<p>A design is presented for a randomized controlled trial to answer the question: do audit procedures which hospitals are expected to carry out to meet requirements for hospital accreditation have a beneficial impact on ambulatory patient care in general and special clinics?</p> <p>Approximately 60 Ontario hospitals reporting general and special ambulatory care clinics to Statistics Canada will be invited to participate in the trial. Outpatient visits to potentially eligible clinics will be documented by hospital medical records staff and submitted to the Hospital Medical Records Institute. Nurse abstractors will identify indicator conditions from this outpatient census and categorically score patient management over three periods of time: a pre-audit period before intervention occurs, a first audit period and a second audit period.</p> <p>Hospitals stratified according to size and function will have been randomly allocated to three groups. Indicator conditions relevant to caseloads and casemix will be assigned to eligible clinics.</p> <p>Groups I and II will both have indicator conditions introduced to clinic staff prior to the first audit period. Only Group I will receive feedback about their performance in the first audit period.</p> <p>After the second audit period it should be possible to separate the effects of audit awareness (Groups I and II), of feedback (Group I) and of extraneous factors (Group III) on patient management. Results will be expressed as mean clinic scores.</p> <p>If improved performances occur in Groups I and II, the usefulness of current accreditation criteria will have been demonstrated. If no change in performance occurs and the indicator condition criteria approach is accepted as being valid in this setting, then it may be appropriate to consider new approaches to accreditation.</p> / Master of Science (MS)

<p>The term developmental dysphasia refers to children who fail to develop speech and language at the normal time and in the normal manner although they do not have a primary emotional disturbance nor a physical handicap, and are not globally mentally retarded or deaf. Empirical investigations of the disorder have studied auditory perception, visual perception, linguistic and articulatory function, attention and orientation, scholastic performance and reading ability, and hemispheric specialization. With the exception of the studies of auditory perception and hemispheric specialization little promising data have been generated. Investigators of auditory perception have suggested that the language disorder in developmental dysphasia may be attributable to an impairment in auditory perceptual processing. Data from studies of the hemispheric specialization of development dysphasics suggest that dysphasics may have aberrant hemispheric specialization.</p> <p>Neuropsychological investigations of adult language disturbance, i.e. adult aphasia, have concluded that the left hemisphere is specialized for certain kinds of motor function, speech and language being one such function, and that it is an impairment in certain kinds of motor function which is crucial to speech and language disturbances, and not an impairment in linguistic processing or symbolic function as has been suggested by many researchers.</p> <p>This research studied developmental dysphasia with the hypothesis that since this disorder involves speech and language difficulties perhaps it might be related to a deficit in certain aspects of motor functioning, specifically, the organization and execution of fine (as contrasted with gross) actions. This motor performance was also considered within the context of hemispheric specialization since: i) previous work has indicated atypical patterns of hemispheric specialization in developmental dysphasics, ii) motor functions appear to he lateralized and iii) the motor tasks lend themselves to being performed by each hand separately.</p> <p>Ten developmental dysphasics were selected according to strict criteria and were administered seven measures of motor ability, several of these being nonstandardized tests designed specifically for this research. Five of these were lateralized tests (i.e., it was required that the task be performed by each hand separately), while the remaining two were nonlateralized measures. The lateralized measures were a repetitive tapping task, the Annett peg moving task, a children's sequence box task, a hand posture imitation task and a hand movement imitation task. The Illinois Test of Psycholinguistic Abilities manual expression test and an oral movement imitation task were the non-lateralized measures. It was found that the dysphasics performed more poorly than their matched control subjects on the hand posture imitation task, the hand movement imitation task and the ITPA manual expression test. On the repetitive tapping, Annett peg moving, children's sequence box and oral movement imitation tasks the dysphasics performed as well as their control subjects: A laterality effect was not observed on any of these measures for either the normal subjects or the dysphasics.</p> <p>These results were interpreted to mean that developmental dysphasics have a deficit in certain aspects of manual motor function. It is proposed that this is a specific and higher order deficit, not observed in all types of motor function. Moreover, it is suggested that it is a deficit in the initiation, organization and execution of motor behavior and not in the perception. Given that a laterality effect was not observed for any of the measures, no definitive conclusions were possible regarding the hemispheric specialization of developmental dysphasics.</p> <p>Data from linguistic measures administered in addition to those used for subject selection, further confirmed the receptive language deficit in the developmental dysphasics and also indicated difficuIties in the processing of written language. These latter data were interpreted to mean that developmental dysphasia may represent a language disorder which encompasses all forms of language behavior, not just oral language reception and production.</p> / Master of Science (MS)

