<p> Suicide is a tragic, complex phenomenon experienced by individuals of all ages, genders and cultures. Given its widespread occurrence, it is important to identify predictive and risk factors in order to develop efficacious prevention and intervention strategies. One factor that has been consistently identified as increasing risk for suicide is being diagnosed with schizophrenia. Persecutory delusions have been most prominently researched in relation to outcome in schizophrenia; however, few studies have investigated the relationship between persecutory delusions and suicide risk for those with this diagnosis. Furthermore, studies that have been conducted are largely quantitative in nature, and therefore are limited by their ability to offer explanations for their results. Understanding quantitative relationships through a theoretical perspective focused on choice and meaning making, such as existential psychology, may increase the specificity and effectiveness of preventative programs and intervention approaches, ultimately leading to more saved lives. This dissertation therefore used archival data from participants in the Chicago Follow-Up Study diagnosed with schizophrenia or schizoaffective disorder to explore the relationship between the course of suicidality and persecutory delusions in schizophrenia through an existential lens. Locus of control and self-esteem were included in the analysis as possible mediating variables. Those with high self-esteem endorsed higher suicidal activity, and those with persecutory delusions endorsed higher suicidal activity and a more external locus of control. Implications of these results suggest both self-esteem and locus of control should be addressed as possible mediating factors in the relationship between persecutory delusions and suicide for those diagnosed with schizophrenia.</p>

<p> Extracellular matrix (ECM) is a key component and regulator of many biological tissues. Several cardiovascular pathologies are associated with significant changes in the composition of the matrix. Better understanding of these pathologies and the physiological phenomenon behind their development depends on reliable methods that can measure and characterize ECM content and structure. In this dissertation, infrared spectroscopic methodologies are developed to study the changes in extracellular matrix of cardiovascular tissue in two cardiovascular pathologies; myocardial infarction and abdominal aortic aneurysm. </p><p> The specific aims of this dissertation were: 1. To develop a Fourier transform infrared imaging spectroscopy (FT-IRIS) methodology for creating distribution maps of collagen in remodeled cardiac tissue sections after myocardial infarction, and to quantitatively compare maps created by FT-IRIS with conventional staining techniques. 2. To develop an FT-IRIS method to assess elastin and collagen composition in the aortic wall. This will be accomplished using ex vivo animal aorta samples, where the primary ECM components of the wall will be systematically enzymatically degraded. 3. To apply the newly developed FTIR imaging methodology to evaluate changes in the primary ECM components (collagen and elastin) in the wall of human AAA tissues. The infrared absorbance band centered at 1338 ^cm-1, was used to map collagen deposition across heart tissue sections of a rat model of myocardial infarction, and was correlated strongly in the size of the scar (R=0.93) and local intensity of collagen deposition (R=0.86). </p><p> In enzymatically degraded pig aorta samples, as a model of ECM degradation in abdominal aortic aneurysm (AAA), partial least squares (PLS) models were created to predict collagen and elastin content in aorta based on collected FTIR spectra and biochemically measured values. PLS models based on FT-IRIS spectra were able to predict elastin and collagen content of the samples with strong correlations (^R2=0.90 and 0.70 respectively). Elastin content prediction from IFOP spectra was successful through a PLS regression model with high correlation (^R2=0.81). </p><p> The PLS regression coefficient from the FT-IRIS models were used to map collagen and elastin human AAA biopsy tissue sections, creating a similar map of each component compared to histologically stained images. The mean value of collagen deposition in each tissue was calculated for 13 pairs of AAA samples where stress had been calculated using finite element modeling. In most pairs with stress values higher than 5 N/m², collagen content was lower in the sample with higher stress value. Collagen maturity had a weak negative correlation (R=-0.35) with collagen content in these samples. </p><p> These results confirm that infrared spectroscopy is a powerful tool that can be applied to replace or complement conventional methods such as histology and biochemical analysis to characterize ECM components in cardiovascular tissues. Furthermore, infrared spectroscopy has the potential for translation to a clinical environment to examine ECM changes in aorta in a minimally invasive fashion using fiber optic technology.</p>

