<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)

<p>Lack of compliance with therapeutic regimens is an important cause of inadequate or incomplete medical care.</p> <p>For the purposes of furthering knowledge about problems of compliance, this thesis first surveys issues of compliance as reported in the current scientific literature and then proceeds with the development of specific strategies to improve compliance and finally with the development of a research design for testing these strategies in a controlled clinical fashion among a cohort of medical patients newly initiated into therapy.</p> <p>The compliance-intervention strategies include, first, special techniques in patient education, utilizing potent behavior-oriented teaching materials, second, a flexible, opportunistic approach to fitting medical appointments and medication-taking into a patient's existing rituals and daily routine, a process here termed "tailoring", and, third, a behavior modification paradigm which reinforces prescribed behavior.</p> <p>Hypertension has been chosen as a disease appropriate for the testing of the strategies because of its high prevalence and its known harmful effects, because of tho existence of efficacious treatments for it, and because of the small proportion of its victims who are receiving adequate treatment, whether for lack of detection of the condition or lack of compliance with its therapy.</p> <p>A steel mill (Dominion Foundries and Steel Company) in Hamilton, Ontario, has been selected as an ideal study site for several reasons. First, the Company is owned by its employees and this has led to an exceptionally stable employee group. Second, it has an active and cooperative employee health service. Thirdly, the health service staff has become concerned about the problem of untreated hypertension through its periodic health assessment program and the high prevalence of hypertension among employees lost from active duty through vascular disease.</p> <p>At the time of this writing the project has been funded through the Medical Research Council and is just getting underway.</p> / Doctor of Philosophy (PhD)

<p>Antithrombin (AT) and heparin cofactor II (HCII) are the predominant inhibitors of thrombin in plasma. They belong to the se rine p[barbelow]rotease in hibitor, or serpin, family of proteins and they inhibit their target proteases through a mechanism that is unique to this family of molecules. AT and HCII provide an ideal substrate on the reactive centre loop and subsequently form 1:1 stoichiometric inhibitory complexes with their target proteases through a mechanism that results in major conformational changes in these serpins. While thrombin acts as a target protease with these serpins, neutrophil elastase (NE), another serine proteases, reacts with AT and HCII within the reactive centre loop. Unlike thrombin, however, the interaction of NE with AT and HCII results in cleavage and inactivation of these serpins, without forming inhibitory complexes with NE. The aim of this thesis was to analyze the effects of mutagenesis of the NE cleavage sites within AT and HCII to determine the limits of amino acid substitutions that would permit AT and HCII to retain function but be less susceptible to inactivation by NE. Analyses of proteins expressed in a cell-free expression system and then in COS-1 mammalian cell culture were used to study the effects of mutagenesis at P4 and then at P4 and P5 in rabbit and human AT. While charged and polar amino acid substitutions severely reduced the function of AT, substitution of the bulkiest residue, tryptophan, at P4 and then at P5 and P5 had minimal effects on the thrombin-inhibitory activity of AT. However, the susceptibility to NE cleavage did not appear to be affected by any substitutions that were made in AT. Analysis of amino acid substitutions in bacterially-derived HCII P6 variants demonstrated a similar flexibility in amino acid composition at the site of NE cleavage, with respect to the ability to inhibit thrombin, although substitution of polar and bulky residues within the reactive centre loop of this serpin increased its resistance to NE inactivation. These results demonstrate that the amino acid composition of the reactive centre loop of AT and HCII is flexible to allow the maintenance of thrombin-inhibitory activity, although some limitations do exist. The effects of residue substitutions within the reactive centre loop on the susceptibility to NE cleavage are less clear, but the presence of bulky amino acids at the primary NE cleavage site, at least in HCII, appears to reduce the proteolytic activity of this protease. The production of an NE-resistant thrombininhibitory serpin provides the basis for the possible development of "hardened serpins" which might be of therapeutic importance in the future.</p> / Doctor of Philosophy (PhD)

