<p>The role of visual-spatial and short-term memory factors in reading and arithmetic disabilities was explored in 30 children with a reading disability: 41 with an arithmetic disability; and 70 who were achieving normally in reading, spelling, and arithmetic. All of the children had a PPVT-R score 80 and/or a WISC-R Block Design score 9. Percentile cut-off scores on the WRAT were used to classify the children into the three achievement or groups. The children were divided into three age groups (7-9, 10-11, 12-14) in order to study possible differences in cognitive performance between each disability group and the normal comparison group as a function of age. Two experimental arithmetic (Mixed Drill, Missing Symbols) and two experimental language tests (McGill Decoding Words and Nonwords), plus 4 visual-spatial tasks (Block Design, Rey-Osterreith CompIex Figure (Copy), Yerkes Blocks, Left-Right Orientation), and 5 short-term memory measures (Rey-Osterreith Complex Figure (Memory), Rey-Davis Form Board, Numerical Square, Digit Span, Phonemic - Confusability Rhyming and Nonrhyming Letters) were, administered to the children. The scores of the reading disabled children, compared to those of the normally achieving children in the same age category differed significantly in all three age groups on the following measures: McGill Decoding Words and Nonwords, Mixed Drill and Missing Symbols, Rey-Osterreith Complex Figure (Copy version), Digit Span, Phonemic - Confusability, and Numerical Square. In addition, the scores of the reading disabled children in the 7-9 age group on the Block Design and Rey-Osterreith (Memory version) tests, and in the 10-11 and 12-14 groups on the Rey-Davis 3-dimensional task, were significantly lower than those of the normally achieving children. There were no differences between the two achievement groups on the Yerkes Blocks and Left-Right Orientation tests. Considering the arithmetic disabled children in the 7-9 and 10-11 age groups, their scores differed significantly from those of the normally achieving children on the Yerkes Blocks test; as did those in the 10-11 and 12-14 age groups on the Block Design, Rey-Osterreith (Copy version), and Phonemic - Confusability (Rhyming letters) tasks. In addition, the groups differed significantly at the 7-9 and 12-14 age levels on the Rey-Osterreith (Memory) and Digit Span tests; and on the Rey-Davis 3-d and Numerical Square tasks at the 12-14 age level. There were no significant differences on the Left-Right Orientation test. The results suggest that while the performance of the reading disabled children in general is essentially normal on some measures of spatial visualization and spatial orientation; it is poor on other tasks measuring language, arithmetic, visual-motor skills, and short-term memory for language stimuli. In addition, only the younger (7-9) reading disabled children appear to have problems involving aspects of visual-spatial abilities (i.e., visual-perceptual, and spatial organization skills), and difficulties in memory for complex visual figures. The results pertaining to the arithmetic disabled children at all three age levels suggest that they have a problem in spatial visualization, and a complex memory difficulty which particularly involves visual materials. The data also point to a problem involving spatial organization and visual-motor skills which is evident after the age of 9. These findings highlight the importance of chronological age and developmental factors in learning disabilities research. They also point to the need to consider both the maturational lag and deficit positions in explaining the complex pattern of cognitive problems in both reading and arithmetic disabilities. In addition, the results indicate the possibility of a predominant involvement of the left cerebral hemisphere in reading disabilities, and a primary role of the right hemisphere in arithmetic disabilities.</p> / Doctor of Philosophy (PhD)

<p>Regular, coordinated contractions of uterine smooth muscle are thought to facilitate the delivery of the fetus(es) at parturition. The development of synchronous activity at term follows the development of many, large gap junctions between uterine smooth muscle cells. The objectives of this thesis were to test the hypothesis that the formation of gap junctions improves direct intercellular communication between the muscle fibers and to determine whether the functional properties of the junctions are regulated. Increased intercellular communication in uterine tissues may facilitate synchronous activity during labor and the regulation of such cell-cell interactions by modulating the function of the gap junctions may participate in the control of uterine contractility during pregnancy and parturition.</p> <p>A technique was developed to study the diffusion of a small radiolabelled glucose analog, 2-deoxyglucose, through small strips of myometrium. Tissues with many gap junctions from rats in labor demonstrated a significantly greater redistribution of tracer compared to muscle removed from days 17-20 pregnant and days 2-3 post partum animals not in labor which had few junctions. This movement of tracer was shown to be the result of intracellular and direct, cell-to-cell diffusion. Thus, there is evidence for improved intercellular communication in the myometrium during parturition when gap junctions are present.</p> <p>The extent of intercellular communication in the parturient myometrium was reduced by elevating the intracellular concentrations of Ca⁺⁺ and cyclic AMP in the absence of a change in the extent of gap junctions. More significantly, however, reduced communication was shown in tissues exposed to specific agents which are thought to play a role in the regulation of pregnancy and parturition. Thus, in addition to providing for the increase in gap junctions in the myometrium at term, the hormonal alterations which precede and accompany labor may also regulate the functional properties of these cell-to-cell membrane channels.</p> / Doctor of Philosophy (PhD)