<p>The mechanisms regulating the rate-determining enzyme of carbohydrate oxidation, pyruvate dehydrogenase (PDH), were examined in human skeletal muscle at rest and during exercise in response to acute respiratory alkalosis and short- and long-term aerobic training. Voluntary hyperventilation-induced respiratory alkalosis (R-Alk) delayed PDH activation during the transition from rest to submaximal exercise. A mismatch between pyruvate production and its oxidation in R-Alk resulted in a 35% higher lactate accumulation. These effects were not seen during steady state exercise. The results from this study suggest that respiratory alkalosis may play an important role in lactate accumulation during the transition from rest to exercise in acute hypoxic conditions, but that other factors mediate lactate accumulation during steady state exercise. Short-term aerobic training did not alter resting skeletal muscle total PDH (PDHt) and PDH kinase (PDK) activities, or their respective protein expressions compared to pre-training. In contrast, long-term aerobic training (Post) compared to pre-training (Pre) resulted in a 31% increased total PDHt activity, partially due to a 1.3 fold increased protein expression of a PDH subunit, PDHE 1 α. Despite the increased PDHt activity post-training, there was an approximate 37% attenuated activation of PDH Post after 15 min of exercise at the same absolute submaximal workload compared to Pre. PDK demonstrated a 2 fold increased activity Post, partially attributed to a 1.3 fold increased PDK2 isoform protein expression. The training-induced increased PDK2 isoform expression, pyruvate-sensitive PDK isoform, coincided with an attenuated skeletal muscle pyruvate content Post during submaximal exercise at the same absolute workload. The results of these findings suggest that aerobically trained human skeletal muscle has an increased maximal capacity to utilize carbohydrates, evident by increased PDHt, but increased metabolic control sensitivity to pyruvate during submaximal exercise through increased contribution of PDK2 to total PDK activity.</p> / Doctor of Philosophy (PhD)

<p>The economic analysis described in this thesis is designed to compare two alternate approaches to post-hospital treatment for a specified group of chronically ill patients who are aged 65 and over and eligible for Home Care at the point of discharge from acute hospitals. Relative costs and health effects will be compared between the Hamilton-Wentworth are programme and the "no programme" situation or the usual of treatment without Home Care, using a cost-effectiveness model. Data will be collected from the Home Care group (experimental) and the No Home Care group (control) in a concurrent randomized clinical trial of the Home Care programme for the specified patients of interest. Costs will be measured as described herein. Health effects of interest will be physical function, social function and morale.</p> <p>The completed results of the study will provide needed information about the magnitude and distribution of costs in each programme alternative for this specific group of patients in Hamilton-Wentworth and about the relation of costs to health effects. The analysis will have relevance to the Hamilton-Wentworth programme and to the Ontario Ministry of Health, as well as planners of similar programmes for similar groups of patients and the patients themselves. The data should add to the growing body of knowledge about the economics of Home Care programmes.</p> <p>The methods developed here for measuring cost in a variety of services and for collection of health service utiIization data could be applied to other studies of similar community-based, multiservice programmes in relation to either specific patient groups or the overall programme impact. The models used for analysis and health effects within the context of a randomized trial should be applicable to other health care evaluations.</p> / Master of Science (MS)

