<p>Are the outcomes of rheumatoid arthritis patients improved when their family physicians are provided with information gathered by specially trained physiotherapists?</p> <p>Two physiotherapists were selected and trained in detailed objective techniques of evaluation and problem identification, leading to a clear and succinct report designed to assist the family physician in treatment decisions. From June 1974 to January 1977, a randomized controlled trial was conducted to assess the effect of these reports on the outcomes of women with rheumatoid arthritis treated in the community by their family physicians.</p> <p>On admission to the trial, patients were randomly allocated to two groups: one experimental group which was assessed according to modern quantitative techniques of evaluation and, following communication of results to family physicians, were treated at home by the trained physiotherapists; and a control group which was assessed according to traditional techniques of evaluation and, following, communication of results to family physicians were treated at home by traditional physiotherapists. All subjects were interviewed initially, at four, and at 12 months by independent assessors who used a standardized prestructured questionnaire designed to measure the level of joint inflammation, functional capacity, compliance and mood.</p> <p>In association with this triaI, a pooled index was developed converting live separate outcome measures into a single prespecified variable, to measure treatment differences.</p> <p>The author's unique contribution to this trial related to: development, formulation and execution of the experimental design, and more specifically, the use of independent assessors in rheumatology, allocation strategies, processing of intakes, supervision and control of data gathering procedures and the introduction of modifications in the design following the protest and during the experiment period that made this trial feasible.</p> <p>This is a "compound" thesis, focussing on the present state of knowledge and rationale for the research, the original design and modifications introduced following the pretest and during the experimental period. The rationale and effects of these modifications will be discussed in detail.</p> / Master of Science (MS)

<p>Hyperkinetic children and their treatment are currently the subjects of heated discussions among medical persons, parents, teachers, government officials, the press and a concerned public. The focus of these discussions is often the appropriateness or inappropriateness of stimulant medications for hyperkinetic children.</p> <p>The first part of this thesis contains a review of a substantial portion of the literature on hyperkinesis including : definitions and diagnosis of hyperkinesis, prevalence of hyperkinetic symptoms and of hyperkinesis, characteristics of children considered hyperkinetic, drug treatments for hyperkinesis, and non-drug treatments for hyperkinesis. The major purpose of the literature review is to examine all available studies of the effectiveness of methylphenidate for hyperkinesis and all available studies of the effectiveness of non-drug treatments for hyperkinesis. This review indicates that methylphenidate is the most effective drug treatment tested and that behaviour modification or operant conditioning is the best tested, effective non-drug treatment for hyperkinesis. The relative effectiveness of methylphenidate and behaviour modification alone or in combination for the treatment of hyperkinesis is not known.</p> <p>In the literature review, Tables are provided which summarize information gleaned from an extensive selection of publications. These Tables include : A) Estimates of the Prevalence of Hyperkinetic Symptoms and of the Hyperkinetic Disorder in Children; B) Some Characteristics which Distinguish Children Diagnosed as Hyperkinetic from Normal Children; C) Some Characteristics which Distinguish Children Diagnosed as Hyperkinetic from Neurotic or Normal Children; D) A Summary of Studies of Methylphenidate for Hyperkinesis; E) The Effectiveness of Methylphenidate versus Placebo for Hyperkinesis : measures on which M and P have differed significantly in therapeutic effectiveness; F) The Effectiveness of Methylphenidate versus other Active Drugs for Hyperkinesis; G) A Summary of Studies of Non-Drug Treatments for Hyperkinesis; H) Evaluation of Miscellaneous Non-Drug Treatments for Hyperkinesis, and I) The Effectiveness of conditioning in the Treatment of Hyperkinesis.