Motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) are used to asses corticospinal tract (CST) function in clinical practice. Advancements in technology have increased TMS precision yet clinical protocols do not reflect the gain in precision required for neuroscientific research. The aim of this study was to determine whether parameters extrapolated from MEP responses accurately reflect CST function. TMS was administered to healthy controls and acute subcortical stroke patients. A sigmoid-shaped dose-response curve was observed in control subjects and patients with lesions outside the CST. Relative amplitude of MEPs is the best descriptor of CST integrity. Absence of a sigmoid relationship indicates CST impairment. / Les potentiels évoqués moteurs (PEM) élicités par la stimulation magnétique trancrânienne (SMT) sont utilisés en clinique pour évaluer la fonction du faisceau corticospinal (FCS). Les avancements technologiques ont amélioré la précision de la SMT. Toutefois, les méthodologies cliniques ne reflète pas la précision requise pour la recherche neuroscientifique. Le but de cette étude était d'analyser les caractéristiques des courbes de doses-effets des PEM pour déterminer s'ils reflètent la fonction du FCS. La SMT a été appliquée chez des sujets sains ainsi que chez des patients ayant subi un accident vasculaire cérébral (AVC). Une relation sigmoïde est présente dans les courbes de doses-effets chez les sujets sains et chez les patients ne présentant pas de lésions directement sur le FCS. De plus, l'amplitude absolue n'est pas un bon descripteur de l'excitabilité cortical à cause de la grande variabilité interindividuelle. L'absence d'une relation sigmoïde indique une déficience grave de la FCS.

A radioimmunoassay was developed to determine the concentration of immunoreactive somatostatin (IRS) in crude and partially-purified extracts of various anatomical regions of the nervous system, including the retina. Affinity chromatography using somatostatin antiserum served to concentrate IRS from the retina and other brain regions. Retinal IRS from rats and humans inhibited the release of growth hormone in a bioassay in a similar manner as did synthetic somatostatin. Affinity chromatography-purified extracts of rat median eminence, anterior hypothalamic-preoptic area, amygdala and cerebral cortex, when subjected to gel filtration chromatography, eluted with similar profiles characterized by four IRS peaks of which the third to elute was largest and had a coincidental elution position with synthetic somatostatin. The IRS in each peak from all four brain regions was biologically active as assessed by its ability to inhibit growth hormone secretion.

Lipid peroxidation has been implicated in the development of atherosclerosis. It is responsible for modification of low density lipoprotein (LDL), injury to endothelial cells and has been reported to alter prostacyclin synthesis. We therefore investigated lipid peroxidation in human LDL and in LDL and aortae from rabbits fed cholesterol-supplemented diets. We also studied the correlation between lipid peroxidation and prostanoid production in vivo and in vitro. / Unsaturated fatty acids in human LDL are oxidized to their monohydroxy derivatives during the incubation with CuSO$ sb4$ and endothelial cells. Gas chromatographic-mass spectrometric analysis of monohydroxy fatty acids revealed a similar mechanism of peroxidation of LDL lipids by endothelial cells as that by CuSO$ sb4,$ i.e., autooxidation of LDL lipids. / Increased amounts of monohydroxy fatty acids in LDL and aorta were observed in rabbits fed cholesterol-supplemented diets. The increased amounts of monohydroxy derivatives of oleic and linoleic acids, but not those of arachidonic acid, were due to the increased amounts of their fatty acid precursors. The increased amounts of aortic monohydroxy derivatives of arachidonic acid, but not those of oleic and linoleic acids, were positively correlated with the severity of the atherosclerotic lesions. / Prostacyclin production by aortae was slightly increased after cholesterol-supplemental diets despite evidence for increased lipid peroxidation in this tissue. This may be because esterified hydroperoxy fatty acids in aorta are not very effective in inhibiting prostaglandin synthesis. In contrast to the moderate changes in aortic PGI$ sb2$ synthesis, there was a dramatic increase in the synthesis of thromboxane B$ sb2$ by aortae from hypercholesterolemic rabbits, suggesting a role for thromboxane A$ sb2$ in atherogenesis.

The objective of the present study was to determine the relationship between dietary intake and the formation of idiopathic upper urinary tract stones. More specifically, the aim of this study was to test the relationship between the formation of idiopathic upper urinary tract stones and diet in new cases and demonstrate how the inclusion of recurrent cases in a study could affect the relationship mentioned above. / A case-control approach was used. A total of 61 new cases was compared to 58 controls. A parallel analysis was made for 62 recurrent cases and 59 controls in order to demonstrate the possible effect of dietary advice received in the past in relation to previous episodes of kidney stones. All controls were selected from patients who had an intravenous pyelogram for a reason other than one related to the formation of a kidney stone and were matched to cases for age and sex. The dietary history of patients was established and constituted the main part of a home interview. Logistic regression was used and potential confounding factors were adjusted for, including family history of stones, ethnic group, and source of the patients. / Some differences in nutrient intake were observed between new cases and their controls. Differences involved oxalates, vitamin D and the combination of proteins, purines and magnesium. As the direction of the observed differences did not fit the research hypotheses and likely explanations were found, it was concluded that there was no relationship between diet and kidney stone formation. / The analysis involving recurrent cases and their controls revealed that there was effectively a dietary bias which affected the estimated intake of calcium, water, magnesium, purines, and possibly proteins and vitamin C as well. It is concluded that any case-control study on kidney stone formation should be done separately for new and recurrent cases.