Temporal lobe epilepsy (TLE) is among the most common chronic seizure disorders, accounting for approximately one-fourth of all cases of epilepsy. Although hippocampal sclerosis is the most common pattern of damage in TLE, there is electrophysiological and neuropathological evidence in both humans and animal models of this condition for the involvement of the parahippocampal region. / In clinical practice, the investigation and treatment of patients with epilepsy has been revolutionized by the advent of MRI, which has been demonstrated to be a reliable and accurate indicator of pathologic findings underlying epilepsy. Advances in image acquisition and processing techniques combined with detailed descriptions of anatomy and cytoarchitectonic borders of parahippocampal structures on histologic sections have created the basis for precise determination of the boundaries of these cortical areas on MRI. This dissertation presents a series of MRI studies aimed at assessing volume changes in vivo of the parahippocampal region, and further elucidating its role in the pathogenesis of TLE. / To accomplish this we developed a standardized MRI protocol to measure the volume of the parahippocampal region structures in vivo. In agreement with previous neuropathological studies (Meencke and Veith, 1991), our results showed that damage to the mesial temporal lobe involves not only the hippocampus and the amygdala, but also the parahippocampal region structures in patients with intractable TLE. Within the parahippocampal region, the entorhinal cortex was the most affected structure. We observed that the atrophy was more severe in the anterior portion of the mesial temporal lobe involving mostly the hippocampal head and body as well as the EC. This pattern of atrophy, characterized by an antero-posterior gradient of pathology, may be explained by a disruption of entorhinal-hippocampal connections. / To evaluate the clinical role of entorhinal cortex volumetry we studied groups of TLE patients with hippocampal atrophy and those with normal hippocampal volumes as well as patients with extra-temporal lobe epilepsy. / Entorhinal cortex volumetry could provide correct lateralization of the seizure focus in 73% of TLE patients with hippocampal atrophy. Entorhinal cortex atrophy seems to be specific to TLE, since we found no atrophy in other forms of epilepsy, including frontal lobe and primary generalized epilepsy. We subsequently demonstrated that entorhinal cortex atrophy ipsilateral to the seizure focus can be the only MRI sign of mesial temporal damage in 64% of patients with normal hippocampal volumes.

Murine acquired immune deficiency syndrome (MAIDS) shares several common characteristics with human AIDS, including immunodeficiency, hypergammaglobulinemia, susceptibility to infection, both B and T cell dysfunctions, lymphadenopathy, splenomegaly and aberrant cytokine production. The etiologic agent of MAIDS has been identified as a defective retrovirus which contains major deletions in its pol and env regions but has largely maintained its gag region. The only gene product of this virus is a 60 kDa gag fusion protein, Pr60 gag, which is necessary and sufficient to induce MAIDS in susceptible mouse strains. The target cells of the MAIDS defective virus have been identified as belonging to the B cell lineage. Infection of these target cells with the MAIDS defective virus leads to their proliferation, which is required for the full development of the disease. / We undertook several approaches in order to more clearly understand the role of the MAIDS defective virus target B cell population in the development of this disease. Studies using SCID, CD4 knockout, and nude mutant mice revealed that a relatively mature B cell population is the target of the MAIDS defective virus, and that these cells can be infected in the absence of CD4+ T cells. Our knowledge of the nature of the MAIDS defective virus target B cells was furthered by the derivation of two independent MAIDS defective virus-infected B cell lines which have characteristics of both mature and immature B cells. These B cell lines were used to demonstrate an in vivo association between Pr60gag and c-Abl. Additional exploration of the Pr60gag-c-Abl interaction revealed that Pr60gag could induce a CD8+ T cell-dependant rejection of v-Abl-transformed pre-B cell lines, and increase the tumor latency of mice inoculated with Pr60 gag-expressing B16F1 melanoma cells. / Taken together, these results enhance our knowledge of the identity and role of the MAIDS defective virus target cells in the pathogenesis of this disease and propose a possible mechanism by which Pr60gag activates the disease process. As well as inducing MAIDS, Pr60 gag may also have potential positive use in cancer therapy.

