Correlations between neuropsychiatric symptoms and beta-amyloid (Aβ) burden in specific brain regions in living Alzheimer’s disease (AD) patients remain to be elucidated. Ten mild AD patients underwent MR and [11C]SB-13 PET imaging. Neuropsychiatric symptoms were quantified with the Neuropsychiatric Inventory (NPI). NPI-depression/dysphoria, -apathy, -agitation/aggression, -anxiety, and -appetite/eating disorders scores were hypothesized to correlate with Aβ burden in particular brain regions. Pearson’s correlation coefficient revealed that depression/dysphoria scores positively correlated (p<0.05) with standardized uptake values (SUVs) from left medial temporal lobe (r=0.67), and agitation/aggression correlated with SUVs from bilateral anterior cingulate (right, r=0.71; left, r=0.78), temporal (right, r=0.71; left, r=0.75), parietal (right, r=0.77; left, r=0.81), and dorsolateral prefrontal cortex (right, r=0.74; left, r=0.73). However, NPI scores did not significantly correlate with better estimates of Aβ burden that use the cerebellum as reference region. Overall, our results confirm the lack of association between Aβ burden and neuropsychiatric symptoms reported in autopsy studies.

Correlations between neuropsychiatric symptoms and beta-amyloid (Aβ) burden in specific brain regions in living Alzheimer’s disease (AD) patients remain to be elucidated. Ten mild AD patients underwent MR and [11C]SB-13 PET imaging. Neuropsychiatric symptoms were quantified with the Neuropsychiatric Inventory (NPI). NPI-depression/dysphoria, -apathy, -agitation/aggression, -anxiety, and -appetite/eating disorders scores were hypothesized to correlate with Aβ burden in particular brain regions. Pearson’s correlation coefficient revealed that depression/dysphoria scores positively correlated (p<0.05) with standardized uptake values (SUVs) from left medial temporal lobe (r=0.67), and agitation/aggression correlated with SUVs from bilateral anterior cingulate (right, r=0.71; left, r=0.78), temporal (right, r=0.71; left, r=0.75), parietal (right, r=0.77; left, r=0.81), and dorsolateral prefrontal cortex (right, r=0.74; left, r=0.73). However, NPI scores did not significantly correlate with better estimates of Aβ burden that use the cerebellum as reference region. Overall, our results confirm the lack of association between Aβ burden and neuropsychiatric symptoms reported in autopsy studies.

Objective: The objective of this thesis was to facilitate clinical trials of the optimal lipid based approach (e.g.: omega-3 containing lipid emulsions or minimization of conventional lipid) for the prevention of Intestinal Failure Associated Liver Disease (IFALD). This was achieved through 3 related projects. Project 1: The first project examined the risk of advanced IFALD associated with exposure to conventional intravenous lipid in a logistic regression model. The study demonstrated that each day of conventional lipid (> 2.5 g/kg/day) was associated with a significant increase in the risk of advanced IFALD [Odds Ratio: 1.04 95% CI: 1.003 – 1.06]. Project 2: The second project surveyed experts in Intestinal Failure regarding their beliefs of the efficacy of lipid minimization and lipid emulsions containing omega-3 fatty acids relative to conventional emulsions. The goal of the project was to develop prior distributions of the treatment response for these therapies that can be used in Bayesian analyses of clinical trials. Our results demonstrated consistent expert opinion that the novel lipid based approaches are superior to conventional therapy. Estimates of the treatment effect were similar for the two approaches (median elicited treatment response, relative to conventional lipid, was a relative risk of 0.53 for omega-3 lipid and 0.45 for lipid minimization). Project 3: The final project was a pilot randomized controlled trial of an omega-3 emulsion. The study demonstrated that the randomized design is a feasible strategy for evaluating lipid based approaches for the prevention of IFALD. A Bayesian preliminary assessment of the results of the trial, suggests a high likelihood that the trial will demonstrate a difference between the conventional and omega-3 emulsion evaluated in the trial. However, since the analysis was blinded, the direction of the difference is not known. Conclusion: This thesis will contribute to the design and analysis of high quality and feasible randomized trials that will allow investigators to address the optimal lipid based approach to the management of IFALD.

