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.

Systematic study of visible transitions in Ti-like high Z ions

The magnetic dipole transitions between fine structure levels in the ground term of Ti-like ions, (3d(4)) D-5(2)-D-5(3), were investigated by observation of visible and near-UV light for several elements with atomic numbers from 51 to 78. The wavelengths are compared with theoretical values we recently calculated. The differences between the present calculations and measurements are less than 0.6%. The anomalous wavelength stability predicted by Feldman, Indelicato and Sugar [J. Opt. Soc. Am. B 8, 3 (1991)] was observed. We attribute this anomalous wavelength stability to the transition from LS to JJ coupling and the asymptotic behavior of the transition energies in the intermediate coupling regime.

Familial genes in sporadic disease: Common variants of a-Synuclein gene associate with Parkinson’s disease

Genetic variation of the alpha-synuclein gene (SNCA) is known to cause familial parkinsonism, however the role of SNCA variants in sporadic Parkinson's disease (PD) remains elusive. The present study identifies an association of common SNCA polymorphisms with disease susceptibility in a series of Irish PD patients. There is evidence for association with alternate regions, of protection and risk which may act independently/synergistically, within the promoter region (Rep1; OR: 0.59, 95% CI: 0.37-0.84) and the 3'UTR of the gene (rs356165; OR: 1.67, 95% CI: 1.08-2.58). Given previous reports of association a collaborative effort is required which may exploit global linkage disequilibrium patterns for SNCA and standardise polymorphic markers used in each population. It is now crucial to identify the susceptibility allele and elucidate its functionality which may generate a therapeutic target for PD.

Physiological stress responses in the edible crab, Cancer pagurus, to the fishery practice of de-clawing

We examined physiological stress responses in the edible crab, Cancer pagurus, subjected to the commercial fishery practice of manual de-clawing. We measured haemolymph glucose and lactate, plus muscular glycogen and glycogen mobilisation, in three experiments where the crabs had one claw removed. In the first, crabs showed physiological stress responses when 'de-clawed' as compared to 'handled only over the short term of 1-10 min. In the second, de-clawing and the presence of a conspecific both increased the physiological stress responses over the longer term of 24 h. In the third, de-clawing was shown to be more stressful than 'induced autotomy' of claws. Further, the former practice caused larger wounds to the body and significantly higher mortality than the latter. Since the fishery practice is to remove both claws, the stress response observed and mortality data reported are conservative.

Assisted Diagnosis of Cervical Intraepithelial Neoplasia (CIN)

This paper introduces an automated computer- assisted system for the diagnosis of cervical intraepithelial neoplasia (CIN) using ultra-large cervical histological digital slides. The system contains two parts: the segmentation of squamous epithelium and the diagnosis of CIN. For the segmentation, to reduce processing time, a multiresolution method is developed. The squamous epithelium layer is first segmented at a low (2X) resolution. The boundaries are further fine tuned at a higher (20X) resolution. The block-based segmentation method uses robust texture feature vectors in combination with support vector machines (SVMs) to perform classification. Medical rules are finally applied. In testing, segmentation using 31 digital slides achieves 94.25% accuracy. For the diagnosis of CIN, changes in nuclei structure and morphology along lines perpendicular to the main axis of the squamous epithelium are quantified and classified. Using multi-category SVM, perpendicular lines are classified into Normal, CIN I, CIN II, and CIN III. The robustness of the system in term of regional diagnosis is measured against pathologists' diagnoses and inter-observer variability between two pathologists is considered. Initial results suggest that the system has potential as a tool both to assist in pathologists' diagnoses, and in training.

Sustainability and the Multifunctional Landscape: An Assessment of the Cairngorms National Park Authority’s Approach to Planning and Management in Upland Scotland.

Upland Scotland contains some of Britain’s most prized areas of natural heritage value. However, although such areas may appear both ‘wild’ and ‘remote’, these are typically working landscapes which symbolise the interdependence of nature and society. The complexity of this relationship means that management responses will need to address a multitude of potentially conflicting priorities whilst at the same time ensuring that sufficient social and institutional capital exists to allow for the promotion of landscape integrity. The introduction of national parks to Scotland in the form of the National Parks (Scotland) Act 2000 allows for a high-level of protection for designated areas in upland Scotland. Yet, whilst the recent Act outlines the statutory purpose and direction national parks should take, it allows a significant degree of flexibility in theway in which the Actmay be implemented. This level of discretion allows for significant local distinctiveness within the model but also raises questions about the potential effectiveness of chosen responses. In order to assess the potential implications of a model rooted in self-determination,we provide a case study review of the institutional basis of the Cairngorms National Park along with an assessment of the strategic character of the first National Park Plan. It is argued that whilst the Cairngorms National Park Authority has developed a significant level of stakeholder engagement, the authority may struggle to bridge the policy-implementation gap. Although a number of shortcomings are identified, particular concerns relate to the potential mismatch between strategic ambition and local level capacity.

