The purpose of this study was to directly compare bone growth into identical porous coated titanium and cobalt-chromium canine implants. A transcortical screw was chosen as the cortical implant model. A straight cylindrical implant was used in cancellous bone. Quantitative analysis was performed using backscattered electron microscopy (BSEM) and computerized digital analysis. Cortical specimens were analyzed after six and twelve week periods of implantation. Bone ingrowth at six weeks for the cobalt-chromium implants averaged 50.4% $ pm$ 10.4% and for the titanium implants averaged 54.1% $ pm$ 5.1%. At twelve weeks, ingrowth for cobalt-chromium was 55.1% $ pm$ 9.2% and for titanium was 57.3% $ pm$ 9.3%. There was no statistically significant difference between the six and twelve week specimens or between cobalt-chromium and titanium for either time period. Cancellous implants were analyzed after twelve weeks and no difference in bone ingrowth between the two materials was observed.

Breast cancer kills through the process of metastasis. In order to improve the prognosis of patients with breast cancer, a better understanding of the underlying factors driving the metastatic process in patients is required. One theory that helps explain the metastatic process suggests that chemokines, such as stromal cell-derived factor (SDF)-1, are overexpressed in specific distant metastatic organs, such as lung, liver, and bone, and serve to home in cancer cells that express their receptors, like CXCR4. The hypothesis of this thesis is that the SDF-1/CXCR4 axis plays an important role in the process of metastasis in breast cancer, and that this ligand/receptor axis can be exploited in the diagnostics and therapy of breast cancer. The first objective of this thesis was to determine if circulating levels of SDF-1 could predict breast cancer metastasis. We found low levels of plasma SDF-1 to be a strong independent prognostic marker, suggesting that the concentration gradient of low plasma SDF-1 and high SDF-1 expressed in the metastatic organ may be critical in driving cancer cells from the circulation to the target organ. We further determined that the levels of plasma SDF-1 were tumor-independent, identifying the first host-derived blood marker predictive of distant metastasis. The second objective was to determine if tumor expression of CXCR4 could modulate the prognostic effect of plasma SDF-1 levels. We found that patients with tumors that highly expressed the activated form of the receptor, phosphorylated-CXCR4, and low plasma SDF-1 levels had a much poorer prognosis than those patients with either risk factor alone. These results highlighted the importance of the dysfunctional relationship between the tumor and the host in the metastatic process. The third objective assessed the therapeutic potential of targeting CXCR4 with a peptide antagonist in a transgenic mouse model. In combination with a / Le cancer du sein tue par le processus des métastases. Dans le but d'améliorer le pronostic des patients atteints du cancer du sein, une meilleure compréhension des facteurs sous-jacents qui conduisent à la transformation métastatique est nécessaire. Une théorie qui explique la transformation métastatique propose que les chimiokines, telles que le stromal cell-derived factor (SDF)-1, sont surexprimées dans des organes métastatiques distants spécifiques, tels que le poumon, le foie, et les os et servent à attirer les cellules cancéreuses qui expriment leurs récepteurs, tels CXCR4. L'hypothèse de cette t hèse est donc que l'axe SDF-1/CXCR4 joue un rôle important dans la transformation métastatique dans le cancer du sein, et que cet axe ligand/récepteur peut être exploité dans le diagnostic et la thérapie du cancer du sein. Le premier objectif de cette thèse était de déterminer si les niveaux circulants de SDF-1 peuvent prédire la présence de métastases du cancer du sein. Nous avons découvert que des niveaux peu élevés de SDF-1 dans le plasma représentent un bon déterminant pronostique indépendant, suggérant que le gradient de concentration de faible niveaux de SDF-1 dans le plasma et de niveaux élevés de SDF-1 dans l'organe métastasé peut être un événement critique dans le transfert des cellules cancéreuses de la circulation sanguine jusqu'à l'organe-cible. Nous avons de plus déterminé que les niveaux plasmatiques de SDF-1 sont indépendants des tumeurs, identifiant le premier marqueur sanguin, dérivé de l'hôte, de prédiction de métastases éloignées. Le second objectif était de déterminer si l'expression tumorale de CXCR4 pourrait moduler l'effet pronostique des niveaux plasmatiques de SDF-1. Nous avons découvert que les patients dont les tumeurs expriment de façon élevée la forme activée du récepteur, CXCR4 phosphorylé, et des niveaux plasmatiq