Introduction : L’hypophosphatémie survient couramment après hépatectomie partielle. La régénération du foie était l’explication initiale. Cependant, les pertes rénales de phosphate observées récemment suggèrent que l’hypophosphatémie est probablement d’origine rénale. Nous avons donc mesuré la fraction d’excrétion urinaire de phosphate (FePO4) après hépatectomie partielle et nous avons étudié le rôle de la parathormone (PTH) et des phosphatonines dans cette hypophosphatémie. Méthodes : Les taux sériques de phosphate, de calcium ionisé, de PTH intacte, de « fibroblast growth factor- 23 » (FGF-23) intact et carboxyle-terminal, de FGF-7, de la « frizzled-related protein-4 » (FRP-4) et de HCO3- ainsi que le pH et la FePO4 ont été mesurés avant la chirurgie et aux jours postopératoires (po) 1, 2, 3, 5 et 7, chez 18 patients ayant subi une résection hépatique partielle. Résultats : Le phosphate sérique était à son plus bas niveau (0,66 ± 0,33 mmol/l; p < 0,001) au jour po 2. La FePO4 culminait à 25,07 ± 2,26 % au jour po 1 (p < 0,05) et était associée avec le taux de la parathormone intacte (r = 0,65; p = 0,006). Le calcium ionisé sérique diminuait à 1,1 ± 0,01 mmol/l, (p < 0,01) en même temps que la parathormone intacte s’élevait à 8,8 ± 0,9 pmol/l, (p < 0,01) au jour po 1; ces deux paramètres étaient inversement corrélés (r = -0,062; p = 0,016). Le FGF-23 intact atteignait son plus bas niveau à 7,8 ± 6,9 pg/ml (p < 0,001), au jour po 3; les valeurs de FGF-23 étaient corrélées avec la diminution du phosphate sérique aux jours po 0, 3, 5 et 7 (p < 0,001). Le FGF-23 carboxyle-terminal, le FGF-7 et la FRP-4 n’étaient pas reliés au phosphate sérique ni à la FePO4. Conclusion : L’hypophosphatémie observée après résection hépatique partielle est liée à une augmentation de la FePO4 qui est sans aucune relation avec les FGF-23 intact ou carboxyle-terminal, le FGF-7 et la FRP-4. La PTH intacte était associée avec la FePO4 uniquement au jour po 1. L’hypophosphatémie après résection hépatique est secondaire à d’autres facteurs non encore identifiés. / Background: Post-hepatectomy hypophosphatemia, first associated with metabolic demands by the regenerating liver, has recently been related to an excessive fractional urinary phosphate excretion (FePO4). We decided to investigate the role of parathyroid hormone (PTH) and of phosphatonins in the latter finding. Methods: Serum phosphate (PO4), ionized calcium (Ca++), HCO3-, pH and FePO4, Intact PTH, carboxyl-terminal and Intact fibroblast growth factor 23 (FGF-23), FGF-7 and frizzled related-protein-4 (FRP-4) were measured before and serially on post-operative days 1, 2, 3, 5 and 7, in 18 patients undergoing liver resection. Results: Serum PO4 was lowest (0.66 ± 0.33 mmol/l; p < 0.001) on po day 2. FePO4 peaked at 25.07 ± 2.26 % on po day 1 (p < 0.05) and was associated with Intact PTH levels (r = 0.65, p = 0.006). Decreased Ca++ levels (1.1 ± 0.01 mmol/l; p < 0.01) and increased Intact PTH levels (8.8 ± 0.9 pmol/l; p < 0.01) observed on po day 1 were negatively related (r = -0.62, p = 0.016). Intact FGF-23 decreased to its nadir 7.8 ± 6.9 pg/ml (p < 0.001), on po day 3 and was correlated with PO4 levels on po days 0, 3, 5 and 7 (p < 0.001). Carboxyl-terminal FGF-23, FGF-7 and FRP-4 levels could not be related either to PO4 concentrations or FePO4. Conclusion: Post-hepatectomy hypophosphatemia is related to an increased FePO4 unrelated to Intact FGF-23 or carboxyl-terminal FGF-23, FGF-7 or FRP-4. I-PTH contributes to excessive FePO4 on po day 1 but not thereafter. Other factors not yet defined should explain post hepatectomy hypophosphatemia.

