<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)

<p>The role of testosterone in follicular development and ovulatIon has been investigated by immunizing female rabbits to testosterone-3-bovine serum albumin (T-3-BSA). The intent of this procedure was to render any endogenously produced testosterone inactive by means of its high affinity binding to specific antibody.</p> <p>In order to determine the time course of the effects of this procedure three groups of 12 - 6 control, 6 experimental - immaturely immunized rabbits were sacrificed at 5, 8 and 11 weeks after immunization. The effects observed at 11 weeks were compared with a group of 10 - 6 control, 4 experimental - maturely immunized rabbits sacrificed after the same length of immunization. In addition a group of 11 - 5 control, 6 experimental - immaturely immunized animals were mated to a proven male 14 weeks after immunization.</p> <p>Animals were boosted regularly and the antiserum titer followed weekly. Blood samples were taken weekly for the determination of FSH and LH levels and the total and percent bound testosterone and estradiol. After sacrifice the ovaries and uteri were removed for histology. Follicular development was examined and the maximum follicular diameter ≥ 1.0 mm and ≥ 1.5 mm was recorded. In mated animals the number of corpora lutea per ovary were counted.</p> <p>SignifIcant antiserum titers to testosterone were observed in all experimental rabbits by 5 weeks of immunization. Over the 14 weeks of the experiment values ranged from 1:700 to 1:52,000.</p> <p>In control rabbits serum testosterone values were less than 0.5 ng/ml while values in experimental rabbits rose steadily over the length of the experiment (group values ranged from 0.6 ± 0.1 ng/ml to 2.1 ± 0.9 ng/ml, 2.2 ± 0.7 ng/ml to 5.7 ± 0.8ng/ml and 4.4 ± 1.2 ng/ml to 6.8 ± 1.2 ng/ml at 5,8 and 11 weeks respectively). Testosterone binding in control animals remained in the 93% to 95% range throughout the experiment while in experimental animals testosterone binding increased significantly to approximately 99% at 5 weeks of immunization and remained constant thereafter.</p> <p>Estradiol values in control rabbits remained relatively constant throughout the ewperiment (group range: 50.7 ± 5.4 pg/ml to 81.8 ± 4.9 pg/ml). A consistent and significant increase in estradiol occurred in experimental animals (group values ranged from 69.5 ± 15.4 pg/ml to 88.5 ± 8.7 pg/ml, 74.5 ± 9.8 pg/ml to 118.5 ± 13.1 pg/ml and 81.6 ± 6.9 pg/ml to 157 ± 30.3 pg/ml at 5,8 and 11 weeks after immunization. Prior to immunization estradiol binding in experimental rabbits was not different from control values (range : 83% to 88%). There was a significant increase in estradiol binding by 5 weeks of immunization in the experimental groups (range: 89.4% to 94.5%). By 11 weeks estradiol binding increased to as much as 97.9%.</p> <p>Follicular development was abnormal in T-3-BSA immunized rabbits. The ovaries contained numerous large cystic and hemorrhagic follicles. At 8 weeks experimental ovaries contained more follicles ≥1.0 mm (27.2 ± 3.1 versus 15.3 ± 2.9, p < 0.01) and ≥1.5 mm (5.83 ± 1.7 versus 0.42 ± 0.2, p < 0.005). At 11 weeks there were more follicles ≥ 1.5 mm in both immature (5.0 ± 0.9 versus 0.92 ± 0.31, p < 0.001) and mature (7.25 ± 0.92 versus 4.17 ± 0.74, p < 0.05) experimental ovaries. Increased vascularization, some thecal cell hypertrophy, and marked interstitial cell hypertrophy were characteristic of the experimental ovaries. There was also a significant increase in the number of ovulations in the experimental rabbits (8.0 ± 2.1 versus 4.4 ± 1.9, p < 0.005).</p> <p>Immunization of female rabbits to testosterone is a useful tool for the study of hormone interactions in the regulation of follicular development and ovulation. In addition it may serve as a useful model for the study of the processes involved in the development of cystic ovaries.</p> / Master of Science (MS)

<p>Quality of care evaluation strategies are needed for meaningful assessment of health care delivery for research, quality assurance and educational purposes.</p> <p>For the purpose of improving strategies for measuring quality of care, this thesis first reviews methodologic features of available measurement strategies as reported in the current scientific literature. Secondly it proceeds with the development of a descriptive research design to evaluate the criterion validity of a strategy for evaluating process items by comparison with comprehensive outcome measures including physical, emotional and social function. Thirdly, the development of a new strategy for measurement of interpersonal skills, which is incorporated into the process evaluation, is described.</p> <p>The objective of the study is to study patients with acute myocardial infarction in order to determine whether measurable differences in the care administered to and received by these patients result in clinically significant differences in these patient's health status six months later. Acute myocardial infarction has been chosen as a disease appropriate for the testing of this strategy because if its high incidence, its functional impact upon the patient, the variation in process management items performed by different physicians, the different clinical settings involved, the relative diagnosis and availability of an inception cohort. A community hospital setting has been selected for the reason that, compared with a teaching hospital setting, the generalisability of the study to the practice of other physicians will be greater since the majority of physicians involved in the care of patients with acute myocardial infarction work in community hospital settings.</p> / Master of Science (MS)

