The accumulation of fat in the marrow cavity is a consequence of the predominant mesenchymal stem cell differentiation into the adipocyte fate at the expense of the osteoblasts. Considering that these changes in stromal differentiation have an effect on bone health, we attempted to study bone marrow fat depots from a metabolic, lipotoxic and regulatory approach. In a fist attempt to study the potential metabolic role of bone marrow fat we observed the effect of calorie restriction (CR) on bone quality and marrow fat of aging rats subjected to a casein and soy protein diet. Bone quality and adipocyte quantification was obtained from rat tibia. Bone as well as adipogenic markers were quantified. CR was found to induce a significant decrease in bone quality. In contrast to CR rats, the ad libitum soy fed rats showed an overall better bone quality. Moreover, the results obtained showed that adipocytes were not mobilized during CR as no changes in leptin levels or adipocyte number were found. Finally we noticed that soy protein and not CR inhibited PPARgamma expression, a transcription factor required for adipogenesis. In summary, results from this first approach showed that bone marrow fat does not participate in lipid metabolism during moderate stages of starvation and that the detrimental effect of CR on bone mass could be prevented using a soy protein regime. A second approach to this subject involved looking at the mechanism through bone and fat interact within the bone marrow. We hypothesized that bone marrow adipocytes’ secretion of fatty acids (FA) induces changes in osteoblast differentiation, function and survival compatible with lipotoxicity. Using a co culture system of human pre-adipocytes and osteoblasts we showed that FAs negatively affect osteoblast differentiation and mineralization. Furthermore the effect could be prevented through the use of a FA syntase inhibitor, cerulenin. Gas chromatography/ mass spectrometry (GC\MS) analysis of co-culture su / L’ostéoporose sénile est souvent associée à une augmentation de gras dans la moelle osseuse. Cette accumulation de gras est une conséquence d’une différentiation prédominante de cellules souches en adipocytes en lieu d’ostéoblastes. Prenant en considération ce changement de différentiation, nous avons décidé d’étudier le gras de la moelle osseuse de trois différentes approches : métabolique, lipo-toxique et régulatrice. Nous avons premièrement observé les effets d’une restriction calorique (RC) sur la qualité osseuse ainsi que sur le gras de la moelle osseuse de rats nourris de caséine ou de soja. Les marqueurs osseux et adipogéniques ont aussi été quantifiés. La RC fut identifiée comme une cause de réduction de qualité osseuse. Contrairement aux rats subjugués à une RC, les rats qui furent subjugués à une diète « ad libitum » de soja ont démontré une qualité osseuse supérieure. Aucuns changements n’ont été identifiés quant aux niveaux d’expression de leptin ou de cellules grasses. Ces derniers résultats indiquent que les cellules grasses de la moelle osseuse ne sont pas mobilisées pendant les périodes de RC. La diète de soja est responsable pour l’attenuation de l’expression de PPARgamma .Les résultats de l’étude ont démontré en premier lieu que le gras de la moelle osseuse ne participe pas au métabolisme de lipides pendant les périodes de famines modérées ; puis en deuxième lieu que les effets de la RC sur les os peuvent être diminués par une diète de soja. En deuxième lieu, nous avons observé le mécanisme par lequel le gras de la moelle participe à la perte osseuse associé au vieillissement. Un modèle de co-cultures cellulaires de pré-adipocytes humains ainsi que d’ostéoblastes nous a permis de démontrer que les acides gras (AG) sécrétés par les adipocytes ont un effet inhibant sur la différentiation ainsi que sur la minéralisation des ostéoblastes. Aussi, nous av

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Ventilation is frequently used in the treatment of cardiogenic and increased permeability pulmonary edema. The effects of ventilation on the computed tomography (CT) density distribution of pulmonary edema are unclear. We hypothesized that ventilation might open up previously collapsed alveoli with consequent reduced lung density, and that some movement of the alveolar edema fluid might also occur from the alveoli to the interstitium. To address this problem, pulmonary edema was induced in 16 supine dogs by airways instillation of a protein solution similar to serum in each lower lung lobe through a double lumen tracheal tube. The dogs were ventilated only on the left side for 1 min (n = 4), 30 min (n = 6) or 60 min (n = 6). The lower lobes were excised, frozen in liquid nitrogen, and imaged in a CT scanner. Representative regions of interest (ROI) were chosen and tissue sections from corresponding regions were taken for extravascular lung water (Qwl/dQl) and regional blood measurements, and for histology to grade interstitial and alveolar edema. There was a significant (P $<$ 0.05) fall in the CT density of the left lower lobes compared with the right lower lobes in the groups ventilated 30 and 60 min, but no differences in Qwl/dQl or blood content. The histological grading showed a trend (P = 0.054) for more interstitial edema in the left lower lobes in the 60 min ventilation group compared with left lower lobes in the 1 min ventilation group. These data show that in our model of instilled alveolar edema, ventilation acts primarily by increasing aeration by 30 min and that it has a minor role in moving fluid to the interstitium.