Antiarrhythmic drugs, designed to prevent or suppress cardiac arrhythmias, may cause the worsening of an arrhythmia already present in a patient or provoke new and qualitatively different arrhythmias. Cardiotoxic effects of antiarrhythmic drugs may be rate-related or due to intoxication, and may lead to serious and potentially lethal ventricular arrhythmias. The goals of my research were (1) to study the mechanisms by which class IC antiarrhythmic drugs cause ventricular arrhythmias and (2) to explain the mechanisms of action of sodium salts in the reversal of class IC cardiotoxicity. / We used flecainide (F) as a prototype of its class to study the mechanism of action of class IC antiarrhythmic agents (AA). Flecainide is a potent sodium channel blocker producing a major effect on conduction velocity and a minor effect on refractoriness. In vitro studies have shown that F causes frequency-dependent reduction of phase 0 upstroke of cardiac action potential (V$ rm sb{max}$) in ventricular tissue. Flecainide, in the physiologic range of heart rates and at clinically relevant concentrations, may produce rate-dependent effects because of its relatively slow binding and unbinding kinetics. / We studied the effects of F in humans during exercise and showed that F produces an enhanced slowing of conduction when heart rate is increased, because of use-dependent sodium channel blockade. We demonstrated that a variety of class I AA produce use-dependent QRS prolongation in man with characteristic kinetics, which are similar to the kinetics of V$ sb{max}$ depression in vitro. We and others have reported proarrhythmic events associated with the rate-related cardiotoxicity of flecainide. Using a canine model of myocardial infarction, we showed the importance of previous myocardial infarction in flecainide-induced proarrhythmia. With epicardial mapping, we identified anisotropic reentry occurred in the mechanism for the ventricular arrhythmias. We reported that reentry occurred in the infarct zone around an arc of conduction block in the transverse direction. / Cardiotoxicity associated with F includes severe conduction slowing and life-threatening ventricular arrhythmias. Sodium salts have been found to reverse the effects caused by some class I antiarrhythmic agents (AA), but the mechanism of action is unknown. Using electrophysiological and biochemical studies, we investigated the role of extracellular sodium concentration ( (Na$ sp+ sb0$)) in modulating F's actions. In order to isolate the role of (Na$ sp+ sb0$), we used a range of (Na$ sp+ sb0$) and equimolar substitution with choline chloride. Our microelectrode experiments showed the ability of (Na$ sp+ sb0$) to modulate directly F's effects on the phase 0 upstroke (V$ rm sb{max}$). Our radioligand studies of displacement of ($ sp3$H) -batrachotoxinin A 20$ alpha$-benzoate ( ($ sp3$H) -BTXB) binding showed that this interaction was due to an effect of (Na$ sp+ sb0$ (on the binding of F to its receptor. We found that EC$ sb{50}$ values for depression of V$ rm sb{max}$ in electrophysiologic experiments and IC$ sb{50}$ values for flecainide displacement of ($ sp3$H) -BTXB in biochemical studies were highly correlated (r = 0.99). A limitation of our electrophysiologic study was the use of V$ rm sb{max}$ as an index of sodium current (I$ rm sb{Na}$). Using the whole-cell voltage clamp technique we found that increasing (Na$ sp+ sb0$) opposed F's blocking effect on I$ rm sb{Na}$, confirming the role of (Na$ sp+ sb0$ (. (Abstract shortened by UMI.)

The effect of disturbed flows on mass transfer to and from an arterial wall was studied both theoretically and experimentally using an idealized model of arterial stenoses in which an annular ring vortex was formed. It was found that the transport of macromolecules, including low density lipoproteins, from flowing blood to a semi-permeable vessel wall is greatly enhanced in regions of disturbed flow with a local maximum locating around the reattachment (stagnation) point. The surface concentration of macromolecules increases with increasing the filtration velocity and decreasing the flow rate. The disturbed flows also facilitated the transport of low molecular weight substances such as biochemicals but not macromolecules from arterial walls to flowing blood. These results strongly suggest that disturbed flows with slow recirculation flow provide favorable conditions for the genesis and development of atherosclerotic lesions by affecting local mass transport phenomena at the blood-vessel wall boundary.

The biochemical characterization of phase I and phase II components considered to be important in the metabolism of carcinogens and other xenobiotics was examined in two experimental models. This was done to elucidate the relationship between the process of carcinogenesis and the selection of a biochemical phenotype which could result in drug resistance, previously described in rat hepatocarcinogenesis models. / A model of mammary carcinogenesis in mice demonstrated no significant biochemical change relating to potential drug resistance among normal, preneoplastic and neoplastic mammary tissues. This is of particular interest since human breast cancer is usually quite drug sensitive at the start of the treatment. / Human colon cancer is probably induced by carcinogenic compounds present in the environmental dietary elements and also exhibits de novo resistance to most antineoplastic drugs. Most of the biochemical elements examined were found to be present in these colon tissues. Additionally, the detoxification pathways including glutathione and its related enzymes, were found to be significantly elevated in colon tumor versus normal adjacent mucosa. The molecular characterization of glutathione S-transferase (GST) isoenzymes using antibodies and cloned molecular probes to specific enzyme forms showed that the anionic form of GST (GST-$ pi)$ is greater in tumors than in the respective normal mucosa. The neutral form (GST-$ mu)$ is conversely decreased in tumor relative to normal. The cationic (GST-$ alpha)$ is present only in 30% of the samples examined, with no difference between tumor and adjacent normal mucosa. The expression of cytochrome P-450 isoenzymes was also examined in a similar fashion; a phenobarbital-inducible form was expressed in most colon tissues examined, and expression of the polycyclic aromatic hydrocarbons-inducible P$ sb3$-450 was present in some colon tissues while mRNA for P$ sb1$-450 was not detected in any. The biochemical alterations found in human colon could be the targets of therapeutic manoeuvers to enhance the efficacy of antineoplastic treatment of human colon cancer.