Aggregation behavior in water of new imidazolium and pyrrolidinium alkycarboxylates protic ionic liquids

A novel class of anionic surfactants was prepared through the neutralization of pyrrolidine or imidazole by alkylcarboxylic acids. The compounds, namely the pyrrolidinium alkylcarboxylates ([Pyrr][CnH2n+1COO]) and imidazolium alkylcarboxylates ([Im][CnH2n+1COO]), were obtained as ionic liquids at room temperature. Their aggregation behavior has been examined as a function of the alkyl chain length (from n = 5 to 8) by surface tensiometry and conductivity. Decreases in the critical micelle concentration (cmc) were obtained, for both studied PIL families, when increasing the anionic alkyl chain length (n). Surprisingly, a large effect of the alkyl chain length was observed on the minimum surface area per surfactant molecule (Amin) and, hence the maximum surface excess concentration (Gmax) when the counterion was the pyrrolidinium cation. This unusual comportment has been interpreted in term of a balance between van der Waals and coulombic interactions. Conductimetric measurements permit determination of the degree of ionization of the micelle (a) and the molar conductivity (?M) of these surfactants as a function of n. The molar conductivities at infinite dilution in water (?8) of the [Pyrr]+ and [Im]+ cations have been then determined by using the classical Kohlraush equation. Observed change in the physicochemical, surface, and micellar properties of these new protonic ionic liquid surfactants can be linked to the nature of the cation. By comparison with classical anionic surfactants having inorganic counterions, pyrrolidinium alkylcarboxylates and imidazolium alkylcarboxylates exhibit a higher ability to aggregate in aqueous solution, demonstrating their potential applicability as surfactant.

An anthrax subunit vaccine candidate based on protective regions of Bacillus anthracis protective antigen and lethal factor

Studies have confirmed the key role of Bacillus anthracis protective antigen (PA) in the US and UK human anthrax vaccines. However, given the tripartite nature of the toxin, other components, including lethal factor (LF), are also likely to contribute to protection. We examined the antibody and T cell responses to PA and LF in human volunteers immunized with the UK anthrax vaccine (AVP). Individual LF domains were assessed for immunogenicity in mice when given alone or with PA. Based on the results obtained, a novel fusion protein comprising D1 of LF and the host cell-binding domain of PA (D4) was assessed for protective efficacy. Murine protection studies demonstrated that both full-length LF and D1 of LF conferred complete protection against a lethal intraperitoneal challenge with B. anthracis STI spores. Subsequent studies with the LFD1-PAD4 fusion protein showed a similar level of protection. LF is immunogenic in humans and is likely to contribute to the protection stimulated by AVP. A single vaccine comprising protective regions from LF and PA would simplify production and confer a broader spectrum of protection than that seen with PA alone.

Temporal extension of Laplacian Eigenmaps for unsupervised dimensionality reduction of time series

A novel non-linear dimensionality reduction method, called Temporal Laplacian Eigenmaps, is introduced to process efficiently time series data. In this embedded-based approach, temporal information is intrinsic to the objective function, which produces description of low dimensional spaces with time coherence between data points. Since the proposed scheme also includes bidirectional mapping between data and embedded spaces and automatic tuning of key parameters, it offers the same benefits as mapping-based approaches. Experiments on a couple of computer vision applications demonstrate the superiority of the new approach to other dimensionality reduction method in term of accuracy. Moreover, its lower computational cost and generalisation abilities suggest it is scalable to larger datasets. © 2010 IEEE.

Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques

Objectives: To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model.

Methods: Maraviroc concentrations in vaginal fluid (Weck-Cel® sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003 – 3.3% w/w) such that test gels included both fully solubilised and predominantly dispersed formulations. The efficacy of the HEC gels against a single high dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations.

Results: Maraviroc concentrations in vaginal fluid (range 104 – 107 ng/mL), vaginal tissue (100-1200 ng/g) and plasma (< 102 ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilised vs. dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily out to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel.

Conclusions: A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 107 ng/mL and 103 ng/g, respectively, are required for complete protection with this compound.

