In the treatment of Parkinson's disease some cases require the ablation of a specific region in the basal ganglia. The accurate localization of this region inside the patient's brain is essential and because direct visual anatomical information for such deep brain structures is not available, the surgeon has to rely on other sources of information such as MRI, CT and x-ray of the patient's brain. However these imaging techniques do not provide sufficient anatomical information, requiring the use of a subcortical brain atlas book to assist in the localization of the different structures. This way of proceeding is cumbersome and results in a certain lack of accuracy in the localization of the different brain structures. / We developed a method that aids the surgeon to obtain the sufficient anatomical information in a simpler and more accurate manner. We provide him with a segmentation of the patient's MRI scan based on the Schaltenbrand and Wahren subcortical atlas. To achieve such segmentation a volumetric version of the atlas was obtained and was then mapped to a model brain MRI using landmark matching. Using an automated tool for the three-dimensional registration of two MRI volumes the deformation transformation between the model brain MRI and the patient's brain MRI was obtained. By applying this same transformation to the volumetric atlas, we obtain a superposition of a volumetric subcortical atlas onto the MRI of the patient's brain in the stereotactic space. This method results in a more accurate localization of the surgical lesion, thus reducing the number of additional interventions which are often necessary when the results of the first procedure are shown to be unsatisfactory. The whole guidance system is now used routinely at the Montreal Neurological Institute and is part of the standard surgical procedure.

Humidifying infant incubators facilitates heat retention, but entails an infection risk from microbial humidifier contamination. The Royal Victoria Hospital nursery was recently reequipped with steam humidity source incubators and converted to incubator humidification. An observational (before-after) study investigated the association between incubator humidification and hypernatremia and (secondarily) other hydration associated outcomes in very premature infants. / Thirty-one incubator humidification and 60 non-humidification period infants were compared. Mean gestational age was 25.83 weeks for both groups. Mean highest serum sodium values were 143.5 (SD 9.4) and 152.9 (SD 4.9) mEq/l respectively (p < 0.001). Differences persisted after adjustment for confounding by age of placement in incubators, and in spite of fluid reduction in the D humidification period. Of infants with umbilical lines 2/16 and 33155 respectively attained serum potassium measurements over 6.9 mEq/l (p = .04). Overhydration outcomes did not differ, but power was limited and confounding was problematic for these analyses. / In summary, incubator humidification is associated with decreased hypernatremia and hyperkalemia in very premature infants.

An isocentric teletherapy cobalt unit provides a viable alternative to an isocentric linac as a radiation source for radiosurgery. An isocentric cobalt unit was evaluated for its potential use in radiosurgery in three areas: (1) the physical properties of its radiosurgical beams, (2) the quality of radiosurgical dose distributions obtained with 4 to 10 non-coplanar arcs, and (3) the accuracy with which the radiosurgical dose can be delivered. In each of these areas the 10 MV beam of a linear accelerator served as a standard for comparison. / The difference between the 80%--20% penumbras of the radiosurgical fields of the cobalt-60 and 10 MV photon beams is remarkably small, with the cobalt-60 beam penumbras on the average only about 0.7 mm larger than those of the linac beam. Differences between the cobalt-60 and 10 MV plans in terms of dose homogeneity within the target volume and conformity of the prescribed isodose volume to the target volume are also minimal, and therefore of limited clinical significance. Moreover, measured obtained isodose distributions of a radiosurgical procedure performed on the isocentric cobalt unit agreed with calculated distributions to within the +/-1 mm spatial and +/-5% numerical dose tolerances which are generally accepted in radiosurgery. The viability of isocentric cobalt units for radiosurgery would be of particular interest for centers in developing counties where cobalt units, because of their relatively low costs, provide the only megavoltage source of radiation for radiotherapy, and could easily and inexpensively be modified for radiosurgery.

Human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) is essential for the formation of the viral double-stranded stranded DNA genome from its RNA template. Blockage of this catalytic function by reverse transcriptase inhibitors leads to inhibition of viral replication. Although 3$ sp prime$-azido-3$ sp prime$-deoxythymidine (AZT) is the most successful anti-viral drug to date, its prolonged use results in the emergence of AZT-resistant viral isolates. Several mutations are consistently found within the reverse transcriptase gene of AZT-resistant viral isolates. Although it is generally accepted that these mutations are responsible for the drug-resistance phenotype, the exact mechanism by which this occurs is poorly understood. For example, cloned viruses harboring these mutations show resistance to AZT in tissue culture, yet recombinant HIV RTs that contain these resistance-conferring "mutations" do not show increased inhibition constant (K$ rm sb{i})$ values for AZT as compared to wild type RTs. / By in vitro infection, polymerase chain reaction, and reconstituted in vitro reverse transcription assays, we have confirmed previous observations (Arts 1994c) that AZT preferentially terminates HIV-1 nucleic acid elongation after the first template switch. We have also shown that nucleoside analogues are more effective chain terminators in situations in which deoxynucleotide triphosphate pools are limiting. Pre-treatment of cells with AZT prior to infection had a stimulatory effect on generation of viral DNA, but only in the case of AZT-resistant variants and not wild-type strains of HIV-1.

