Abstract not available

Abstract not available

Master of Science (Medicine) / Clinical studies have demonstrated an arousal deficit in infants suffering Obstructive Sleep Apnoea (OSA), and that treatment to alleviate the symptoms of OSA appears to reverse the deficit in arousability. Some sudden infant deaths are thought to be contingent upon such an arousal deficit. This research utilised young piglets during early postnatal development, and exposed them to intermittent hypercapnic hypoxia (IHH) as a model of clinical respiratory diseases. Arousal responses of control animals were compared to the animals exposed to IHH. Comparisons were also made between successive exposures on the first and the fourth consecutive days of IHH. Time to arouse after the onset of the respiratory stimulus, and frequency of arousals during recovery, demonstrated that arousal deficits arose after successive exposures and that these were further exacerbated on the fourth study day. After an overnight recovery period, the arousal deficit was apparently dormant, and only triggered by HH exposure. These studies confirm that both acute and chronic deficits can be induced on a background of otherwise normal postnatal development, suggesting that deficits observed in the clinical setting may be a secondary phenomenon.

Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival. Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance. About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening. This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population. AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis. It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway. Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024). A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA. Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006. The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms. Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined. From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.

The upper respiratory tract (URT) of humans is complex and interconnected region and comprises several major ecosystems including the oral cavity, oropharynx, nasal cavity, sinuses, nasopharynx and middle ear. Most of the anatomical locations within the URT are colonised with a normal bacterial microbiota, within which are often organisms having the potential to cause disease. The diseases of the URT are both varied and frequent in their occurrence, and conditions such as otitis media, rhinosinusitis and pharyngitis are sources of morbidity and mortality in adults and children in both developing and developed countries. The study of diseases of the URT has traditionally been based on application of culture-based methods in which the infection-implicated organisms are first grown in vitro and then studied further. Ongoing advances in DNA-based techniques have led to the development of new molecular tools for the study of infectious diseases. One such technique is PCR-denaturing gradient gel electrophoresis (PCR-DGGE). This is a PCR-based tool that allows the investigation of microbial communities independent of culture. Although this technique has been applied extensively in the study of the gastrointestinal tract, the vagina and endodontic infections in humans, there have been few reports of its application to URT infections. PCR-DGGE was applied in the present study to investigate (a) the bacteria present in the middle ear of children suffering from otitis media with effusion (OME), (b) the microbiota associated with the sinuses in patients with chronic rhinosinusitis (CRS) and (c) perioperative changes in the bacterial population of the middle meatus of patients undergoing nasal or sinus surgery. The analysis of the middle ear fluid samples indicated an increased role in OME for the newly-discovered pathogen Alloiococcus otitidis and also the possible involvement of certain coryneform bacteria and coagulase-negative staphylococci in the aetiology of this condition. PCR-DGGE analysis of patients with CRS revealed a polymicrobial disease with considerable variability in the predominant species detected when multiple, serial samples were evaluated. The perioperative audit showed that when good clinical practice is adhered to, there was no apparent introduction of potentially-harmful organisms into the middle meatus. Streptococcus salivarius is a common, commensal inhabitant of the oral cavity of humans and has also been shown to inhabit the nasopharynx of infants. S. salivarius is also a well known producer of bacteriocins with activity directed against Streptococcus pyogenes. One such strain, S. salivarius K12, is now marketed in New Zealand as the probiotic, K12 Throat Guard[TM]. In the present study, S. salivarius K12 was compared with two additional strongly-inhibitory S. salivarius (strains T18A and T30A) for activity against the common causative pathogens of otitis media. A paediatric formulation of strain K12 was also tested in a pilot clinical trial for its ability to colonise the URT of young children. Although the levels of colonisation of these subjects was not as high as typically obtained with use of the K12 Throat Guard[TM] formulation, it was considered that further development of the paediatric formulation is warranted, particularly with respect to use of a different pre-treatment regimen. In other studies, the molecular basis for the unusual in vitro inhibitory activity of S. salivarius strain T30A was investigated. Although this still remains unresolved, other observations made during the course of this study have led to the introduction of a schema for the division of inhibitory S. salivarius into three groups based on (a) their sensitivity to the lantibiotic salivaricin A and (b) the structure of their salivaricin A genetic locus. This grouping is analogous to the "rock-paper-scissors" system previously described for colicin-producing strains of E. coli. Streptococcus pneumoniae is a major human pathogen responsible for a variety of diseases in humans. There have been very few reports of bacteriocin production by S. pneumoniae when compared to other streptococcal species. In the present study a putative cluster of bacteriocins encoded by the blp locus has been investigated. The distribution of the individual blp determinants within this locus was evaluated in a collection of S. pneumoniae strains using PCR. The blp genes were detected in 92% of 57 tested strains and a variant form (termed the B-form) of the cluster was identified that appeared to have arisen due to a genetic recombination event. In this case an approximately 250 bp portion of the blpMNO cluster appears to have recombined into blpK of the blpIJK cluster. Attempts were made to express the putative bacteriocin peptide genes in an Escherichia coli expression system. Failure to achieve expression was taken to indicate that these bacteriocin-like peptides may be toxic for the host producer cells under these test conditions. Future attempts to achieve expression of the Blp peptides, could explore the use of different fusion proteins, a Gram-positive expression host or a cell-free protein expression system.