<p>A PROTOCOL FOR THE DESIGN OF A RANDOMIZED CLINICAL TRIAL IN A FAMILY PRACTICE SETTING IS DESCRIBED. THE TRIAL IS DESIGNED TO TEST IF TWICE A DAY (B.I.D.) ANTIBIOTICS PRODUCED BETTER COMPLIANCE THAN THE STANDARD FOUR TIMES A DAY (Q.I.D.) REGIMENS. THE DISEASE MODELS OF STREPTOCOCCAL PHARYNGITIS AND UNCOMPLICATED URINARY TRACT INFECTION ARE USED BECAUSE OF THEIR SIMILARITY AND BECAUSE THEY ARE COMMON IN THE FAMILY PRACTICE SETTING. COMPLIANCE MEASURES INCLUDE URINE ASSAY FOR ANTIBIOTIC PILL COUNTS AND DROP OUT RATES. COMPLIANCE WILL BE ANALYZED IN RELATIONSHIP TO THE TYPE OF REGIMEN, SIDE EFFECTS AND DISEASE OUTCOME.</p> / Master of Science (MS)

Caspersson (1970) discovered that each chromosome pair has a characteristic banding pattern when chromosomes are stained with the fluorescent dye, quinacrine. With this dye there are certain chromosome regions which are polymorphic. These regions can be used as markers in the study of the inheritance of chromosome anomalies. The purpose of this study was to determine, using chromosome markers, the parental origin of the extra chromosomes found in triploid and D, G trisomic spontaneous abortuses. Polymorphisms in the chromosomes of parents of 15 triploid and 12 trisomic abortuses were compared with those of their abortus to determine which parent donated the extra chromosome(s). The distribution of the markers was used to determine whether the error occurred during meiosis I or meiosis II or, in the case of triploids, to distinguish between a meiotic error and dispermy. Of the 15 triploids examined, 7 were informative as to the origin of the extra set of chromosomes. In 3 of these there was failure to extrude to second polar body during oogenesis. In 3 other cases it was impossible to distinguish between an error during meiosis of spermatogenesis and dispermy. The other informative case definitely arose by dispermy. Mechanisms for the origin of triploidy were discussed, in particular, aging of gametes. Only 1 of the 12 trisomies examined was informative. This was a trisomy 22 in which the extra 22 was from the mother but it was not possible to distinguish between non-disjunction during meiosis I and meiosis II. Possible mechanisms for the production of trisomies were discussed including maternal irradiation, autoimmune processes, possible endocrine factors and drugs.</p> <p>A number of technical factors which influence the appearance of polymorphic regions were also discussed. / Master of Science (MS)

<p>This thesis is a report of the evaluation of laboratory utilization by a Family Practice Clinic. The evaluation covered the month of October, 1975. All encounter forms generated by patient visits in October were included in the study sample.</p> <p>The encounter form records whether a patient is new to the clinic, the nature of his visit, whether the visit is the first for a given problem or a follow-up visit, the diagnosis made at the visit, and any laboratory procedure ordered. These variables were combined in an instrument that determined the motive a physician might have for ordering a laboratory investigation.</p> <p>Three motives for ordering a laboratory procedure were defined, ie. casefinding, monitoring or diagnostic use. Tests requested were classified into the three categories. The classification instrument was validated and shown to be reliable. The data used from the encounter was shown to be only 50% reliable with unrecorded information being the major factor contributing to the unreliability of the data.</p> <p>The study showed that requests for laboratory procedure can be classified by the three motives for requesting them, ie. diagnosing, casefinding or monitoring. Sixty-one percent of the tests were used for diagnosis, 11% for casefinding and 28% for monitoring. Age, sex, nature of visit and the diagnosis of the patient were shown to be important variables in explaining the physician's use of the laboratory.</p> <p>The results indicate that the classification logic is an operational tool but in this study its validity has not been completely assured.</p> / Master of Science (MS)

<p>The relationship of patterns of hemispheric specialization to verbal and non-verbal cognitive abilities were studied as well as the effects of birth stress on the etiology of left-handedness. Using verbal and non-verbal dichotic listening tests 28 right- and left-handed boys and girls with a mean age of 10.6 years, were assessed as being unilaterally or bilaterally organized for processing verbal and non-verbal material. The subjects were also assessed for verbal and non-verbal ability using standard intelligence tests. Birth records were obtained in order to assess whether birth stress resulted in perinatal anoxia, the agent for altering hand preference. It was found that:</p> <p>1) Boys may show a left ear effect for some nonverbal material but girls may not.</p> <p>2) Bilateral organization for processing non-verbal material is not necessarily correlated with poorer spatial ability in girls.</p> <p>3) The relationship of bilateral organization for processing verbal material with overall verbal ability were inconclusive.</p> <p>4) There is no evidence to indicate that birth stress and/or oxygen deficit are necessary for left-handedness to occur, since both right- and left-handers exhibit these factors to the same degree and at least some of the left-handers appear to show no evidence of birth stress at all.</p> / Master of Science (MS)

<p>The purpose of this thesis is to describe a research design for evaluating the effectiveness of comprehensive primary health care in rural areas of Sierra Leone.</p> <p>Comprehensive primary health care, which is based on community participation within the framework of a policy of self-reliance and self-development is seen by many as the answer to solving the health problems of deveIoping countries.</p> <p>In setting the scene for evaluating the effectiveness of comprehensive primary health care in rural Sierra Leone, a description of the background of the country is given highlighting the major geographical, demographical and socioeconomical features. The state of health in the developing countries as a whole is also reviewed (Chapter 3).</p> <p>Chapter 4 explores the concept of comprehensive primary health care and reviews the operational aspects in the African context.</p> <p>In an attempt to establish some basis for the design of an effectiveness evaluation of comprehensive primary health care, the main methodologic issues in the presented setting are explored (Chapter 5).</p> <p>Having identified the main methodologic issues specific solutions and their justifications are proposed (Chapters 6,8,9).</p> <p>Finally, a specific protocol of the proposed research design is presented.</p> / Master of Science (MS)