The world-wide dissemination of the human immunodeficiency virus type 1 (HIV-1) has led to a wide number of approaches aimed at controlling and understanding viral replication. Although antiviral drugs have been important in the treatment of HIV-1-infected individuals, toxicity and resistance have mandated new efforts and strategies. / We have tried to develop a trans-dominant gene therapy approach, by showing that mutated Gag-Pol polyproteins can be incorporated into viral particles. In our studies, Gag-Pol proteins that were mutated in protease (PR) and combinations of mutations in PR and reverse transcriptase (RT) inhibited the production of fully processed and infectious viral particles when coexpressed with the infectious HIV-1 molecular clone, pBH10. Viral particles produced after cotransfection of COS-7 cells with both pBH10 and Gag-Pol, mutated in PR alone or in both RT and PR, showed abnormal processing and lower infectivity, suggesting that a trans-dominant negative effect had occurred. These effects were not seen when Gag-Pol with a deleted integrase ($ Delta$IN) and the same RT and PR mutations were co-expressed with pBH10. Complementation experiments in which pBH10 mutated in PR was co-expressed with wild-type Gag-Pol showed that the latter could be incorporated into viral particles. Finally, COS-7 cells stably transfected with Gag-Pol mutated in PR or in both PR and RT, and subsequently transfected with pBH10, showed diminished production of viral particles.

To evaluate why discordance may occur between regression coefficients from cross sectional and longitudinal analyses when ventilatory function is related to ageing, a population was created by computer, and modelled to simulate functional change during life. The program incorporated the effects of many factors known to influence lung function measurements, which were adjusted experimentally so that their contributions to any discordance could be assessed. Regression analyses showed that significant discordance could be induced if the oldest birth cohort failed to reach the same maximal level of function as the youngest; if a quadratic ageing term was excluded from the independent regression variables; or if the effects of certain confounders were present. Discordance occurred additionally if cross sectional estimates became imprecise, but then the differences (often marked) from longitudinal estimates were not significant. It is concluded that discordance may be fundamental and unavoidable (though explicable), or merely a consequence of imprecision.

Background. Anticholinergic (ACH) medications are among biologically plausible and potentially modifiable risk factors of delirium. But the epidemiological findings on its role in hospitalized elderly patients are conflicting. Objectives. To evaluate the association between use of ACH medications and delirium severity and the potential effect-modification on this association by dementia. Methods. A cohort of 278 medical inpatients aged 65 years and over with diagnosed delirium was prospectively followed up with the Delirium Index (DI) every 2--7 days up to 3 weeks in a primary acute care hospital. Their DI scores were associated with measures of ACH medication exposure in the previous day using the mixed linear regression model adjusting for potential confounders or effect modifiers. Results . A total of 47 potential ACH medications were used in the cohort (mean: 1.4 per patient per day). An increase in daily ACH medication exposure of one such medication was on average associated with a subsequent increase in delirium severity of 0.52 DI points (95% CI: 0.3--0.8) after adjusting for dementia, baseline DI score, length of follow-up and concurrent use of non-ACH medications. Dementia did not modify the association. Sensitivity analyses using alternative definitions of ACH medications or excluding antipsychotics did not change the results. Conclusions. Exposure to ACH medications is independently and specifically associated with a subsequent increase in symptom severity of delirium among elderly medical inpatients.

This thesis relates to the study of drug effectiveness using observational designs. First, we investigate the ability of inhaled corticosteroids, an anti-asthma medication, in preventing hospitalization for asthma. We then address methodological issues related to temporal dimensions of drug exposure and to the estimation of time-dependent rate ratios in case-control studies. To examine these questions, a cohort of 19,168 newly treated asthmatics was selected from the computerized databases of Saskatchewan Health. / Using a sub-cohort of 2,059 patients hospitalized for asthma, we found that regular users of inhaled corticosteroids were about 40 percent less likely to be readmitted to hospital for asthma than nonusers of these medications, and this after only 15 days of therapy. The beneficial effects lasted up to six months and waned thereafter. Using a case-control sample from the entire cohort, we found that therapy with inhaled corticosteroids, initiated early after the onset of symptoms of asthma, was more effective than theophylline in preventing the first hospitalization for asthma. When compared with anti-allergic agents, early treatment with inhaled corticosteroids was not found to significantly reduce the risk of asthma hospitalization, however. / Finally, we showed that the common use of exposure time-windows defined solely in terms of the outcome produces biased estimates of rate ratios that vary over time. Application of principles based on time-related dimensions of exposure provides, however, valid case-control estimates of time-dependent rate ratios. / In conclusion, we were able to show that regular use of inhaled corticosteroids is highly effective in preventing asthma hospitalizations. We also showed the importance of defining the exposure in terms of both the onset of therapy and the time of the outcome for the valid estimation of time-dependent rate ratios in case-control studies.