<p>Indirect calorimetry was used to examine energy expenditure at rest and dietary-induced energy expenditure in normal-weight and overweight volunteers, whose daily energy intakes were similar. The influences of exercise, exercise training, and insulin on dietary-induced energy expenditure were also assessed. At rest energy expenditure was 70.3 kcals/hour in the overweight volunteers, 7.4 kcals/ hour greater than in the normal-weight volunteers. Consumption of a mixed meal of nearly 1000 kcals elicited similar increases in energy expenditure in the normal-weight and overweight volunteers of 10.8 kcals/hour and 12.5 kcals/hour respectively. The results refute the suggestion that a deficiency in energy expenditure at rest or in dietary-induced energy expenditure could be responsible for the greater propensity towards obesity in the overweight volunteers.</p> <p>When exercise preceded the meal, the oxygen debt of exercise summated with the dietary-induced energy expenditure in the normal-weight group. The post-prandial response in the overweight group was similar whether or not exercise preceded the meal, even though the metabolic response to exercise alone was not impaired in the overweight group.</p> <p>Six volunteers (four normal-weight and two over-weight) completed an exercise training programme, and increased their fitness level. However, dietary-induced energy expenditure in response to the 1000 kcal meal was similar before and after training.</p> <p>Hyperinsulinaemia in six normal-weight, non-diabetic volunteers did not influence the post-prandial energy response, although the infusion of insulin and glucose itself elicited an obligatory increase in energy expenditure.</p> <p>The work described in the thesis thus suggests that in mildly overweight individuals there is no evidence that reductions in post-prandial energy expenditure account for their excess weight, but that the lack of a further increase in post-prandial energy expenditure following exercise may do so. The results of the thesis indicate that exercise training does not alter post-prandial energy expenditure, and that hyperinsulinaemia does not influence post-prandial energy expenditure.</p> / Doctor of Philosophy (PhD)

<p>The relationship between fibre structural adaptation to strength and endurance training and the fibre physiological adaptations to these training procedures has been unexplored in humans. Methodological difficulties in fibre identification have prevented these investigations since traditional fibre classification techniques utilize various enzymes which are inactivated during fixation for electron microscopy. However, myoglobin is unaffected by glutaraldehyde fixation.</p> <p>In this study, structural and functional properties of the triceps surae were studied to determine the effects of endurance and strength training on: 1. the relationship between the fibre volume of sarcoplasmic reticulum and transverse tubules (SR) to the time to peak torque (TPT) of the isometric twitch; and 2. the relationship between fibre volume of mitochondria to muscle fatiguability. Needle biopsies were obtained from the gastrocnemii and soleus muscles and fibre types were classified for electron microscopy analysis on the basis of their myoglobin content. Electron micrographs were taken from the interior of 35 type I and 35 type II fibres of each muscle and were analyzed blindly by a stereological short-line test. Contractile properties were obtained from the isometric twitch in the triceps surae complex and separately from the gastrocnemii and soleus.</p> <p>Structural and contractile properties were examined in two subject groups: 1. a cross-sectional group made up of 6 subjects each of active controls, strength athletes and endurance athletes (N=18); and 2. a longitudinal training group (N=7) whom, in a unilateral training model, exercised one leg with a strength protocol and the other leg with an endurance protocol for 16 weeks.</p> <p>The results indicated that TPT was greater (p<.05) following chronic strength vs. endurance training (119.0 vs. 95.3 ms respectively) but TPT was decreased (p<.01) by 24% and 16% following short-term strength and endurance training respectively. The fibre volume of SR was not altered by strength or endurance training in either cross-sectional or longitudinal training groups. Resistance to fatigue at an absolute load was increased by 1.7 fold after short-term strength training and by 3.5 fold after short-term endurance training. Mitochondria volume was unaffected by either training protocol in the gastrocnemii but lower (p<.05) in type I fibres of the soleus after short-term strength (5.76%) vs. short-term endurance training (7.26%).</p> <p>It was concluded that functional adaptation to strength or endurance training may occur independent of fibre organelle volume adaptation to these training programs.</p> / Doctor of Philosophy (PhD)