</p> <p>The second part of this thesis is a research proposal which has been developed on the basis of the current state of knowledge pertaining to the treatment of Hyperkinesis. The proposed research is designed to determine which of three very promising treatments for hyperkinesis has the greatest effectiveness and fewest side-effects: methylphenidate, behaviour modification, or methylphenidate plus behaviour modification. The protocol covers the following areas : Rationale for the study; Selection criteria for hyperkinetlc children; Collection of the sample of children; Sample size required; Pre-treatment assessments; Assignment to treatments; Methylphenidate treatment at .7mg/kg/day; Behaviour modification program including 8 sessions; Methylphenidate and behaviour modification in combination; Post-treatment assessments; Data analysis and budget for the study. This protocol could be adapted for use by other investigators interested in the area.</p> / Master of Science (MS)

<p>The energy required for the performance of light exercise is largely supplied by the aerobic oxidation of fat and carbohydrate. As the intensity of exercise increases, the percentage of energy derived from anaerobic processes, predominantly the breakdown of muscle glycogen to lactic acid, is increased proportionally. Evidence suggests that the increase in anaerobic metabolism influences the mobilization of free fatty acids from adipose tissue. Studies have shown that lactate inhibits FFA mobilizltion in dogs. In man, it was found that plasma FFA are reduced during heavy exercise and remain low as long as plasma lactate is increased. However, when lactate is increased under these conditions, the pH is reduced.</p> <p>To separate the effects of pH and lactate in the blood, subjects performed three identical exercise tests with artificially induced changes in blood pH prior to two of the studies. Ammonium chloride and sodium bicarbonate were ingested over a three hour period prior to exercising to produce an acidosis and alkalosis, respectively. Calcium carbonate was given as a placebo for the control study. In all subjects, the studies were performed in a random order, in a fasted state and were separated by at least 72 hours. Arterialized venous blood was sampled from a vein in the hand.</p> <p>The maximum power output of each subject was measured by a progressive exercise test to exhaustion on a cycle ergometer. During the studies, they exercised at 33% and 66% of their maximum power output for 20 minutes each, followed by 90% until exhaustion.</p> <p>This protocol resulted in a significant separation in both blood pH and exhaustion times at the 90% workload. The mean exhaustion times were 4 min., 2.5 min., and 6.5 min. for the control, acidosis and alkalosis studies, respectively.</p> <p>The plasma lactate concentrations were also significantly different. The lowest lactate levels were found during acidosis and the highest during alkalosis.</p> <p>Plasma glycerol and FFA concentrations were similar during the control and alkalosis studies, but significantly lower during acidosis. The lowest levels of glycerol and FFA were found when the pH was lowest, but plasma lactate was also lowest.</p> <p>These results suggest that changes in pH are more important than changes in lactate, per se, in the inhibition of FFA mobilization during severe exercise. In addition, it appears that acidosis causes either a decreased rate of production of lactic acid, a decreased rate of efflux of lactate from muscle, or an increased utilization of lactate by other tissues.</p> <p>Although the mechanisms cannot be determined from this study, the results suggest that acidosis inhibits glycolysis as well as FFA mobilization, reducing the anaerobic production of energy. This presents no serious problem during moderate exercise, but seriously impairs performance of heavy work.</p> / Master of Science (MS)

<p>The in vitro metabolism of testosterone, progesterone and androstenedione was studied in liver, testes, hypothalamus and cortex incubations of normal BALB/c♂, BALB/c♀ and a number of sex-mutant mice carrying the testicular feminization (Tfm) and sex-reversal (sxr) genes.</p> <p>The metabolism of testosterone was studied in liver homogenates of BALB/c♂ , Tfm (o⁺)⚥ and Tfm (oʰᵛ)⚥. Androstenedione was identified as the major metabolite of testosterone, in all incubations, indicating the presence of 17β-hydroxysteroid dehydrogenase activity. Comparison of the percentage conversions of testosterone to androstenedione suggested that of the three genotypes studied, the activity of 17β-hydroxysteroid dehydrogenase was lowest in the Tfm (oʰᵛ) liver.</p> <p>Similarly, the metabolism of testosterone and progesterone was studied by double-labelled tracer experiments using testes minces from BALB/c⚥ , Tfm (o⁺)⚥ and Tfm (oʰᵛ)⚥ mice. The conversion of progesterone to testosterone was greatest in BALB/c♂ incubations and least in the Tfm (o⁺) incubations. These data suggest that the relative activities of the 17-ketoreductase for the conversion of androstenedione to testosterone are in the order: BALB/c♂ > Tfm (oʰᵛ) ⚥ > Tfm (o⁺).