Cardiovascular pathology is seen in both animals and humans after domoic acid intoxication. Whether this damage is direct (i.e., cardiotoxic) or indirect (i.e., CNS/autonomic seizures) is not known. We have previously shown that acute in vitro domoic acid (0.05-0.25[mu]M; 10 min) treatment of isolated cardiac mitochondria compromises mitochondrial FADH and NAD⁺-linked respiratory control and mitochondrial energetics. Domoic acid was shown to traverse and bind the cellular membrane of H9c2 cardiac myoblasts. However it did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Exposure of intact H9c2 cells to domoic acid only resulted in complex II-III activity impairment and assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid. Acute ex vivo domoic acid treatment of an isolated myocardium in Langendorff perfusion mode failed to result in cardiac haemodynamic dysfunction, however there appeared to be small but significant decrease in mitochondrial oxygen utilization. The absence of any substantial damage to intact cardiomyocytes and isolated myocardium suggested that domoic acid does not have a direct toxicological effect on cardiac energetics. We therefore investigated the possibility that cardiovascular pathology is an indirect consequence of autonomic seizure activity. Domoic acid was administered intraperitoneally or intrahippocampally and the development of cardiac pathologies was assessed and compared. Sprague-Dawley rats receiving either i.p. or i.h. domoic acid were assessed behaviourally and shown to reach similar levels in their cumulative seizure scores. Assessment of the cardiac haemodynamics (LVDP, dP/dt, heart rate and coronary flow) revealed a significant time-dependent decrease in function at 1, 3, 7 & 14-days post-i.p. and 7 & 14-days post-i.h. domoic acid administration. Measurement of ventricular mitochondrial oxygen utilization revealed a similar time-dependent decrease in respiratory control, which appeared to be associated with increased proton leakage, shown by an increase in state-4 respiration rate (P<0.01). Assessment of the mitochondrial electron transport chain (complexes I-V) and the mitochondrial marker of integrity, citrate synthase, showed marked time-dependent impairment in both models of domoic acid -induced seizures. Oxidative stress did play a small role in the myocardial damage as indicated by the small decrease in aconitase activity (P<0.05). Plasma IL-1α, IL-1β and TNF-α levels were significantly increased from 3-days post seizures. Haematoxylin & Eosin staining of ventricular sections revealed the formation of contraction bands, inflammation and oedema, confirming a structural pathology. Cardiac damage did not differ between i.p. and i.h. animals, suggesting cardiac damage following domoic acid results from CNS autonomic seizures and resultant sympathetic storm. This thesis has demonstrated, for the first time, that the cardiac pathology seen following domoic acid exposure is most likely to be a result of CNS activation and resultant seizure episodes, and is not a consequence of the direct interaction between domoic acid and the myocardium. We have also demonstrated for the first time, that seizure episodes result in chronic cardiac dysfunction and a structural pathology which is similar, but not identical to that seen following isoprotenerol administration in vivo.