<p>Central dopaminergic systems have been implicated in CNS disorders such as schizophrenia and Parkinson's disease. The characteristics of dopamine (DA) receptors has been well studied using a variety of pharmacological and biochemical techniques. DA receptor function is known to be modulated by the endogenous tripeptide pro-leu-gly-NH2 (PLG). A combination of novel pharmacological (guanosine-5' -O -(3[ 35 S]thio)triphosphate; [35 S]GTPγS binding) and molecular biological (differential display mRNA by RT-PCR; ddPCR) techniques were used to examine the function of endogenously expressed D2 DA-receptors in the striatum. Studies were undertaken to increase our understanding of the mechanism of action of PLG and its role in D2 receptor regulation and signal transduction. Measurement of antagonist effects in the absence of D2 receptor stimulation revealed that basal [35 S]-GTPγS binding was significantly decreased by haloperidol, butaclamol and chlorpromazine but not clozapine, sulpiride and spiperone. Thus haloperidol, butaclamol and chlorpromazine acted as negative antagonists; while clozapine, sulpiride and spiperone acted as silent antagonists. The role of PLG in D2 receptor stimulation of Gi G-proteins was examined using the [35 S]-GTPγS binding technique. The possible effect of PLG on NPA-stimulated [35 S]GTPγS binding was assessed at both maximal (1 μM NPA) and submaximal (0.1 and 0.03 μM NPA) levels of D2 receptor stimulation. It was found that PLG did not significantly alter [35 S]-GTPγS binding in bovine striatum either in the absence or presence of D2 receptor stimulation; indicating that PLG does not alter the rate of GDP:GTP exchange in the Giα G-protein subunit. Haloperidol and clozapine have distinct pharmacological profiles and have differential effects on many systems in the brain. This likely accounts for the tendency toward the development of extra pyramidal side effects (EPS) with the use of haloperidol but not clozapine. In an attempt to elucidate the mechanism of action of PLG, ddPCR was utilised to discover genes that are regulated by protracted treatment with PLG (20 mg/kg, i.p. for 28 days). In the present study, I have attempted to further the understanding of D2 receptor coupling to G-proteins in the striatum with respect to agonist efficacy and negative versus silent antagonism. I have also determined that PLG does not modulate D2 receptor signal transduction by altering the rate of GDP:GTP exchange in Gi. Furthermore, I have used the [35 S]-GTPγS binding technique to compare the effects of typical and atypical neuroleptic treatment on D2 receptor coupling to Gi. (Abstract shortened by UMI.)</p> / Doctor of Philosophy (PhD)

<p>There is a high rate of pregnancy failure in humans. The greatest loss occurs at the time of implantation or immediately after the embryo has implanted. Up to 50-60% of this loss can be attributed to embryonic chromosomal abnormalities. The absence or anomalous amounts of physiologic factors which are necessary for implantation and early embryonic development may be the cause of pregnancy failure. Since the embryo is foreign, it is specifically necessary to explore the role of rejection and failure of mechanisms that suppress rejection at implantation.</p> <p>The murine system has been used to investigate the identity of immunosuppressive molecules produced during the process of preimplantation embryo development. Supernatants from mouse in vitro fertilized (IVF) embryo cultures can suppress in vitro lymphocyte proliferation stimulated by the mitogen concanavalin A. Medium conditioned by incubation with mouse epididymal spermatozoa alone were even more inhibitory to mitogen stimuhued lymphocyte proliferation. Thin layer chromatography detected the polyamines spermine in sperm, and spermidine as well as spermine in IVF embryo culture supernatants. Evidence was obtained that these were possibly the ill vitro molecules that were immunosuppressive and were likely produced by the embryo. The diamine putrescine was also detected but was not immunosuppressive.</p> <p>The conclusion from the studies suggest that polyamines may have a role in vivo in suppressing uterine immune response thereby assisting the embryo in the process of implantation. Failure of embryos to produce sufficient amounts of polyamines perhaps due to chromosome abnormalities, may explain failure of embryo implantation. As well, the failure of IVF embryos to produce adequate quantities of polyamines which are known to be essential for cell proliferation, could lead to embryo division arrest. In this broad sense polyamines may be viewed as "growth factors" i.e. defined molecules essential for cell division.</p> / Doctor of Philosophy (PhD)