The mechanisms implicated in voiding and continence are far from being settled in the normal as well as in neurogenic bladder dysfunction. Understanding these mechanisms is an essential step in the management of the bladder dysfunction secondary to neurological lesions. In the course of our studies, we demonstrated the existence of a fine coordination "synergism" between the several components of the lower urinary tract i.e., detrusor, proximal urethral muscle and periurethral striated muscles. This synergism is found to be responsible for adequate bladder emptying during voiding in the animal model with intact neural axis. The synergism between the bladder and its outlet is under the control of a higher centre in the brain stem and mediated through the spinal cord and peripheral nerves. The cause of failure of bladder emptying following a spinal lesion was shown to be a lack of synergism between the bladder and its outlet. An animal model for chronic multiple sclerosis-like disease was developed and proved to show a good urodynamic and neurological correlation with that found in the human afflicted with multiple sclerosis. / The pharmacological investigation on the bladder and urethra shows that there is selective distribution of cholinergic, adrenergic and purinergic receptors along the individual layers of the smooth muscles of the urethra. On the other hand, the importance of the Calcium ions in the contractility of the detrusor muscle was also studied. The effect of some Calcium ions antagonists on the detrusor contractility was evaluated. They show selective inhibition on the detrusor contraction both in vivo and in vitro. The calcium antagonists may present a new treatment modality for controlling bladder instability.

The hypothalamic supraoptic nucleus (SON) in the rat contains neurons that synthesize either vasopressin (VP) or oxytocin and that receive prominent afferent connections of cardiovascular origin. In vivo electrophysiological studies were undertaken to characterise the selective depression of VP-secreting cell activity consequent to activation of peripheral baroreceptors. Electrical stimulation of the diagonal band of Broca evoked a similar selective inhibition of supraoptic VP neurons. Extracellular recordings in the diagonal band confirmed the involvement of this site in the baro-reflex input to the SON. Local application of bicuculline, a GABA antagonist, abolished both the diagonal band-evoked and the baroreceptor-induced inhibition of VP-secreting neurons. Anatomical observations at the ultrastructural level indicated that the diagonal band projection to the SON is indirect and involves an GABAergic interneuron located in the perinuclear zone adjacent to the SON. / Another input to the SON that was studied arises in the subfornical organ, a circumventricular structure known to contain angiotensin II immunoreactive neurons. Electrical stimulation of the subfornical organ evoked an excitatory response in SON neurons that could be selectively attenuated by locally applied saralasin, an angiotensin II antagonist. This finding suggests a role for the peptide angiotensin II as a neurotransmitter in this projection. / The collective results are discussed in the context of the three major neurocardiovascular pathways that influence vasopressin secretion from the neurohypophysis.

At present, the only effective treatment for atherosclerotic arterial obstruction is surgical revascularization. Unfortunately, in some patients, this is unsuccessful due to the extent of the disease; most of these patients require amputation of the limb because of severe pain or gangrene. / By expanding on the experimental work of others, we were able to successfully save the limbs of experimental animals (canine) with obstructed arteries by restoring circulation via the use of the venous system (which is not affected by atherosclerosis). Subsequently, we have also been able to save the limbs of a small group of patients using a similar procedure. Angiograms in the clinical and experimental setting revealed reversed flow in the venous bed with new vessel formation around and distal to the arteriovenous reversal. In the present study, we investigated whether or not the reversed venous flow provided nutrient perfusion to the hind limb, the role of severe ischemia in the development of the network of vessels appearing around and distal to the arteriovenous reversal and whether these vessel are newly formed. In addition, we also examined the role of lipid angiogenic factor and controlled exercise, as stimulants in the development of this network of vessels. / We have demonstrated that the reversed venous flow provides nutritive perfusion to the limb as measured by transcutaneous oxygen. In addition, we have shown that severe ischemia plays a major role in neovascularization of the canine hind limb in the presence of arteriovenous reversal, as determined angiographically. We have also demonstrated that there is increased capillary growth in the presence of severe ischemia following arteriovenous reversal and that this capillary neoformation can be enhanced by in vivo administration of lipid angiogenic factor or controlled exercise. Finally, we have demonstrated increased tritiated thymidine uptake by endothelial cell nuclei in hind limbs with arteriovenous reversal, suggesting that there is new endothelial formation.