<p>The acidosis accompanying short-term maximal exercise has been quantified and the mechanisms contributing to its control examined. Maximal exercise lasting 30 s was performed on a constant-velocity cycle ergometer. In 3 subjects, acid-base changes were examined across the working quadriceps femoris muscle after arterial and femoral venous catheterisation (Part A). The acid-base changes across the inactive forearm muscle were examined in 6 subjects following arterial and deep forearm venous catheterisation. Gas exchange was measured breath-by-breath during exercise and recovery (Part B). Muscle biopsies were taken from the quadriceps femoris muscle in 6 subjects and analysed for intracellular strong ion changes using neutron activation analysis (Part C).</p> <p>The intracellular acid load was due to both increased CO₂ production and strong anion production; the muscle [lactate] increased to 30 mmol/kg w.w. after 30 s exercise. The CO₂ and strong ion concentration contributed 25% and 75%, respectively, to the increase in intracellular [H⁺]. The weak acid concentration was assumed not to change during exercise and recovery. CO₂ and strong ions were removed from the intracellular fluid during recovery.</p> <p>Initially CO₂ output from the muscle reduced the intracellular PCO₂; the femoral venous PCO₂ increased to 105 mm Hg. The increased CO₂ flux to the lungs increased the CO₂ elimination from the body; the CO₂ output increased to 3060 ml/min by the end of exercise. The lungs were effective in removing the excess CO₂ delivered to them as the arterial PCO₂ was less than resting levels throughout recovery. Elimination of excess CO₂ from muscle was complete by 3 min recovery.</p> <p>Strong ion exchange occurred more slowly; lactate disappeared at a rate of 2 mmol/kg w.w./min. Immediately after exercise the intracellular-femoral venous [lactate] gradient was 40 mmol/l and favoured diffusion of lactate into the circulation. Approximately 55-60% of the lactate diffused from the muscle, the remaining lactate was oxidised or converted to glycogen. Lactate was taken up by the inactive forearm muscle; the v-a [lactate] difference was approximately 4.5 mmol/l. Only about 45% of the lactate taken up by the inactive tissue was oxidised, the remaining lactate was metabolised to other metabolic end points. Lactate uptake by inactive tissue reduced the anion concentration of the body and increased the strong ion difference across the inactive tissue. Recovery of acid-base balance is not complete until all the lactate has been removed from the body.</p> / Doctor of Philosophy (PhD)

<p>Ribonucleotide reductase catalyzes the first unique step in DNA synthesis by reduction of all four ribonucleotides to the corresponding deoxyribonucleotides. Herpes simplex virus (HSV), which codes for at least three enzymes of DNA metabolism (thymidine kinase, DNA polymerase and DNAase) was found to induce a novel ribonucleotide reductase activity upon infection of mammalian cells. The HSV-2 induced reductase was purified essentially free of the endogenous cellular enzyme and found to differ from the cellular reductase in several of its biochemical properties, most notably in its resistance to allosteric inhibition by dTTP and dATP (Huszar and Bacchetti, 1981). In addition, a rabbit antiserum was prepared (Rl serum) which was capable of specifically immunoprecipitating the HSV-2 induced reductase, thus demonstrating that the induced and cellular enzymes could also be immunologically distinguished (Huszar et al., 1983). Further experiments established that Rl serum cross-reacted with two monoclonal antibodies, both specific for HSV-2 polypeptides of approximately 144,000 and 38,000 daltons, which were capable of either immunoprecipitating the HSV-2 induced reductase (H11 antibodies) or directly neutralizing it in solution (Bg7 antibodies) (Huszar et al., 1983).</p> <p>These data demonstrate that either one or both of the HSV-2 144,000 and 38,000 dalton polypeptides are associated with viral ribonucleotide reductase activity. Based on the mapping of these polypeptides (Anderson et al., 1981; Docherty et al., 1981; Galloway et al., 1982a), these data also locate the coding sequences for at least a component of the enzyme between .56 - .60 map units on the viral genome within DNA sequences associated with cell transformation. The identification of viral DNA sequences coding for, and of viral polypeptides associated with, the HSV-2 ribonucleotide reductase will facilitate studies on the relevance of the enzyme to viral replication, latency and cell transformation.</p> / Doctor of Philosophy (PhD)