Objective: To appraise whether adverse events following oral implant placement may be associated with peri-operative use of non-steroidal anti-inflammatory drugs (NSAIDs). Methods: All patients with recorded implant failures between 1979 and 2012 in the Implant Prosthodontics Unit were contacted to solicit additional information about potential peri-operative use of NSAIDs. Results: From a total of 168 patients with 292 implant failures between 1979 and 2012, 122 consented to participate and had intact records. Just over half (56.6%) reported no peri-operative NSAID usage. However, compared to patients who did not use peri-operative NSAIDs, four times as many had complicated medical histories and twice as many patients taking NSAIDs suffered multiple implant failures. Conclusions: Patients with a variety of systemic diseases may be adversely affected by the inhibitory effect of NSAIDs on bone healing. Further prospective clinical studies are warranted to clarify this potential causative relationship in humans.

Objective: The objective of this thesis was to facilitate clinical trials of the optimal lipid based approach (e.g.: omega-3 containing lipid emulsions or minimization of conventional lipid) for the prevention of Intestinal Failure Associated Liver Disease (IFALD). This was achieved through 3 related projects. Project 1: The first project examined the risk of advanced IFALD associated with exposure to conventional intravenous lipid in a logistic regression model. The study demonstrated that each day of conventional lipid (> 2.5 g/kg/day) was associated with a significant increase in the risk of advanced IFALD [Odds Ratio: 1.04 95% CI: 1.003 – 1.06]. Project 2: The second project surveyed experts in Intestinal Failure regarding their beliefs of the efficacy of lipid minimization and lipid emulsions containing omega-3 fatty acids relative to conventional emulsions. The goal of the project was to develop prior distributions of the treatment response for these therapies that can be used in Bayesian analyses of clinical trials. Our results demonstrated consistent expert opinion that the novel lipid based approaches are superior to conventional therapy. Estimates of the treatment effect were similar for the two approaches (median elicited treatment response, relative to conventional lipid, was a relative risk of 0.53 for omega-3 lipid and 0.45 for lipid minimization). Project 3: The final project was a pilot randomized controlled trial of an omega-3 emulsion. The study demonstrated that the randomized design is a feasible strategy for evaluating lipid based approaches for the prevention of IFALD. A Bayesian preliminary assessment of the results of the trial, suggests a high likelihood that the trial will demonstrate a difference between the conventional and omega-3 emulsion evaluated in the trial. However, since the analysis was blinded, the direction of the difference is not known. Conclusion: This thesis will contribute to the design and analysis of high quality and feasible randomized trials that will allow investigators to address the optimal lipid based approach to the management of IFALD.

Objective: To appraise whether adverse events following oral implant placement may be associated with peri-operative use of non-steroidal anti-inflammatory drugs (NSAIDs). Methods: All patients with recorded implant failures between 1979 and 2012 in the Implant Prosthodontics Unit were contacted to solicit additional information about potential peri-operative use of NSAIDs. Results: From a total of 168 patients with 292 implant failures between 1979 and 2012, 122 consented to participate and had intact records. Just over half (56.6%) reported no peri-operative NSAID usage. However, compared to patients who did not use peri-operative NSAIDs, four times as many had complicated medical histories and twice as many patients taking NSAIDs suffered multiple implant failures. Conclusions: Patients with a variety of systemic diseases may be adversely affected by the inhibitory effect of NSAIDs on bone healing. Further prospective clinical studies are warranted to clarify this potential causative relationship in humans.