Humoral immune function was studied in surgical patients. The antibody response to vaccination with a protein antigen, tetanus toxoid (TT), was reduced among all patients, especially those with reduced delayed type hypersensitivity (DTH) and increased degree of physiological derangement. The antibody response to a polysaccharide antigen, pneumococcal polysaccharide (PPS), was normal. In trauma patients, the antibody response to TT was normal. The in vitro production of specific and total immunoglobulin (Ig) by blood mononuclear cells was studied. Patients that failed to produce a serum antibody response to TT also failed to produce anti-TT in vitro. Anti-PPS production was normal. More total Ig was produced by patients, especially those with reduced DTH responses. Some patients showed a reduction, rather than the normal increase, in Ig synthesis with mitogen stimulation. These data show evidence of humoral immune deficiency to protein antigens, and in vivo activation of the B cell system.

Obesity and its comorbidities are an ever-expanding cost of affluent societies. Energy homeostasis is mediated by a network of hormonal signals that originates from many tissues, including white adipose tissue (WAT). Acylation stimulating protein (ASP) is a lipogenic hormone secreted by WAT that stimulates triglyceride (TG) storage (i.e. non-esterified fatty acid (NEFA) trapping) by increasing glucose uptake and NEFA esterification. ASP deficient mice are characterized by reduced body weight and WAT mass and delayed postprandial TG and NEFA clearance. The key enzyme in the regulation of TG clearance is lipoprotein lipase (LPL). The overall objective of this thesis was to examine the mechanisms by which ASP deficiency leads to delayed postprandial TG clearance and altered body composition in KO mice and to regulate, in coordination with other hormones, energy balance and metabolic profile in morbidly obese subjects following weight loss. / Novel findings in this thesis suggest that (1) in 3T3-L1 adipocytes, ASP increases hydrolysis, uptake and esterification of TG-rich lipoproteins (in situ LPL activity) by increasing NEFA trapping within the adipocytes thus decreasing NEFA inhibition of LPL activity, (2) In ex vivo study in mice, ASP deficiency was found not to result in any intrinsic tissue differences in glucose or NEFA oxidation or storage in WAT, skeletal muscle or liver, however, NEFA trapping was enhanced in brown adipose tissue (BAT) of KO mice. Moreover, ASP enhances in situ LPL activity, TG clearance and lipogenesis in WAT while in muscle ASP induces the opposite effects to those in WAT and increases lipolysis and (3) In in vivo study on morbidly obese subjects following gastric-bypass induced weight loss, the changes in ASP and adiponectin were predictive of weight loss, improved insulin sensitivity and apolipoprotein B concentration. In addition, the orexigenic gastric hormone, ghrelin, remains below normal levels in all subjects following surgery, which may favors maintenance of weight loss. / In conclusion, these findings underscore the central role of WAT and ASP pathway in the regulation of TG clearance and energy homeostasis and suggest that, in vivo, an effective ASP pathway favors NEFA trapping in the physiological depot, which would promote optimal insulin activity.

The aim of this work was to investigate the role of CD4 + T cells, central to airway inflammation in asthma, in airway remodeling. Structural changes that occur in asthmatic airways in association with inflammation include an increase in airway smooth muscle mass, which participates in causing airway hyperresponsiveness. We aimed to gain further insights into the mechanisms that may link inflammation with remodeling using a rat model of experimental asthma. We hypothesized that CD4+ T cells drive airway smooth muscle remodeling. Adoptive transfer of CD4+ T cells from ovalbumin-sensitized rats induced increased proliferation and inhibition of apoptosis of airway myocytes in naive recipients upon repeated antigen challenge, which resulted in an increase in airway smooth muscle mass. CD4+ T cells genetically modified to express green fluorescent protein were localized by confocal microscopy in juxtaposition to airway smooth muscle cells, suggesting that CD4 + T cells may modulate smooth muscle cell function through direct cell-cell interaction in vivo. We subsequently co-cultured antigen-stimulated CD4+ T cells with cell cycle-arrested airway smooth muscle cells and demonstrated by flow cytometry that CD4+ T cells induce myocyte proliferation, dependent on T cell activation and direct T cell/myocyte contact. Reciprocally, direct cell contact prevented activation-induced T cell apoptosis as well as spontaneous apoptosis of resting T cells, suggesting T cell/myocyte cross-talk. Our data demonstrate that CD4+ T cells drive airway smooth muscle remodeling in experimental asthma, and suggest that a mechanism involving a direct "synapse" participates in CD4+ T cell regulation of myocyte turnover and induction of remodeling. The goal of genetically modifying CD4+ T cells involved technical challenges relevant to the field of gene therapy and are dealt with in detail in this thesis. Retroviral gene transduction coupled with antigenic stimulation was