<p>Atopic asthma is immunologically-driven condition characterized by reversible bronchoconstriction and Th2-polarized eosinophilic airways inflammation. As such, the development of Th2 responses is a key step in the pathogenesis of the disease. We utilised a murine model of respiratory mucosal sensitization to examine the roles of different cytokines in the generation of polarized immune-inflammatory responses in the airways. Mice were sensitized to ovalbumin (OVA) by daily aerosol exposure in the context of airway expression of GM-CSF, resulting in a Th2-polarized eosinophilic inflammatory response in the airways, reminiscent of asthma; the addition of IL-12 to the airway microenvironment deviated this response toward the Th1 phenotype. We analyzed expression of key Th1-and Th2-associated genes in the lymph nodes during Th1- and Th2-polarized sensitization, and showed that cytokine expression compartmentalized to the respiratory tract can have a profound impact on the nature of developing immune responses in the draining lymph nodes. Next, we investigated the necessity for IL-4 during GM-CSF-driven respiratory mucosal sensitization. We analyzed a variety of Th2-associated factors, including transcription factors, cytokines, chemokine receptors, and cell surface markers, and found that IL-4 was not necessary for Th2-polarization in this model. Finally, we examined whether IL-10 played a rol in mediating Th2 polarization, and observed that mice treated with anti-IL-10 antibodies or genetically deficient in IL-10 showed impaired development of Th2-polarized immune-inflammatory responses. This research highlights the importance of the cytokine microenvironment of the airways in determining the nature of the ensuing immune-inflammatory response, and defines some of the molecular requirements for the polarization of Th responses during respiratory mucosal sensitization in vivo.</p> / Doctor of Philosophy (PhD)

<p>Shortened platelet survival observed in individuals with thromboembolic vascular disease could be due to platelet consumption or turnover in thrombi or platelet turnover on the damaged vessel wall. The object of this study was to examine the relationship between:</p> <p>a) platelet consumption and exchange in thrombi and platelet survival</p> <p>b) platelet accumulation and turnover on the injured vessel wall and platelet survival.</p> <p>Indwelling catheters were inserted into rabbit aortae to induce repeated vessel injury and macroscopic chrombus formation. Radiolabelled platelets monitored platelet participation in thrombosis and platelet accumulation on the injured vessel wall. Morphological studies assessed the thrombus characteristics and the cellular events on the vessel wall.</p> <p>During the first 24 hours following the insertion of indwelling aortic catheters, thrombi formed, attained their maximum size and maintained a constant weight thereafter. ⁵¹Cr-labelled platelet incorporation into thrombi following the growth, decreased by about 50% by 3 days. Loss of radioactivity from the thrombus during the time when thrombus weight remained constant indicated platelet lysis, phagocytosis or loss of whole platelets from the thrombus.</p> <p>Both morphological studies and studies using platelets doubly labelled with ¹²⁵I and ⁵¹Cr demonstrated that some of the platelets initially incorporated into thrombi lysed. Studies of changes in platelet density as well as studies showing thrombi retained some capacity to accumulate circulating platelets indicated that platelets exchanged in thrombi and some of the platelets that had participated in thrombus formation returned to the circulation as less dense platelets.</p> <p>The consumption and exchange of platelets in thrombi during the acute phase of growth correlated with maximal shortening of platelet survival time. When platelet survival studies were carried out 1 week after insertion of the catheter (at a time when thrombus growth had ceased and platelet accumulation into thrombi was decreased) platelet survival continued to be shortened. At this time, the extent of platelet accumulation on the injured vessel wall was similar to that observed at the time of insertion of the catheter suggesting platelet interaction with the injured vessel wall influenced platelet survival.</p> <p>Studies using long and short catheters demonstrated that short catheters induced comparatively less vessel injury than long catheters but thrombus formation was significantly increased. Platelet survival studies carried out at 3 days after insertion of long or short catheters (when thrombus growth had ceased) indicated that the short catheters had no significant effect on platelet survival whereas long catheters continued to shorten platelet survival time.</p> <p>In conclusion, extensive thrombus formation with evidence of platelet exchange in thrombi is associated with significant shortening of platelet survival time. However, this effect is detectable only during the acute phase of thrombus formation. In contrast, repeated vessel injury in association with continuing platelet turnover on the vessel wall can shorten platelet survival time.</p> <p>Therefore, shortened platelet survival time is a manifestation of acute thrombus formation, repeated vessel injury or both.</p> / Doctor of Philosophy (PhD)