Chronic heart failure is an increasingly prevalent condition associated with high mortality and a heavy burden on patients, families, and society. Despite evidence that psychosocial variables are associated with the clinical evolution of other forms of cardiac disease, little is known about the prognostic impact of these factors for patients with asymptomatic left ventricular dysfunction (LVD) or overt heart failure. The purpose of this study was to evaluate social isolation, mood (anxiety, depression, and vigor), low socioeconomic status, non-White ethnicity (in U.S. patients), life stress, and poor self-rated health as possible correlates of health outcomes for patients with systolic LVD. / A secondary analysis was performed on clinical and psychosocial data for 4991 (of 6797) American, Canadian and Belgian patients aged 21 to 80 with left ventricular ejection fractions &le;35% enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) clinical trials. Psychosocial correlates of mortality, clinical deterioration, arrhythmias, hospitalizations, and quality of life (functional status, life satisfaction, and symptom levels) were examined using logistic and Cox proportional hazards model regressions, before and after adjustment for patient clinical characteristics. / Results showed that some measures of social isolation (being unmarried, making visits to and receiving visits from others infrequently) were associated with the majority of the negative health outcomes studied. Contrary to expectations, neither high depression, nor high anxiety predicted risk of either cardiac-related mortality or ventricular arrhythmias. However, both depression and anxiety were linked with measures of clinical deterioration, hospitalizations for any cardiac cause, as well as poor quality of life at 1 year. Low vigor, low socioeconomic status, non-White ethnicity, and low self-rated health were all consistently associated with poor quality of life and heightened risk of all of the adverse events studied except arrhythmias. / Psychosocial factors appear to be independent predictors of mortality and morbidity in advanced cardiac disease characterized by moderate to severe LVD. This suggests that it is worth evaluating these parameters in patients with, or at risk for, heart failure and tailoring clinical interventions to address the impacts these factors may have on different health outcomes.

Urokinase (uPA), a member of the serine protease family, and its cell surface receptor (uPAR) have been implicated in promoting the progression of various human malignancies including hormone dependent malignancies such as breast and prostate cancer. However, the underlying molecular mechanisms regulating uPA production in breast and prostate cancer progression are poorly understood. / In the current studies, we have examined the role of uPAR in breast cancer progression by developing a homologous model of uPAR overexpression by a rat breast cancer cell line Mat B III. Overexpression of uPAR resulted in increased breast cancer growth, invasion and metastasis in vitro and in vivo. Development of this syngeneic breast cancer model allowed me to examine the ability of the anti-estrogen, tamoxifen (TAM) and a synthetic active site inhibitor of uPA, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to prevent breast cancer progression. TAM and B-428 treatment alone or in combination effectively prevented breast tumor growth, invasion and metastasis in vitro and in vivo. Morever, TAM and B-428 treatments caused a decrease in uPAR gene expression and protein production. These results underscore the utility of anti-proteolytic agents (B-428) in addition to standard hormone therapy (TAM) in advanced breast cancer patients where the uPA/uPAR system plays a key role in tumor progression. Regulation of uPA production by androgens in prostate cancer was then examined in the androgen insensitive PC-3 cells transfected with the functional human androgen receptor cDNA (PC-3T). Androgens down regulate uPA gene expression and protein production in androgen sensitive PC-3T cells. Furthermore, restoration of androgen responsiveness in PC-3T cells caused a dramatic decrease in tumor growth, invasion and metastasis in vitro and in vivo. Due to the ability of sex steroids to inhibit uPA gene expression, I have also examined the correlation between hormone sensitivity and uPA expression in several hormone responsive (HR) and hormone insensitive (HI) breast and prostate cancer cell lines. uPA mRNA was expressed only in the highly invasive, HI breast (MDA-231) and prostate (PC-3) cell lines. Failure of uPA mRNA expression in the minimally invasive, HR breast (MCF-7) and prostate (LnCAP) cells was due to transcriptional suppression of uPA gene. Southern blot analysis usi