Prostate cancer (PCa) is among most prevalent causes of cancer death in North American men. Hence mechanisms of progression are poorly understood. The host laboratory reported on the up-regulated FER tyrosine kinase in PCa, comparatively to the benign prostate, and on its nuclear accumulation in higher grade tumors. In vitro, FER also contributed to cell survival and growth. In searching for FER partners, the tyrosine phosphorylated (pY)-actin was discovered for the first time in mammalian cells. In this study, pY-actin levels were correlated to aggressive phenotypes of PCa cell lines. FER was shown to phosphorylate actin directly and to bind actin via its SH2 domain. Furthermore, levels of complexes increased in response to stress, once targeting cytoskeletal actin in a process accentuating levels of predominantly nuclear, globular and tyrosine phosphorylated actin. Considering data in amoeba, it is proposed that FER and pY-actin provide tumors with cell survival advantages to resist stress, thereby contributing to PCa progression. / Le cancer de la prostate (CaP) est une cause majeure de décès en Amérique duNord. Or, les mécanismes de progression demeurent obscurs. Le laboratoire d'accueil arapporté la surexpression de la tyrosine kinase FER dans le CaP comparativement à laprostate bénigne, et son accumulation dans le noyau des cellules tumorales de haut grade.In vitro, FER contribue à la survie et la croissance des cellules du CaP. La recherche despartenaires de FER a conduit à la découverte de l'actine et de sa phosphorylation surtyrosine (pY), une première chez les cellules de mammifères. Dans cette étude, nousdémontrons que les niveaux de pY-actine corrèlent avec le phénotype agressif des lignéescellulaires de CaP. FER phosphoryle l'actine directement et s'y lie via son domaine SH2.De plus, les niveaux de complexes augmentent en réponse à un stress qui cible l'actine ducytosquelette, en un processus qui accentue les niveaux nucléaires d'actine globulairephosphorylée sur tyrosine. Considérant les données chez l'amibe, il est proposé que FERet la pY-actine confèrent aux tumeurs, des avantages de survie et de résistance au stress quicontribuent à la progression du CaP.

Studies into the calmodulin content and activity of tissues from hypertensive and normotensive rats and mice have shown the existence of a factor which potentiates calmodulin's capability to stimulate Ca$ sp{2+}/$CaM-dependent phosphodiesterase (CaM-PDE) and which is detected more in hypertensive animals. This CaM-PDE activator is present in the heart, kidney, erythrocytes, and aortic smooth muscle cells. The augmentation of the CaM-PDE activator is found, as well, in human hypertensives. CaM-PDE activator content is modulated by dietary calcium and sodium. Physicochemical and biochemical characterization of the activator reveal it to be a heat-stable, hydrophobic, protease-sensitive factor with a molecular mass of 4 kDa. Subcellular fractionation studies have revealed that the CaM-PDE activator resides principally in the cytosol although there is a small difference in its subcellular distribution between normotensives and hypertensives. Partial purification of the activator to the step of isocratic, reversed-phase HPLC shows the samples from hypertensive mice to partition into three activity peaks while the normotensives partition into two.

The role played by a parathyroid hormone-like peptide (PLP) in the pathogenesis of hypercalcemia associated with malignancy has been examined. Elevated circulating levels of PLP were found more frequently in hypercalcemic cancer patients. A reduction of tumor burden in two of these patients resulted in concomitant decreases in both plasma calcium and plasma PLP. Immunoneutralization of endogenous PLP in a rat model of malignancy associated hypercalcemia resulted in a rapid and sustained reversal of the biochemical abnormalities manifest in the disease state. These studies, therefore, provided strong evidence for a role for PLP in the pathogenesis of hypercalcemia associated with neoplasia. The frequent association of squamous cell carcinoma with hypercalcemia and elevated circulating PLP levels prompted examination of a keratinocyte model of tumor progression for evidence of dysregulated PLP expression. Increased constitutive production of PLP, accompanied by resistance to previously identified regulatory agents, was demonstrated in the progression to the malignant phenotype. Finally, a potential autocrine or paracrine role for PLP in keratinocyte cell growth was suggested by the demonstration of functional adenylate cyclase-linked PLP receptors on an established keratinocyte cell line. These studies have therefore provided important insights into the role played by PLP as both an endocrine factor involved in the pathogenesis of malignancy associated hypercalcemia and as a potential autocrine/paracrine factor in keratinocyte homeostasis.

Oral sorbent therapy, as an adjunct or a replacement for dialysis therapy, is one area of research with great potential. If successful it can help kidney failure patients avoid a "life on the machine" existence. For the past twenty years the major problem was in finding an effective oral sorbent for urea. The use of oral microcapsules containing a urease-silica adduct and ion exchanger zirconium phosphate, though successful in reducing urea levels, resulted in a number of problems including a negative calcium balance. In this thesis it is demonstrated that the use of microcapsules containing a urease-zeolite preparation may be a potential route to urea removal. The use of zeolite ion exchangers, and zeolite W in particular, can alleviate the above mentioned problems of zirconium phosphate. In addition, the use of enzyme envelopes on zeolite support, which replaces silica, can reduce the amount of ingested material by at least 25%. The present "in vitro" study shows that the microcapsules remove up to 80% of urea in less than one hour. Preliminary "in vivo" experiments on Sprague-Dawley uraemic rats treated with ingested microcapsules indicate reductions in urea level and a lengthening of survival times compared to controls.