<p>In order to establish a model of arenavirus infection of monocytes, human peripheral blood monocytes (PBM), human promyelocytic HL60 cells and human THP-1 promoncytic cells were infected with Pichinde virus (PV). PV replication was analyzed using a variety of assays which detected viral antigen, RNA and progeny virus. While human PBM were susceptible to PV infection and replication, HL60 cells did not support PV replication, even when cells were induced to differentiate to monocytes with the phorbol ester, PMA. THP-1 cells supported high levels of PV replication only when cells were exposed to PMA. THP-1 cells not treated with PMA supported lower levels of PV replication. Infection of PMA treated THP-1 cells by PV was dependant on protein kinase C (PKC) activation and host cell transcription.</p> <p>The restriction of PV replication in untreated THP-1 cells was characterized further. Experiments with lysosomotropic compounds demonstrated that equal amounts of PV were bound and internalized by both THP-1 cells and PMA treated THP-1 cells. These studies also indicated that PV enters THP-1 cells by endocytosis into acidic vesicles. The expression of PV specific RNAs in PMA treated and untreated THP-1 cells were also examined. PV SRNA genomes, antiger omes, GPC mRNA, NP mRNA and L RNAs were expressed at higher levels in PMA treated THP-1 cells versus untreated THP-1 cells. Degradation of input viral S RNA could not account for the reduction of PV RNA replication in the untreated THP-1 cells. Increasing the multiplicity of infection of untreated THP-1 cells with PV was only able to partially overcome the restriction of virus multiplication. This suggested that the restriction of PV replication in the THP-cells occurred later than the initial binding and penetration stages but at, or just prior to, primary transcription of viral mRNAs. These studies supported a role host cell factors and a dependence on the activation or differentiation state of the THP-1 cell in order to support PV replication.</p> <p>In order to gain further insight into the mechanisms utilized by PV to initiate transcription and replication, the 5' termini of PV S RNA genomes, antigenomes, GPC mRNA and NP mRNA were characterized. All termini sequenced had at least one extra nontemplated base. In clones that contained a single extra nucleotide, this was invariably a G nucleotide. Clones containing single nontemplated G nucleotides were only the derived from PV infected total cellular RNA. The 5' termini of NP and GPC mRNAs had on average 4-8 nontemplated bases. In addition, on genomic sense RNAs the base a -1 did not appear to be conserved. These data have important implication with respect to the mechanisms of PV transcription and replication initiation and are discussed in the context of two possible models.</p> / Doctor of Philosophy (PhD)

<p>In animal models it has been demonstrated that stimulation of muscle glycogenolysis is associated with the activation of phosphorylase b (phos b) to phosphorylase a (phos a). In similar experiments in rat skeletal muscle, we found that sclatic nerve stimulation increased glycogenolysis in the first 15 sec. of stimulation in close correlation with an increase in the phos a activity. However by 30 sec. the phos a had returned to resting levels although glycogenolysis continued at a stimulated rate.</p> <p>We did a series of experiments in human subjects to determine whether activation of phos b to phos a was essential in the activation of skeletal muscle glycogenolysis. Six normal male subjects underwent maximal voluntary isometric contraction of the quadriceps for 60 sec. Muscle needle biopsies were obtained at 0,10,20 and 60 sec. after onset of contraction. The rate of muscle glycogenolysis increased from less than 2.05 ± .35 at rest to 17.5 ± 0.7 umol/g during contraction, calculated from the increase in muscle lactate concentration. Enzyme analysis in the same biopsies revealed that the phos a: total phosphorylase ratios remained unchanged (0.05 ± 0.006). In separate experiments 5 normal male subjects exercised on a cycle ergometer at 66% of their VO₂ max. work load until exhaustion. After 40 min. exercise at 66% VO₂ max. load the muscle lactate concentration rose from 1.1 ± 0.005 umol/g at rest to 11.6 ± 0.8 umol/g. When subjects were exercised at 90% VO₂ max. until exhaustion; the change in muscle lactate was taken as a semi-quantitative reflection of the rate of muscle glycogenolysis. The change in the rate of music lactate production increased from 0.2 umol/g/min at the end of 66% work load, to 1.2 umol/g/min at exhaustion, indicating that glycogenolysis was stimulated. The phos a: total phosphorylase ratio and the active to total phosphorylase b kinase ratio remained unchanged at the end of 40 min. exercise and at exhaustion, from the resting value. We conclude that activation of phosphorylase (phos b to phos a conversion) is not an absolute prerequisite for stimulating glycogenolysis in skeletal muscle.</p> / Master of Science (MS)

<p>Hypertension is a chronic affliction which has a significant economic and health impact on Canadian society. Efforts to control hypertension are likely to produce significant returns, if the programs are effective in treating the hypertensive population. Before research efforts can be profitably directed at determining the most efficient method of achieving hypertension control, the state of, and deficiences in, the present health care system must be identified. The best approach to obtaining the information needed to evaluate the present system, is through a special-purpose, population-based survey.</p> <p>The proper methodologic design of a population survey requires the use of probability sampling procedures. In addition, the blood pressure should be measured at several visits, using a standardized procedure. Examination of the literature reveals that no study satisfies all of the basic standards.</p> <p>It is possible to identify six steps that must be followed if hypertension control is to be achieved. These steps form a conceptual model that can provide the basis of a general measurement strategy that can be used to assess the degree of hypertension control in a specific community.</p> <p>This measurement strategy is used to develop a survey design to measure the degree of hypertension control in the Province of Ontario. A specially-created interview team will examine 3,850 individuals, located in selected geographic areas across the Province. Blood pressure will be measured using a Hawksley Random-zero Sphygmomanometer, at a maximum of three separate visits. Questionnaires will be developed to obtain valid information about health knowledge, attitudes and beliefs. The survey design will permit regional comparisons.</p> / Master of Science (MS)