</p> <p>Progesterone metabolism was studied in testis incubations of normal male (BALB/c♂), testicular-feminized, sex-reversed (Tfm+(oʰᵛ) Blo/+++, sxr/+ ♂) and sex-reversed (+Ta++/+++, sxr/+♂) mice. Comparison of the amounts of androstenedione and testosterone formed from P suggests that differences are present in the relative activity of the testis 3-ketoreductase. The relative activity is in the order BALB/c♂ > +Ta++/+++, sxr♂ > Tfm+(oʰᵛ) Blo/+++, sxr♂.</p> <p>The metabolism of androstenedione was also studied in testes incubation of Tfm (o⁺)⚥ and Tfm (oʰᵛ)⚥ mice. The formation of testosterone was similar in all incubations. A number of unidentified metabolites of androstenedione were detected in the Tfm (oʰᵛ)⚥ incubations which were not present in the Tfm (o⁺) incubations.</p> <p>Finally, the aromatization of testosterone was studied in hypothalamus and cortex incubations of normal BALB/c♂, BALB/c♀, and testicular feminized Tfm (o⁺)⚥ and Tfm (oʰᵛ)⚥mice. A new, rapid method was developed for studying aromatization based toluene-sodium hydroxide partitioning and a novel estrogen methylation procedure known as extractive alkylation. Using this method the formation of estrone and estradiol was detected. The conversion of testosterone to estradiol by hypothalamus minces was about 1.5 times greater in normal BALB/c♂ than BALB/c♀ and about the same as in Tfm (o⁺) and Tfm (oʰᵛ). Total aromatization by cortex minces was about 30-50% that of the hypothalamus. The major metabolite of testosterone in normal BALB/c ♂ and BALB/c ♀ incubations was estrone while in the Tfm (o⁺) and Tfm (oʰᵛ) incubations it was estradiol-17β.</p> <p>The studies confirm the work of others which suggests that the metabolism of steroids is altered in the liver and testis of the Tfm (o⁺)/Y⚥ mouse. The present work extends these observations to include a number of other mice carrying the Tfm and sxr genes. Using the extractive alkylation technique aromatization was detected in Tfm hypothalamus and although the overall quantitative yields of estrogen from testosterone were similar to normals, qualitative differences were evident which may be significant to the explanation of altered hypothalamic-pituitary gonadotrophin relationships in Tfm (o⁺) and Tfm (oʰᵛ) mice.</p> / Master of Science (MS)

<p>Crohn's disease is characterized by altered epithelial physiology including ion secretion and disrupted epithelial barrier. It has been suggested that the pathophysiology and epithelial damage in Crohn's disease may be due to inappropriate immune reactions. The purpose of my studies was to examine the role of cells of the monocyte/macrophage lineage in mediating epithelial physiology. Confluent monolayers of the T84 colonic epithelial cell line were co-cultured with human monocyte/macrophages (peripheral blood monocytes [PBM], or lamina propria mononuclear cells [LPMC]) from controls or patients with crohn's disease ± the activating agents, bacterial lipopolysaccharide (LPS) and/or the bacterial tripeptide, f-met-leu-phe (fMLP). Monolayers were then removed and epithelial secretory (baseline short circuit current [Isc] and ΔIsc to 10-5 forskolin) and barrier transepithelial resistance [TER]) were measured 48h later in the Ussing chambers. Epithelial functional parameters were unchanged after co-culture with non-activated PBM. Addition of activating agent (LPS or LPS/fMLP) significantly increased Isc and reduced TER with PBM from both control and Crohn's disease. No pathophysiology occurred after co-culture with control LPMC ± LPS. However, non-activated LPMC from patients with Crohn's disease spontaneously induced changes in T84 physiological parameters similar to those produced by activated PBM. A non-pathogenic control strain of E. coli , added to the luminal compartment of the culture well, induced comparable changes in epithelial physiology in the presence of PBM. The role of Tumor Necrosis Factor α (TNFα) in the regulation of epithelial secretory and barrier functions was examined. TNFα production was significantly increased by activated PBM and non-activated LPMC from Crohn's disease. The epithelial abnormalities could be successfully abrogated by inclusion of a neutralizing antibody to TNFα. These studies show that monocyte/macrophages are potent immune cells which may mediate some of the pathophysiology in inflammatory disorders of the gut. TNFα is a key factor mediating the monocyte/macrophage induced epithelial pathophysiology.</p> / Doctor of Philosophy (PhD)