<p>Every day a physician treating patients carries out a series of experiments - whether he is aware of it or not. Many of the decisions he makes need to be made against a background of inadequate information concerning the effectiveness of the therapies he prescribes.</p> <p>This manuscript begins with a review of the currently available scientific literature concerning gastro-oesophageal reflux - its pathogenesis, diagnosis and therapy. Then, the design of a prospective randomized control trial of therapy for persistent clinically significant gastro-oesophageal reflux is described. The design is for an intervention study to determine the effectiveness of therapy in patients randomized to either surgical or medical treatment for this disorder.</p> <p>Subjects for the study will be drawn from among patients referred from primary care physicians to gastroenterology clinics for treatment. These patients to be eligible will have to have failed to respond to standard medical therapy.</p> <p>Data for analysis will be collected utilizing a self administered questionnaire to record symptoms and the degree of incapacity caused by them.</p> <p>It is hoped that results obtained from the performance of the trial described in this document will be of assistance in guiding the decision making process of physicians caring for patients with symptomatic gastro-oesophageal reflux.</p> / Master of Science (MS)

<p>This thesis is a study of chronic methylmercury exposure in two Indian Reserves in Northwestern Ontario - White Dog and Crassy Narrows.</p> <p>The study consists of three major divisions which are the analysis of trends in human mercury levels in the two communities from 1970 to 1978; the design of a study to examine three major research questions; and conclusions drawn from the study.</p> <p>The analysis of data from White Dog and Grassy Narrows indicate that mean human mercury levels have declined significantly in the 1970 to 1978 period. This attributed to the success of programs designed to discourage the consumption of local fish.</p> <p>A cross-sectional prevalence study is designed to address the question concerning possible neurological effects of chronic methylmercury exposure in White Dog and Grassy Narrows. A second sub-study utilizes a sample of individuals for whom early information is available on peak mercury levels to examine the question of a mercury exposure gradient. A retrospective study of stillbirths and congenital abnormalities is designed to examine the effect of prenatal exposure to methylmercury.</p> / Master of Science (MS)

<p>The lineage identity of a particular cell within a multi-cellular organism is defined by the repertoire of mRNA it expresses. Changes to the transcript repertoire can affect cell identity and stage of differentiation. Chromatin as the biologically relevant target of transcription factors has a direct impact on cell identity and differentiation, with changes to its structure central to lineage choice, cellular identity and differentiation. The requirement of chromatin remodeling in these developmental processes is evident throughout myogenesis, with changes to the cell's chromatin structure occurring during both the specification of myoblasts and the differentiation of specified myoblasts to myotubes. This thesis examines three distinct aspects of chromatin remodeling in relation to myogenesis. Firstly, the role of Snf2h in MyoD-mediated repression of target genes during myoblast proliferation was investigated. Snf2h was identified as a MyoD-interacting protein in a repressed transactivator yeast two-hybrid screen. Overexpression of either an active or inactive form of human SNF2H in myoblasts accelerated the differentiation process without affecting either growth rate or cell cycle kinetics. Furthermore, the chromatin structure surrounding the myogenin E boxes was more open in myoblasts expressing inactive human SNF2H compared to control myoblasts suggesting functional Snf2h complexes are required to repress differentiation specific genes during growth and subsequently maintain the myoblast proliferative state. From these and published results, a model describing the role of Snf2h in myogenesis is suggested. This model proposes that Snf2h activity facilitates the repression of MyoD target genes by histone deacetylases. In addition, genome-wide changes to histone H4 acetylation and histone H3-K9 dimethylation during myoblast differentiation were assessed. The patterns of genome-wide histone modifications in proliferating myoblasts were distinct from the patterns observed in myotubes, suggesting distinct mechanisms are targeting histone-modifying activity in myoblasts and myotubes. Furthermore, in our study, hyperacetylation of histone H4 and hypomethylation of histone H3 did not correlate strongly with transcriptional status. Our results support the hypothesis of the Histone Code Model, which theorizes that a combination of distinct histone modifications and not individual histone modifications defines the transcriptional competence of a particular gene. (Abstract shortened by UMI.)</p> / Doctor of Philosophy (PhD)