Community convergence and recruitment of keystone species as performance indicators of artificial reefs

An experimental artificial reefwas constructed in Strangford Lough, Northern Ireland as part of trials to regenerate damaged biogenic reefs formed by the horse mussel Modiolus modiolus. Experimental reef plots were constructed using Pecten maximus shell as cultch. Clumps of live adult M. modiolus were translocated from nearby natural reefs into cultchwith a high profile (elevated cultch), cultch with a lowprofile (flattened cultch), as well as directly into the seafloor. The aim of the study was to test the hypothesis that translocated mussel clumps would increase habitat complexity thus accelerating community succession and enhancing natural recruitment of M. modiolus spat. These effects were predicted to be greater on elevated cultch due to greater protection from
predators and increased accessibility to food resources. Within the artificial reef array the translocated clumps had a significant positive effect on recruitment compared to cultch without mussels with average densities of spat settled on the translocated M. modiolus clumps ranging from 100 to 200 individuals m-2 compared to 4 to 52 spat m-2 on cultch without mussels. Recruitment of M. modiolus spat was also significantly higher on translocated horse mussels when compared to natural reefs where densities of 8–36 spat m-2 were recorded.
Reef elevation appeared to provide some degree of protection from predators but differences in translocated M. modiolus survival on the different elevation treatments were not significant. In total, 223 taxa were recorded 12 months after reef construction. The presence of translocated clumps ofM. modiolus was the main driver of the increases in faunal diversity and species abundance. Application of objective criteria to assess the performance of artificial reefs suggested that translocation of M. modiolus clumps alone achieved most of the restoration objectives. Consequently this pilot study demonstrates a straightforward and realistic intervention technique that could be used to kick start the regeneration and expansion of impacted mussel and similar biogenic reefs elsewhere.

The combined effect of diabetes and ionising radiation on the retinal vasculature of the rat

The clinical impression that pre-existing diabetes exacerbates radiation injury to the retinal vasculature was studied in STZ diabetic rats. Half of 2 groups of streptozotocin (STZ)-induced diabetic rats and 1 group of normal animals had their right eyes irradiated with 1000 cGy of 90 KVP x-rays. The prevalence of acellular capillaries in trypsin digests of the retinal vasculature was quantified for each of the 6 groups of animals at 6.5 months post-irradiation. The prevalence of acellular capillaries in both non-irradiated diabetic groups was significantly higher than in controls while the irradiated animals in each of the three main categories showed a statistically significant increase compared to their non-irradiated equivalents. However, the net increase in acellular capillaries following irradiation was much greater in rats with an 8 month term of pre-existing diabetes (180%) than in those which had only been diabetic for 3 months (36%). The results of this study suggest a synergistic relationship between pre-existing diabetes and ionising radiation in the development of retinal vasculopathy, and that the potentiation of the vascular damage is dependent on the duration of diabetes prior to radiation exposure.

Fasciola hepatica:studies on vaccination of rats and mice with a surface antigen prepared from fluke homogenate by means of a monoclonal antibody

T1 tegumental antigen was isolated from a homogenate of eight- to 10-week-old Fasciola hepatica using a T1-specific monoclonal antibody bound to sepharose in an antibody-affinity column. Rats and mice were vaccinated with T1 antigen in Freund's complete adjuvant, and control groups received equivalent amounts of non-T1 antigen (eluted from the antibody-affinity column) or ovalbumin. On completion of the immunisation programme, serum samples were collected for ELISA and IFA testing. The animals were challenged by oral infection with F hepatica metacercariae or, for several vaccinated rats, by intraperitoneal transplantation of live adult flukes. At autopsy, worm-burden and liver damage was assessed for each animal and the condition of transplanted flukes was examined. Comparison of test and control groups of animals showed that neither T1 nor non-T1 antigens provided significant protection against challenge, although specific antibody responses against the appropriate sensitising antigen were engendered. Flukes transplanted to the peritoneal cavity of immunised rats survived without damage, although they became encased in hollow fibrous capsules of host origin. The results lend support to the pre-existing concept that glycocalyx turnover by discharge of T1 secretory bodies at the apical surface of migrating flukes provides an efficient means of protection for the parasite against host immunity.

Active use of DFIG based Wind Farms for Transient Stability Improvement during Grid Disturbances

The doubly-fed induction generator (DFIG) now represents the dominant technology in wind turbine design. One consequence of this is limited damping and inertial response during transient grid disturbances. A dasiadecoupledpsila strategy is therefore proposed to operate the DFIG grid-side converter (GSC) as a static synchronous compensator (STATCOM) during a fault, supporting the local voltage, while the DFIG operates as a fixed-speed induction generator (FSIG) providing an inertial response. The modeling aspects of the decoupled control strategy, the selection of protection control settings, the significance of the fault location and operation at sub- and super-synchronous speeds are analyzed in detail. In addition, a case study is developed to validate the proposed strategy under different wind penetrations levels. The simulations show that suitable configuration of the decoupled strategy can be deployed to improve system voltage stability and inertial response for a range of scenarios, especially at high wind penetration. The conclusions are placed in context of the practical limitations of the technology employed and the system conditions.