<p>Fibrinolysis is the process by which blood clots are solubilized. For the purposes of intravascular fibrinolysis, tissue-type plasminogen activator (t-PA) catalyzes the rate-limiting step by converting the zymogen, plasminogen (Pg), to the active enzyme, plasmin. Plasmin then degrades the fibrin meshwork, generating soluble fibrin degradation products. Because the catalytic efficiency of Pg activation by t-PA is higher in the presence of fibrin than that in the presence of fibrinogen(Fg), t-PA is designated a fibrin-specific Pg activator. Despite this designation, t-PA causes systemic plasminemia and fibrinogenolysis when given to patients. Recently, it was demonstrated that the fibrin-specificity of t-PA is compromised because (DD)E, a major soluble degradation product of crosslinked fibrin, stimulates Pg activation to the same extent as fibrin. This project was initiated to gain a better understanding of how (DD)E compromises the fibrin-specificity of t-PA by characterizing the interactions of t-PA and Pg with fibrin, (DD)E and Fg. t-PA binds to fibrin through two classes of sites, one high affinity, finger-dependent site, and one low affinity, kringle-dependent site. In contrast, t-PA binds (DD)E and Fg solely through its second kringle domain, because these interactions are blocked by lysine or its analogues. Both t-PA and Pg bind (DD)E with affinities similar to those for fibrin, thereby explaining why (DD)E stimulates t-PA-mediated Pg activation to the same extent as fibrin. t-PA primarily binds to carboxy-terminal lysines on (DD)E because the affinity of t-PA for (DD)E is reduced 160-fold when (DD)E is exposed to carboxypeptidase B (CPB) or the active form of thrombin activatable firbinolysis inhibitor (TAFIa), an endogenous CPB-like enzyme. In contrast, the affinity of Pg for (DD)E is reduced only 2- to 4-fold when (DD)E is exposed to CPB or TAFIa, suggesting that Pg binds primarily internal lysine residues on (DD)E. t-PA and Pg have weak affinity for Fg, thereby explaining why Fg is a poor stimulator of Pg activation by t-PA. These studies demonstrate that the fibrin-specificity of t-PA is compromised by its kringle-dependent interactions with (DD)E and, to a lesser extent, Fg. The limited fibrin-specificity of t-PA has prompted the development of Pg activators with greater selectivity for fibrin. Two such agents are the activator isolated from the saliva of the vampire bat (b-PA), and a bioengineered t-PA variant, TNK-t-PA. b-PA is structurally distinct from t-PA in that b-PA lacks a lysine-binding kringle. TNK-t-PA was designed to have a longer half-life than t-PA, resistance to inhibition by plasminogen activator inhibitor-1, and increased fibrin-specificity over t-PA. When the fibrin-specificities of t-PA, b-PA, and TNK-t-PA were compared, the hierarchy of fibrin-specificity (b-PA > TNK-t-PA > t-PA) correlated with the ratio of their activity in the presence of fibrin relative to (DD)E. Whereas all activators have similar activities in the presence of fibrin, they are distinguished by their activity in the presence of (DD)E. b-PA, the most fibrin-specific, exhibits minimal stimulation by (DD)E, whereas t-PA, the least fibrin-specific, exhibits the greatest stimulation by (DD)E. Stimulation by (DD)E, in turn, reflects the affinity of the activator for (DD)E. b-PA does not bind (DD)E, presumably because it lacks a lysine-binding kringle. t-PA binds (DD)E with high affinity, whereas TNK-t-PA has ∼9-fold lower affinity for (DD)E than t-PA. These studies highlight the importance of (DD)E in compromising the fibrin-specificity of t-PA. Furthermore, they suggest that the fibrin-specificity of t-PA or t-PA variants could be improved by abolishing their lysine-binding properties.</p> / Doctor of Philosophy (PhD)

<p>Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disorder characterized by the premature destruction of autoantibody-sensitized platelets. For many years, elevated platelet-associated IgG (PAIgG) was thought to be a diagnostic characteristic of ITP. However, observations that PAIgG is increased in both immune and non-immune thrombocytopenia, questioned the clinical significance of PAIgG measurements, and the mechanism(s) by which IgG accumulates in platelets. The origin of IgG on the surface of platelets of patients with non-immune thrombocytopenia, is not known. Additionally, it is not clear why these IgG-sensitized platelets escape destruction by phagocytic cells of the reticuloendothelial system. In this investigation, possible biological explanations for the elevated PAIgG in adult patients with ITP and non-immune thrombocytopenia, were examined. Traditionally, laboratory investigation of ITP, has focused on the development of serologic assays to measure anti-platelet autoantibodies. As an alternative investigative approach, ultrastructural techniques were used to evaluate platelets from patients with ITP and non-immune thrombocytopenia. Using these techniques, it was possible to