<p>The mechanisms underlying light-adaptation in goldfish retinal horizontal cells were investigated. The receptive-field size of horizontal cells was reduced by background illumination, but by a mechanism not mediated by dopamine, the only known modulator of horizontal cell receptive-field size. Light-induced changes in receptive-field size were shown to vary depending on which of two adaptation states the retina was in prior to background illumination. Presentation of background illumination to a dark-adapted retina resulted in a light-sensitized retina in which horizontal cell receptive-field size and responsiveness was increased. Application of background illumination to light-sensitized retinas lead to light-adapted retinas, in which horizontal cell receptive-field size was decreased.</p> <p>Two new putative adrenergic neurons were identified immunohistochemically in the goldfish retina. These cells, in particular a new type of interplexiform cell that could provide direct synaptic input to horizontal cells, raised the possibility that the light-dependent reduction in horizontal cell receptive-field size might be due to the release of an adrenergic transmitter. However, studies showed that the effects of adrenergic transmitters on horizontal cells were more consistent with an action at dopamine receptors than at adrenoreceptors. Because it was previously shown that the light-dependent reduction in horizontal cell receptive-field size did not depend on the action of dopamine, it was concluded that the adrenergic neurons are unlikely to be involved in this change.</p> <p>Studies on the effects of nitric oxide suggest that this free radical gas may be involved in the background illumination-induced reduction of horizontal cell receptive-field size. This was demonstrated by showing that horizontal cells are immunoreactive for nitric oxide synthase and that two inhibitors of nitric oxide synthase reduced the effects of background illumination on horizontal cell receptive-field size.</p> / Doctor of Philosophy (PhD)

<p>Proteases participate in various aspects of different biological processes to serve purposes as diverse as nutrition and biological controls, all of which are effected by the cleavage of peptide bonds. Nevertheless, proteolysis is an irreversible process because there is no known biological repair mechanism for a broken peptide bond. To ensure that proteases act only beneficially, proteolytic activities are regulated by different control mechanisms, one of which is composed of the natural protease inhibitors. The inhibitors neutralize the proteases by complex formation. The interactions between inhibitors and proteases in vitro have been well documented whereas information on the in vivo behaviours of protease-inhibitor complexes is limited at present. α₂M-protease complexes have been shown to disappear from the circulation extremely rapidly while the clearance of α₁AT-protease complexes is comparatively slow. Thus, it seems, probable that different elimination pathways may exist for different types of protease-inhibitor complexes. The purpose of this study is to examine the in vivo behaviours of some AT Ill-protease complexes, with an attempt to elucidate a probable elimination pathway for such complexes.</p> <p>Complexes of rabbit, human and rat AT III with rabbit plasmin and of rabbit AT III with rabbit or bovine thrombin were formed from radioactively-labelled proteins and separated from the uncomplexed reactants by preparative electrophoresis. In certain cases, unlabelled proteins were complexed and the complexes were labelled after they had formed. The in vivo behaviour of the complexes was studied in rabbits by the measurement of plasma radioactivity. The integrity of the complexes after injection into the rabbits was monitored by gel filtration of selected plasma samples on Sephadex G-200. Affinity chromatographic columns, such as Sepharose-AT III, -trypsin, -heparin and -lysine were used for the isolation and study of the various components. The stability of AT III-protease complexes under different in vitro conditions was examined by gel filtration and polyacrylamide gel electrophoresis. As a comparison, the complex of rabbit α₁AT with rabbit plasmin was also studied. α₁AT-plasmin complex was separated from uncomplexed materials by affinity chromatography on a Sepharose-lysine column.</p> <p>The AT III-protease complexes tested were eliminated considerably more slowly than α₂M-protease complexes. The speed of elimination of AT III-protease complexes resembled that of α₁AT-protease complexes. All five combinations of AT III-protease complexes dissociated soon after injection into rabbits, though to variable extents. However, rabbit AT III-plasmin complexes were stable for at least 6 h at 37°C in vitro. Post-complex AT III and post-complex plasmin appeared to have been altered as compared to the corresponding native proteins. Thus post-complex AT III lost more than 80% of its affinity for Sepharoseheparin and this form of the inhibitor no longer bound to Sepharosetrypsin (80% of the control AT III bound to conjugated trypsin). However, post-complex AT III was eliminated only marginally faster than the native AT III and it retained its reactivity with antibodies raised against normal AT III. Post-complex plasmin did not bind to Sepharose-AT III or -Trasylol but about 86% of its ability to bind to Sepharose-Iysie was preserved. Whether the above observations for AT III-protease complexes in rabbits hold true in other species, remains to be established.</p> / Master of Science (MS)