The pathologic effects of sex steroids on the hypothalamic arcuate nucleus of adult rats were examined using numbers of reactive microglia and astrocytic granules as quantitative indices of neuropathology. / Microglial and astrocytic reactions were observed in adult female rats entering a state of "persistent estrus" following a single injection of 2 mg estradiol valerate (EV) or exposure to continuous illumination. Lower doses of EV failed to elicit both the persistent estrus state and significant glial responses. In EV-treated animals, a hypothalamic lesion could be prevented by prior ovariectomy or by pituitary-ovarian suppression with medroxyprogesterone acetate indicating that an ovarian factor is responsible for the neuropathological changes. This ovarian product is probably estradiol since dose-related enhancement of glial reactivity occurs in male rats treated with multiple injections of EV. / Arcuate pathology developed spontaneously in "senile persistent estrus" female and aging male rats. In females, but not in males, early gonadectomy suppressed age-related arcuate glial reactivity. Conceivably, estrogen withdrawal or EV-treatment respectively retards or accelerates histologic aging of the female gonadotropic hypothalamus. / Testosterone treatment occasionally elicited mild arcuate glial responses, possibly through prior aromatization to estradiol. In contrast, 5 (alpha)-dihydrotestosterone (a non-aromatizable androgen) appeared to suppress astrocytic granule counts below control values. / The EV-induced persistent estrus rat may serve as a useful model for Clover disease of the ewe and the human polycystic ovarian syndrome.

Closure of bone defects that do not heal spontaneously require some form of bone inducing agent in order to ensure complete repair. Autogenous bone is the clinical gold standard for the management of these types of defects. Present research is aimed at finding acceptable alternatives to harvesting autogenous bone grafts in patients for obvious reasons. Recent literature supports that demineralized bone matrix (DBM) is osteoinductive, although this is not the case for all commercially available forms of DBM. / An in vivo study was conducted which attempted to evaluate the healing of critical sized defects in New Zealand white rabbit calvarium using various grafting materials. By combining demineralized bone matrix and a poloxamer gel carrier, a putty-like material that is surgically convenient can be delivered to these defects and allowed to heal.

Background. Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization. This study hypothesizes that using the Omental graft to wrap the ischemic heart will lead to formation of multiple collateral anastomoses between surrounding systemic arteries and the coronary arteriolar system of right and left coronary arteries. / Results. Left ventricular end diastolic pressure was reduced in the group treated with revascularized Omental graft compared to vehicle group. Ejection fraction was also improved in revascularized group then infarcted group. Measurements of the myocardial infarction area showed more reduction in the MI area of the revascularized group than in the vehicle group, however this difference did not reach statistical significances. In comparison between free and pedicle Omental grafts, the free Omentum was shown to be superior over the pedicle in terms of cardiac function EF% (41.3 +/- 0.75 Vs. 35.6 +/- 0.75, P = 0.01), and infarction size (36.2 +/- 6.6 Vs. 39.5 +/- 13, P = NS). All different Omental grafts showed the ability to form a neovascularization between the ischemic myocardium and the surrounding structures.

Subcortical band heterotopia (SBH) is a rare neuronal migration disorder, characterized by bilateral bands of neurons abnormally located in the cerebral white matter. It occurs mostly in females, 80% of whom harbor mutations in the DCX (Xg22.3-q23) gene. / To determine whether males and females with SBH have a similar clinical spectrum and genetic basis, we analyzed and compared the clinical, imaging, and molecular features in 30 males and 60 previously reported females with SBH. / The range of clinical phenotypes in males with SBH overlapped that in females. However, MRI studies revealed that some SBH subtypes such as incomplete posterior SBH, diffuse SBH with posterior predominance and pachygyria-SBH were more frequently or exclusively observed in males. Conversely, diffuse SBH and diffuse SBH with anterior predominance were more frequent in females. The preponderance in males of either the mildest or the most severe SBH subtypes correlated with the overrepresentation of normal/borderline intelligence and severe mental retardation respectively. Conversely, females who had SBH of intermediate severity exhibited mostly mild or moderate mental retardation. Mutations in DCX were detected in 33% of males; 8% had mutations of the LIS1 (17p13.3) gene and 4% a partial trisomy of chromosome 9p. / These studies demonstrate that SBH in males is a clinically and genetically heterogeneous, mostly sporadic syndrome, and suggest other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes; functional, somatic or germline mosaicism; and mutations of other genes.