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This thesis reviewed current theories of the post-ischemic injury. Special emphasis was placed on the concept of reperfusion injury. / In a series of four experiments, this thesis evaluated neutrophil function, localization, depletion, and inhibition in ischemic cutaneous and myocutaneous flaps. Neutrophil function as measured by phorbol myristate acetate stimulated superoxide production was found to be enhanced on reperfusion of ischemic myocutaneous flaps. $ sp{111}$Indium labelled neutrophils were found to localize in post-ischemic cutaneous and myocutaneous flaps. Post-ischemic cutaneous flap survival was not improved by either cyclophosphamide induced neutrophil depletion or ibuprofen neutrophil inhibition. Post-ischemic myocutaneous flap survival was significantly improved by both cyclophosphamide induced neutrophil depletion and ibuprofen neutrophil inhibition. Thus, the cumulative evidence from these experiments yielded surprisingly different conclusions for cutaneous and myocutaneous flaps. The post-ischemic injury in cutaneous flaps was not mediated by the neutrophil. In contrast, the neutrophil did partially mediate the complex post-ischemic injury of myocutaneous flaps.

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The properties of (beta)-N-acetylhexosaminidase (HEX EC 3.2.1.30 and 3.2.1.53) in canine serum during endotoxin induced experimental shock were investigated. / In normal canine serum, HEX activity is very low and the enzyme exists in two major isoenzymic forms: a predominant acidic form (HEX A) and a basic form (HEX B). Both HEX A and HEX B as well as a third isoenzyme HEX A('1) are also present in canine tissues. Only HEX A and HEX B are present in the urine. / "Shocked" serum contains very high levels of total HEX activity with increased activity of both isoenzymes HEX A and HEX B, as well as the appearance of an additional isoenzyme (HEX A('1)). In shock, HEX A('1) accounted for over 28% of total serum HEX activity. HEX A was diminished while HEX B was significantly higher. / HEX A('1) differs in physical and enzymatic properties from HEX A and HEX B of normal serum. It is suggested that HEX A('1) is released from tissues during shock. / Methylprednisolone prevented in vitro the intracellular activation of HEX, and in vivo prevented the increase in serum HEX activity during shock.

Prostatic adenocarcinoma is virtually unique in its tendency to produce osteoblastic bone lesions. The hypothesis of the present thesis was that the basis of this osteogenic response to skeletal metastases of prostate cancer is mediated by the production of trophic factors from prostatic tissue. I have therefore examined the mitogenic activity of extracts of human prostatic tissue and of some known growth factors in isolated fetal rat osteoblasts, fetal fibroblasts, and osteoblast-derived rat osteosarcoma cells. The results demonstrate that material with characteristics of peptides can be extracted from prostatic tissue and appears distinct from a variety of known growth factors. Employing reverse-phase and gel permeation high performance liquid chromatography, I was able to obtain several homogeneous peaks of UV absorbance with an apparent selective growth factor activity for cells of the osteoblast phenotype. This novel selective mitogenic activity for osteoblast-like cells was not present in the extracts from all normal and malignant tissue tested other than prostate, and it was absent also from extracts of pre-pubertal prostate. These results demonstrate that the prostate gland contains selective mitogens for osteoblast-like cells, a characteristic which appears to be unique among known mitogens. These mitogens appear furthermore to be androgen dependent. The above data may explain the unique ability of metastatic prostatic cancer to produce blastic reaction in the skeleton. Furthermore the data suggest that products of the normal and abnormal prostate gland may play an important role in skeletal physiology and pathophysiology.

Health is defined as a state of complete physical, mental and social well-being, and not merely the absence of disease. Quality of life refers to a person's perception of well-being and life satisfaction. Chronic liver failure can have significant negative impact on a patient's cognitive abilities and can cause physical debilitation. Thus, it is not surprising that cirrhotic patients often have severe impairment in their quality of life (QOL). From the perspective of the health care system, patient's health-related quality of life (HRQL) is the more relevant construct. Success of liver transplantation (OLT) is often measured by length of survival, as opposed to patient perceptions of personal health. / The primary objective of this study is to identify which of the Short-Form Health Survey (SF-36), EuroQuol (EQ-5D) VAS, and General Health Questionnaire-30 (GHQ-30) is the most responsive for detecting HRQL change for patients pre- and post-liver transplantation. The secondary objective is to compare the relative efficiency of the HRQL measures to traditional liver biochemistry parameters.