Bibliography: leaves 151-179. / xx, 179 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines aspects of the distribution of leukocyte subpopulation in human corpus luteum, cytokine determination in human preovulatory follicular fluid, as well as the effects of cytokines on human granulosalutein cells; with the aim of investigating one of the ovarian regulatory systems, which may be controlled by immune cell-derived cytokines. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1993

PURPOSE: To compare glenohumeral joint position sense (JPS), concentric internal (IR) and external rotation (ER) strength, functional ability, and level of satisfaction in patients who underwent three types of glenohumeral capsulorrhaphy with age-matched controls. RESEARCH DESIGN: Four 4x2 and two 4x3 ANOVAs were used to identify differences in JPS and concentric IR/ER strength between groups: Open Capsulorrhaphy (n=21), Thermal Capsulorrhaphy (n=16), Arthroscopic Capsulorrhaphy (n=14) and Controls (n=22). Pearson correlation analyses were performed to determine the relationship between objective American Shoulder and Elbow Surgeons (ASES) evaluations and subjective Shoulder Rating Questionnaire (SRQ) scores. Stepwise multiple regression analyses were performed to predict ASES and SRQ scores from various objective and subjective outcome measures. SUBJECTS: 73 adults (51 postsurgical patients, 22 healthy controls; mean age, 23.7 ± 6.8 yrs) participated in this retrospective study. The 51 patients who underwent capsulorrhaphy for recurrent, anterior glenohumeral instability were evaluated at an average of 32.1 months postsurgery. MEASUREMENTS: JPS was measured bilaterally using a reproduction of passive positioning protocol at 2 target angles: 60% and 90% of maximum passive external rotation (60% and 90% ER[subscript max]). Concentric IR and ER peak torques were measured bilaterally at 90°/sec, 180°/sec and 270°/sec. Objective postoperative function was quantified with the clinician-based ASES form, while functional status and patient satisfaction were assessed with the patient-based SRQ form. RESULTS: The accuracy of JPS in patients' surgical limbs was similar to that present in their contralateral, uninjured shoulders at both target angles. The Open group demonstrated significantly better involved-limb JPS acuity (4.2° ± 1.9°) than the Arthroscopic group (6.8° ± 3.2°) and Control group (6.6° ± 3.5°) (p<.05). However, the Open group had 31% less IR strength than Control subjects and 33% less than the Arthroscopic group, with IR peak torques significantly less in their postsurgical shoulders than their uninvolved limbs (p<.002). There was a strong, positive correlation (r =.64, p≤.001) between objective ASES and subjective SRQ scores. Patients' postoperative level of pain and ASES scores were significant predictors of their SRQ clinical scores (R=.81, p<.003). CONCLUSIONS: Glenohumeral JPS and rotator cuff strength were similar in both the postsurgical and uninvolved shoulders of the Arthroscopic and Thermal groups. Patients in the Open capsulorrhaphy group demonstrated significantly better involved-limb JPS than Arthroscopic and Control groups. The large strength deficits observed in the Open group, particularly in IR, were of significant concern. We observed a higher failure rate, more revision surgeries, and lower patient satisfaction with the Thermal capsulorrhaphy technique. Patient-based outcomes were significant predictors of operative success as measured by clinician-based evaluation. Prospective, randomized controlled studies are still needed to evaluate the outcomes of these glenohumeral capsulorrhaphy procedures over the longer term. / Graduation date: 2005

No description available.

No description available.