<p>The muscle of the pregnant uterus transforms into an active and reactive tissue at term which is necessary for expulsion of the fetus and termination of pregnancy. Gap junctions develop between the smooth muscle cells of the uterus immediately prior to term and disappear after delivery. Gap junctions may be providing the structural basis for improved communication between myometrial cells during labor thereby leading to the synchronized coordinated muscle activity required for effective labor. Although gap junctions appear to have significant implications in the termination of pregnancy, the regulation of their presence in the myometrium is not completely understood but may depend upon hormonal changes that occur prior to parturition.</p> <p>In the studies reported in this thesis, quantitative thin section electron microscopy showed that high doses of estradiol stimulated, whereas progesterone when administered with estradiol, suppressed the presence of myometrial gap junctions in non-pregnant animals. The steroid hormones regulate the presence of gap junctions by controlling the synthesis of the junction proteins probably through their receptor mechanism. In addition, high doses of estradiol may selectively stimulate the synthesis of a prostaglandin which may be required for the development of gap junctions. Prostaglandins appear to be involved in junction regulation since inhibitors of cyclo-oxygenase potentiated estradiol stimulation of gap junctions. Moreover, treatment of pregnant animals with estradiol resulted in the presence of numerous myometrial gap junctions and abortion. These results demonstrate that the steroid hormones and prostaglandins regulate the presence of myometrial gap junctions and that their presence in the myometrium may be a requirement for the occurrence of term as well as preterm labor.</p> <p>Cell-to-cell communication via gap junctions is also believed to be involved in the control of cellular and tissue growth. The myometrium grows dramatically throughout pregnancy to accommodate the growing fetus. Moreover, the steroid hormones, in particular estradiol, stimulates growth of the uterus and prostaglandins also appear to be involved in the process. Since the hormones and prostaglandins regulate uterine growth and the presence of myometrial gap junctions (see above), the relationship between the two events was further evaluated in this thesis. Studies on non-pregnant animals after various hormonal treatments and in untreated pregnant animals demonstrated that regulation of uterine growth (of which the myometrium is a major component) and the presence of gap junctions in the myometrium are dependent upon the hormonal environment. The results suggest a complex interaction between the steroid hormones, a product of the cyclo-oxygenase and/or lipoxygenase pathway for control of gap junctions and myometrial growth. Myometrial growth may occur because of the lack of gap junctions but the cessation of growth of this tissue does not depend on the presence of the junctions. The development and presence of gap junctions, however, may be partially dependent upon myometrial growth.</p> / Doctor of Philosophy (PhD)

<p>Saunders and his associates reported that during submaximal neuromuscular blockade, vital capacity was reduced to a greater extent than would have been predicted according to the reduction in the maximal inspiratory pressure in a simple in a simple mechanical model (J. Appl. Physiol. 44:589,1978). Disproportionate respiratory muscle weakness and a different recruitment pattern for different voluntary efforts were proposed as possible explanations.</p> <p>This issue was addressed by measuring the rectified electromyogram of the diaphragm, intercostal, scalenes, and sternomastoid muscles during maximal and submaximal static inspiratory manoeuvres. Two studies were performed. The control series of experiments showed that at very low levels of static pressure, only the diaphragm was activated. Further increases in pressure then recruited the intercostal/accessory muscles, in some subjects more than in others. There was generally an orderly increase in the rectified EMG in all muscles with elevations in pressure. For particular levels of pressure to be produced at lung volumes above the relaxed end-expiratory position, the EMG was increased. Compared to the maximum EMG elicited with maximal static pressures or full inspirations, resting ventilatory requirements still leave a large myo-electric reserve.</p> <p>In the submaximal neuromuscular block study, the mean maximal inspiratory pressure was decreased from 103 to 39 cm H20, but only two of the five subjects behaved in the manner observed by Saunders and his associates. There was no clear evidence that the diaphragm was less affected than the other muscles. In many cases however, a submaximal level of pressure was achieved by augmented EMG in all muscles. It is suggested that curare interferes with the conversion of electrical events into whole muscle tension and/or that the impaired chest wall volume compartments are inefficient at producing static pressure.</p> / Doctor of Philosophy (PhD)