Angiotensin II (AngII), the major effector of the renin angiotensin system, mediates kidney disease progression by signalling through AT-1 receptor (AT-1R), but there are no specific measures of renal AngII activity. Accordingly, we sought to define an AngII-regulated proteome in primary human proximal tubular cells (PTEC) in order to identify potential AngII activity markers in the kidney. We utilized stable isotope labelling with amino acids (SILAC) in PTECs to compare proteomes of AngII-treated and control cells. Of 4618 quantified proteins, 83 were differentially regulated. SILAC ratios for 18 candidates were confirmed by Selected Reaction Monitoring (SRM) assays. Both SILAC and SRM revealed the nuclear factor erythroid 2-related 2 (Nrf2) target protein, heme oxygenase-1 (HO-1) as the most significantly upregulated protein in response to AngII stimulation. AngII-dependent regulation of HO-1 gene and protein was further verified by qRT-PCR and ELISA in PTECs. In order to extend these in vitro observations, we utilized a systems biology approach. We thus overlaid a network of significantly enriched gene ontology (GO) terms from our AngII-regulated proteins with a dataset of differentially expressed kidney genes from AngII-treated wild type mice and AT-1R knock-out mice. Five GO terms were enriched both in vitro and in vivo, and all included HO-1. Furthermore, four additional Nrf2 target proteins were functionally important in vitro and in vivo. We then studied HO-1 kidney expression and urinary excretion in AngII-treated wild type mice and mice with PTEC-specific AT-1R gene deletion. Deletion of the AT-1R gene in PTECs lowered both kidney expression and urine excretion of HO-1, confirming AngII/AT-1R mediated regulation of HO-1. In summary, our in vitro experiments identified novel molecular markers of AngII activity in PTECs and the animal studies demonstrated that these markers also reflect AngII activity in PTECs in vivo. These interesting proteins hold promise as specific markers of renal AngII activity in patients and in experimental models.

Abstract: Objective: To compare the long-term viability of percutaneously injected crushed auricular cartilage to surgically implanted cartilage in the rabbit. Methods: Auricular cartilage was harvested bilaterally in 10 New Zealand white rabbits. A 1 cm2 cartilage graft was harvested and implanted surgically on the upper nasal dorsum. The remaining cartilage was crushed and percutaneously injected on the lower nasal dorsum. Volume and mass of each graft were compared between pre-implantation and after 3 months of observation. A histological study was conducted to evaluate chondrocyte viability and degree of fibrosis on the grafts. Results: Mass and volume remained similar for surgically implanted cartilage grafts. Mass and volume diminished by an average of 47% and 40% respectively after 3 months for the injected crushed cartilage grafts. Chondrocyte viability was an average of 25% lower in the injected grafts. Conclusion: Cartilage injection is a promising technique that must be refined to increase long term chondrocyte viability. Developing an appropriate injection apparatus would improve this technique. / Résumé : Objectif: Comparer la viabilité à long-terme de cartilage auriculaire broyé injecté de façon percutanée au cartilage implanté chirurgicalement chez le lapin Méthodes: Prélèvement de cartilage auriculaire bilatéralement chez 10 lapins blancs « New Zealand ». Pour chaque lapin, une greffe de cartilage de 1 cm2 fut prélevée et implantée chirurgicalement au niveau du dorsum nasal supérieur. Le reste du cartilage fut broyé puis injecté de manière percutanée sur le dorsum nasal inférieur. La masse et le volume de chaque greffon furent mesurés lors de la chirurgie initiale et 3 mois plus tard. Une étude histologique a été entreprise afin de comparer la viabilité des greffons et le degré de fibrose. Résultats: La masse et le volume des greffons de cartilage entier sont demeurés semblables suite à l’implantation. La masse et le volume des greffons de cartilage injecté ont diminué en moyenne de 47% et 40% respectivement suite à l’implantation. L’analyse histologique a démontré une diminution moyenne de 25% de la viabilité chondrocytaire pour les greffons de cartilage injecté. Conclusion: L’injection de cartilage est une technique prometteuse devant être raffinée pour augmenter la viabilité chondrocytaire à long-terme. Le développement d’un instrument d’injection approprié faciliterait la technique.

INTRODUCTION: The association of Sleep-Related Movement Disorders (SRMDs) such as Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLMs) with cerebrovascular disease is underexplored. Emerging evidence links them to vascular disease, for which white matter hyperintensities (WMHs) are a well-recognized biomarker. METHODS: We conducted a cross-sectional hospital-based observational study in which high-risk TIA and minor stroke patients were assessed for vascular risk factors, WMHs and polysomnography-determined sleep variables. RESULTS: Ninety-seven patients were enrolled, of whom 44 completed polysomnography. Twenty-five percent had RLS, which was associated with lower quality of life. Independent of the effect of classical vascular risk factors, PLMs (but not RLS) were associated with WMHs on linear regression analyses (p=0.016). CONCLUSIONS: SRMDs are prevalent after minor stroke/TIA. RLS is associated with poor quality of life, while PLMs are associated with WMHs. Whether PLMs are implicated in the pathogenesis of WMHs or whether WMHs exacerbate PLMs remains uncertain.