Brain inflammation is a hallmark of Alzheimer's Disease (AD) neuropathology. This involves microglial activation which has been well characterized around fibrillar plaques in humans and in transgenic mouse models. Plaques are initiated by the accumulation of Abeta1-42 (beta-amyloid) which is a highly aggregating, neurotoxic protein derived from alternative processing of APP (amyloid precursor protein). Genetic factors involved in influencing the intensity of an inflammatory response have been shown clearly in other pathologies but not in AD. Therefore, an in vitro model of microglial activation by Abeta1-42, was developed using mouse strains having a low (A/J) or high (C57BL/6) inflammatory response. Interferon-gamma-primed C57BL/6 microglia underwent morphological changes from resting (ramified) morphology to activated (ameboid) morphology, increases in nitric oxide (NO) production, and very high levels of tumor necrosis factor alpha (TNF-alpha) when stimulated with Abeta1-42. On the other hand, A/J microglia underwent few morphological changes, had increased levels of NO and had minimal increases in TNF-alpha levels when submitted to the same treatment. Thus, microglial activation to Abeta1-42 was influenced by the magnitude in inflammatory response which may be determined by genetic factors. The timing of an inflammatory response in the process of Abeta deposition is still under debate. Therefore, to define the kinetics of the inflammatory response in brain amyloidogenesis, TgCRND8 mice which overexpress hAPP and aggressively develop amyloidosis, were used to characterize the evolution of diffuse and fibrillar plaque formation and gliosis. Histopathological analysis revealed diffuse plaques as early as 12 weeks of age. Fibrillar (senile) plaques and microgliosis were seen at 13 weeks of age whereas astrocytic clustering began at 14--15 weeks of age. Microglial activation was found to be correlated strongly to Abeta deposition and fibril

The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to produce a neurochemically selective and progressive destruction of dopamine pathways. The resulting motoric deficits and histopathology reproduces several key features of Parkinson's disease, a neurodegenerative disorder for which there is no known cure. The objective of the present thesis was to characterize the in vivo neurotoxicity of 6-OHDA in dopamine pathways, and to examine the mechanisms underlying dopamine cell death. / Infusion of 6-OHDA into different dopamine pathways revealed that the nigrostriatal projection was more vulnerable than the mesolimbic dopamine pathway. In addition, a considerable portion of cell bodies was preserved despite significant losses of dopamine markers in nigrostriatal and mesolimbic nerve terminal regions. The partial sparing of cell bodies was enhanced by hypothermia associated with surgical anesthesia. This neuroprotective effect was localized to a specific subregion within the mesolimbic dopamine cell body area. The preservation of dopamine cell bodies following 6-OHDA administration may have functional significance since somatodendritic dopamine release has been demonstrated in this brain area. / The studies in Chapter 3 examined the contribution of two proteases, calpain and caspase-3, in mediating the degeneration resulting from 6-OHDA administration. Calpain activation occurred early and remained elevated in nigrostriatal cell body and terminal field subregions, whereas caspase-3 activation was only transient. Adenoviral delivery of the calpain inhibitor, calpastatin, completely prevented the elevation in calpain activity following 6-OHDA administration. Moreover, calpastatin delivery significantly improved motor deficits associated with nigrostriatal dysfunction. The behavioural protection was not, however, accompanied by a sparing of nigrostriatal dopamine markers, but was unexpectedly associated with a preservation of mesolimbic dopamine markers. These findings suggest that calpain activation contributes to dopamine cell death, but this effect may be brain region dependent. / Collectively, our findings highlight differential vulnerability amongst midbrain dopamine neurons, of possible relevance to Parkinson's disease. In addition, our work suggests that calpains may represent a future therapeutic target for the treatment of Parkinson's disease. However, present drawbacks associated with this approach indicate that additional studies are necessary before such neuroprotective compounds can be employed to treat Parkinson's disease.

Lung transplantation is a therapeutic option for patients affected with end-stage lung diseases. However, several complications may arise following the procedure, such as Bronchiolitis Obliterans (BO). This condition, characterized by small airway fibrosis, remains a major cause of morbidity and mortality in patients following lung transplantation. It is thought to be a manifestation of chronic rejection within the airways, with hallmark inflammation and fibroproliferation. TGF-beta and other cytokines, including IL-1, IFN-gamma and PDGF, have been implicated in the pathogenesis of fibrosis, mostly in animal models. IL-11 and IL-17 are novel profibrotic cytokines that induce fibroblasts and epithelial cells to produce excess extracellular matrix. They have recently been identified as having a role in tissue remodelling and induction of tissue fibrosis. We hypothesize that IL-11 and IL-17 are involved in chronic lung rejection (Bronchiolitis Obliterans) and that their expression could be a predictive and prognostic marker of chronic lung rejection. / The objectives of the study were to investigate the expression of IL-11 and IL-17 (mRNA and protein) in endobronchial biopsies from lung transplant patients and to define the correlation between the expression of IL-11 and IL-17 and the development of chronic rejection.