of London Clay, an Eocene clay sub-stratum, and Cu, Ni, and Zn mobility was measured in centrifuge infiltration tests, both as single elements and in dual competition. Single-element K-d values were also obtained from batch sorption tests, and the results from the two techniques were compared. It was found that K-d values obtained by batch tests vary considerably depending on the metal concentration, while infiltration tests provided a single K-d value for each metal. This was typically in the lower end of the range of the batch test K-d values. For both tests, the order of mobility was Ni > Zn > Cu. Metals became more mobile in competition than when in single-element systems: Ni K-d decreased 3.3 times and Zn K-d 3.4 times when they competed with Cu, while Cu decreased only 1.2 times when in competition with either Ni or Zn. Our study showed that competitive sorption between metals increases the mobility of those metals less strongly bound more than it increases the mobility of more strongly bound metals.

Computerised Diagnostic Decision Support System for the Classification of Pre-Invasive Cervical Squamous Lesions.

Previous studies have revealed considerable interobserver and intraobserver variation in the histological classification of preinvasive cervical squamous lesions. The aim of the present study was to develop a decision support system (DSS) for the histological interpretation of these lesions. Knowledge and uncertainty were represented in the form of a Bayesian belief network that permitted the storage of diagnostic knowledge and, for a given case, the collection of evidence in a cumulative manner that provided a final probability for the possible diagnostic outcomes. The network comprised 8 diagnostic histological features (evidence nodes) that were each independently linked to the diagnosis (decision node) by a conditional probability matrix. Diagnostic outcomes comprised normal; koilocytosis; and cervical intraepithelial neoplasia (CIN) 1, CIN II, and CIN M. For each evidence feature, a set of images was recorded that represented the full spectrum of change for that feature. The system was designed to be interactive in that the histopathologist was prompted to enter evidence into the network via a specifically designed graphical user interface (i-Path Diagnostics, Belfast, Northern Ireland). Membership functions were used to derive the relative likelihoods for the alternative feature outcomes, the likelihood vector was entered into the network, and the updated diagnostic belief was computed for the diagnostic outcomes and displayed. A cumulative probability graph was generated throughout the diagnostic process and presented on screen. The network was tested on 50 cervical colposcopic biopsy specimens, comprising 10 cases each of normal, koilocytosis, CIN 1, CIN H, and CIN III. These had been preselected by a consultant gynecological pathologist. Using conventional morphological assessment, the cases were classified on 2 separate occasions by 2 consultant and 2 junior pathologists. The cases were also then classified using the DSS on 2 occasions by the 4 pathologists and by 2 medical students with no experience in cervical histology. Interobserver and intraobserver agreement using morphology and using the DSS was calculated with K statistics. Intraobserver reproducibility using conventional unaided diagnosis was reasonably good (kappa range, 0.688 to 0.861), but interobserver agreement was poor (kappa range, 0.347 to 0.747). Using the DSS improved overall reproducibility between individuals. Using the DSS, however, did not enhance the diagnostic performance of junior pathologists when comparing their DSS-based diagnosis against an experienced consultant. However, the generation of a cumulative probability graph also allowed a comparison of individual performance, how individual features were assessed in the same case, and how this contributed to diagnostic disagreement between individuals. Diagnostic features such as nuclear pleomorphism were shown to be particularly problematic and poorly reproducible. DSSs such as this therefore not only have a role to play in enhancing decision making but also in the study of diagnostic protocol, education, self-assessment, and quality control. (C) 2003 Elsevier Inc. All rights reserved.