localize IgG in platelets, and determine the immunomorphologic characteristics of PAIgG in patients with immune and non-immune thrombocytopenia. The results of these investigations demonstrated, that apart from differences in numbers, ITP platelets and platelets from patients with non-immune thrombocytopenia are morphologically identical to normal platelets and show no evidence of structural abnormalities. Additionally, elevated total PAIgG levels in thrombocytopenic patients are not attributable to alterations in the physical characteristics of platelets, including increased platelet size or increased numbers of storage granules per platelet, but reflected quantitative abnormalities in the pool of exogenous a-granule proteins. Immunomorphologic characteristics of PAIgG in patients with ITP and non-immune thrombocytopenia differ. In patients with ITP, elevated PAIgG is observed both within and on the surface of platelets. In patients with non-immune thrombocytopenia, elevated PAIgG was observed within but not on the platelet surface. In these platelets, IgG is not elevated on the platelet surface and, consequently, platelets were not prematurely cleared by phagocytic cells of the reticuloendothelial system. These results further explain why patients with non-immune thrombocytopenia have a normal platelet lifespan. Demonstrations that immunomorphologic characteristics of surface PAIgG, in platelets from patients with non-immune thrombocytopenia change over time suggests that in vitro leakage of α-granule IgG onto the surface of platelets may account for the origin of surface PAIgG in these patients. Immunomorphologic characteristics of surface PAIgG in patients with immune and non-immune thrombocytopenia suggest that rim patterns of surface PAIgG in ITP reflect the binding of autoantibodies to glycoprotein targets on the platelet surface whereas, "beaded necklace" patterns of surface PAIgG in non-immune thrombocytopenia reflect IgG exocytosis from internal platelet storage pools in vitro . In summary, ultrastructural techniques have been useful for the study of early structural events leading to the pathogenesis of disease and more recently have been utilized in studies of platelet pathology. Whereas current measurements of PAIgG do not provide good diagnostic or prognostic value, ultrastructural patterns of IgG distribution in ITP platelets may in themselves, or in conjunction with other laboratory measures, provide additional information about a common thrombocytopenic disorder.</p> / Doctor of Philosophy (PhD)

<p>This study is a partial evaluation of a program of foster care for chronic psychiatric patients (Residential Homes for Special Care) in 41 homes in Hamilton and surrounding area, Ontario.</p> <p>A review of the development of foster care and of controversies over its value, as well as a review of the existing evaluative literature is included.</p> <p>An attempt was made to use adequacy of neuroleptic maintenance is chronic schizophrenic residents as a tracer condition for evaluation of quality of care given by primary care physicians.</p> <p>The objectives of the program were examined and operating definitions evolved for measures to evaluate some of these objectives. These included a field worker's rating of the quality of hostesses and an audit of prescription written by attending physicians for adequacy of neuroleptic maintenance, occurrence of drug interactions and prescribing frequency.</p> <p>The cohort studied was all 178 residents first admitted to foster care in the area in the years 1966 to 1969. These residents were followed for a three year period using existing health records. Data were complete on every resident for all variables excepts some drug prescription measures.</p> <p>Home factors such as rural location and inferior quality of hostesses were important determinants of rehospitalisation. Residents first placed in rural homes had many more rehospitalisations than those first placed in urban homes, although there were no significant differences in the age, sex, number and duration of previous psychiatric hospitalisation or diagnosis between these groups.</p> <p>Resident factors such as younger age, female sex and shorter duration of previous psychiatric hospitalisation were significant determinants of discharges from the program.</p> <p>The prescription audit measures did not predict outcome, but examination of the prescriptions did reveal 17 patients on prolonged tricyclic antiderressant therapy, 10 for more than four years.</p> / Master of Science (MS)