<p>In the work described in this theses, hormonal and physiological responses to exercise were investigated in women in relation to the menstrual cycle. Alterations in estradiol, progesterone, luteinizing or follicle stimulating hormones with exercise may interfere with the delicate hormonal balance which is necessary for regular ovulatory menstrual cycles. At rest, estradiol and progesterone have effects on carbohydrate and lipid metabolism, on pulmonary and cardiovascular function and on the plasma concentrations of a number of other hormones, all of which may also be important during exercise. As wide fluctuations in resting levels of the ovarian steroids occur during a normal menstrual cycle, they may influence exercise performance or the physiological adaptations to exercise at different times in the cycle.</p> <p>To investigate these issues, nine subjects were studied during cycle ergometer exercise at three exercise intensities on two occasions in the menstrual cycle. Tests were conducted when resting levels of estradiol and progesterone were low, in the early follicular phase, and when the concentrations of both hormones were elevated, in the mid-luteal phase. Separation into the two phases was confirmed by hormone analysis.</p> <p>For the first time, it has been shown that in women, exercise is associated with an increase in the plasma levels of estradiol, progesterone, luteinizing hormone and follicle stimulating hormone. The response of the ovarian hormones is more marked in the luteal phase while the gonadotropins are affected only in the follicular phase. The magnitude of the increase in all four hormones is related to the intensity of exercise. These alterations in ovarian and gonadotropic hormone levels with exercise may possibly help to explain the occurrence of menstrual, irregularities in women engaged in strenuous physical activity.</p> <p>In the luteal phase, at a time when resting levels of estradiol and progesterone are higher, exhaustive exercise was maintained for longer than in the follicular phase. The difference was associated with a lower blood lactate concentration in the luteal phase, in the absence of differences in heart rate, oxygen uptake or cardiac output. This suggests that the effect of the menstrual cycle on the capacity to exercise is exerted at a local level in exercising muscle rather than through changes in oxygen delivery. A final study in this thesis showed an increased epinephrine response to exercise in the follicular phase. Further studies are required to investigate the part played by epinephrine in modulating the biochemical responses to exercise.</p> <p>Exercise results in increases in the plasma levels of estradiol, progesterone, luteinizing and follicle stimulating hormones that are dependent on both the intensity of exercise and the phase of the menstrual cycle. In addition, there is an improvement in performance of high intensity exercise in the luteal phase, in association with lower levels of plasma lactate. The mechanisms which underlie these findings remain to be elucidated.</p> <p>With the exception of the catecholamine assays, the work reported in this thesis was performed by the author. This includes the remaining hormone assays, lactate analysis, exercise tests and calculation of the data and most of the statistical analysis.</p> <p>Portions of this work have been published and/or presented previously:</p> <p>Jurkowski, J.E., N.L.Jones, W.C.Walker, E.V.Younglai and J.R.Sutton Ovarian hormonal responses to exercise. J.Appl.Physiol:Respirat,Environ. Exercise Physiol. 44:109-114.1978.</p> <p>Jurkowski, J.E.,N.L.Jones, J.R.Sutton, C.J.Toews Exercise performance and blood lactate levels in relation to the menstrual cycle. Med Sci Sports 9:70,1977. (abstract)</p> <p>Jurkowski, J.E.,J.R.Sutton.and P.M.Keane Effect of the menstrual cycle on the plasma catecholamine response to exercise in normal females. Canadian J.Appl.Sport Sci. 3:194,1978. (abstract)</p> / Master of Science (MS)