<p>It has been repeatedly demonstrated that radiation induces chromosome aberrations in mouse oocytes and spermatocytes. However, the results of previous studies, in which the frequency of aberrations recovered from irradiated oocytes and spermatocytes were compared, are conflicting (reviewed by L. B. Russell, 1962, L. B. Russell, 1968). The development of new techniques for making chromosome preparations from oocytes (Edwards, 1965; Tarkowski, 1966) and spermatocytes (Evans et al., 1964) has made it possible to reinvestigate the radiosensitivities of spermatocytes and oocytes.</p> <p>In the present study, the frequency of chromosome aberrations recovered from irradiated dictyotene oocytes was compared to the frequencies of aberrations recovered from irradiated pachytene and diplotene spermatocytes.</p> <p>Oocytes and spermatocytes were collected from mature mice one day and five days after exposure to a single acute dose of 300R ϒ-radiation. At the time of irradiation, all of the oocytes were in dictyotene while the spermatocytes collected one day and five days post-irradiation were in diplotene and pachytene, respectively. The average number of oocytes collected from irradiated mice was no different from the average number collected from controls. Although the ability of oocytes collected one day post-irradiation to mature in vitro (58.0%) was not affected, significantly fewer (53.6%) of the oocytes cultured five days post-irradiation matured in vitro. Since the frequency of abnormal cells vas the same in oocytes cultured one day and five days post-irradiation, it is unlikely that oocytes with chromosome aberrations were selectively inhibited from maturing in vitro.</p> <p>The frequencies of chromosome aberrations in dictyate oocytes cultured one day and five days after irradiation were not significantly different from the frequency of aberrations in diplotene spermatocytes (20.7%). However, significantly more chromosome aberrations (32.0%) were recovered fraa irradiated pachytene spermatocytes than from either dictyate oocytes or diplotene spermatocytes. Some variation in the relative frequencies of aberrations was found.</p> / Master of Science (MS)

<p>The discovery of Q-banding made it possible to identify every member of the human chromosome complement. Spontaneous abortions known to have a better than average chance of presenting with a chromosome anomaly were selected for cytogenetic analysis. A highly successful technique for culturing chorion from these specimens was developed. Direct chromosome preparations were obtained from the coverglasses on which the fibroblasts were subcultured. The characteristics of each specimen were noted as that as the information pool gives, it may be possible to define abortion syndromes.</p> <p>Fifty-nine per cent of the specimens selected were abnormal. These abnormalities included trisomies 2, 8, 14, 16 and 22, triploidy and tetraploidy. Vesicular villi, maternal age over 40 and conception coincident with maternal ingestion of contraceptives were found to be excellent forcasters of chromosome anomalies. Only one embryo, 69, XXY, in which congenital malformations could be identified was collected during the duration of this project. A possible polymorphism in a non-heterochromatic region of chromosome 17, in a 16-trisomy specimen, was noted.</p> <p>Heteromorphic bands have made it possible to distinguish between the members of a homologous pair of chromosomes 3, 4, 13, 14, 15, 21 and 22. A study of such markers in a twin abortus allowed for speculation on the zygosity of the embryos. Similar polymorphisms were used to determine whether the extra set of chromosomes in two triploid abortuses was of maternal or maternal origin. Distribution of these marker chromosomes was also used to determine when in meiosis the event of abnormal development occurred. The point was stressed, that some cell-to-cell variability does occur in these heteromorphic Q-bands and that great care must be taken in distinguishing maternal and paternal marker chromosomes, before the distribution of these parental chromosomes can be used to make statements about abnormal development events.</p> <p>Heteromorphic bands have made it possible to distinguish between the members of a homologous pair of chromosomes 3, 4, 13, 14, 15, 21 and 22. A study of such markers in a twin abortus allowed for speculation on the zygosity of the embryos. Similar polymorphisms were used to determine whether the extra set of chromosomes in two triploid abortuses was of maternal or paternal origin. Distribution of these marker chromosomes was also used to determine when in meiosis the event of abnormal development occurred. The point was stressed, that some cell-to-cell variability does occur in these heteromorphic Q-bands and that great care must be taken in distinguishing maternal and paternal marker chromosomes, before the distribution of these parental chromosomes can be used to make statements about abnormal developmental events.</p> / Master of Science (MS)