Introduction: Colorectal cancer (CRC) is the fourth-most common cancer in Canada with a high mortality rate. Familial adenomatous polyposis (FAP) is a hereditary form of CRC; FAP patients carry germline mutations of the tumour suppressor gene adenomatous polyposis coli (APC). The function of Dlx genes in the gastrointestinal tract (GIT) has not been previously explored. Methods: Immunofluorescence (IF) was performed to identify Dlx2+ intestinal cells. Chromatin immunoprecipitation (ChIP) was performed to identify DLX2-Apc promoter interaction. Quantitative real time polymerase chain reaction (qRT-PCR) was performed on mouse small and large intestines (normal and Dlx1/Dlx2 mutant mice). Electrophoretic mobility shift assays (EMSA) and reporter assays were carried out to investigate direct binding and activity, respectively, of DLX2 on the Apc promoter in-vitro. Dlx2 expression was explored in ApcMIN mice and human CRC tumor specimens. Results: Dlx2 is highly expressed in mouse embryonic and adult intestinal epithelia. Moreover, Dlx2 is expressed in the ApcMIN mice GIT as well as in some human CRC tumor specimens. ChIP, EMSA and reporter gene assays demonstrated that DLX2 protein specifically interacts with the Apc promoter in-situ and activates its expression in vitro. In-vivo and in-vitro, β-catenin protein levels are increased when DLX2 is absent or reduced by shRNA to Dlx2. Conclusions: Regulation of APC expression during development is poorly understood. We have evidence that DLX2 interacts with the Apc promoter in-vivo. We have shown that DLX2 induces Apc transcription by directly binding to the Apc promoter in-vitro. We also showed that β-catenin expression is altered in the Dlx1/Dlx2 mutant GIT. This finding implicates the involvement of DLX2 in the canonical Wnt signalling pathway. Ultimately, restoring APC expression may be a novel strategy towards preventing progression of intestinal polyps to adenocarcinoma. This research will contribute to our knowledge of the genetic and epigenetic regulatory pathways that control intestinal development, mucosal self-renewal and CRC.

Introduction: Colorectal cancer (CRC) is the fourth-most common cancer in Canada with a high mortality rate. Familial adenomatous polyposis (FAP) is a hereditary form of CRC; FAP patients carry germline mutations of the tumour suppressor gene adenomatous polyposis coli (APC). The function of Dlx genes in the gastrointestinal tract (GIT) has not been previously explored. Methods: Immunofluorescence (IF) was performed to identify Dlx2+ intestinal cells. Chromatin immunoprecipitation (ChIP) was performed to identify DLX2-Apc promoter interaction. Quantitative real time polymerase chain reaction (qRT-PCR) was performed on mouse small and large intestines (normal and Dlx1/Dlx2 mutant mice). Electrophoretic mobility shift assays (EMSA) and reporter assays were carried out to investigate direct binding and activity, respectively, of DLX2 on the Apc promoter in-vitro. Dlx2 expression was explored in ApcMIN mice and human CRC tumor specimens. Results: Dlx2 is highly expressed in mouse embryonic and adult intestinal epithelia. Moreover, Dlx2 is expressed in the ApcMIN mice GIT as well as in some human CRC tumor specimens. ChIP, EMSA and reporter gene assays demonstrated that DLX2 protein specifically interacts with the Apc promoter in-situ and activates its expression in vitro. In-vivo and in-vitro, β-catenin protein levels are increased when DLX2 is absent or reduced by shRNA to Dlx2. Conclusions: Regulation of APC expression during development is poorly understood. We have evidence that DLX2 interacts with the Apc promoter in-vivo. We have shown that DLX2 induces Apc transcription by directly binding to the Apc promoter in-vitro. We also showed that β-catenin expression is altered in the Dlx1/Dlx2 mutant GIT. This finding implicates the involvement of DLX2 in the canonical Wnt signalling pathway. Ultimately, restoring APC expression may be a novel strategy towards preventing progression of intestinal polyps to adenocarcinoma. This research will contribute to our knowledge of the genetic and epigenetic regulatory pathways that control intestinal development, mucosal self-renewal and CRC.

Introduction: Une procédure fréquente pour la prévention de l’arthrose de la cheville est une ostéotomie corrective du tibia distal (SMOT). Le Distal Tibia Nail (DTN ; Mizuho®), a été développé pour la réduction des fractures du tibia distal. L’objectif de ce projet était d’analyser la faisabilité du DTN pour des procédures SMOT effectuées avec une ouverture médiale (MWO). Méthodes : Au total 16 Sawbones® ont été instrumentés par un DTN ou une plaque (MDTP, Synthes®), suivi par la simulation d’une MWO. Quatre phases d’expérimentation étaient définies : Phase-0, Sawbones sans implant ni MWO ; Phase-1, échantillons avec un implant et MWO. Phase-2, les échantillons de la Phase-1 avec le cortex latéral fracturé ; Phase-3, simulation d’une fracture de type A3. La raideur et le mouvement inter-fragmentaire (IFM) étaient analysés. Des tomographies des échantillons ont été prises à Phases 0 et 1. Résultats : Jusqu’à 80% de différence était présente enter les Sawbones® de Phase-0 ; dans les Phases 1 et 2, des différences importantes se sont montrées entre des implants mais équivalent à <2 mm d’IFM. Le DTN a démontré une résistance très élevée aux charges appliquées en comparaison avec le MDTP pour la fixation des fractures A3. Des facteurs expérimentaux tels que la raideur initiale des Sawbones®, l’axe de chargement, et le positionnement de l’échantillon dans la machine d’essai, peuvent tous avoir une influence importante sur la raideur mesurée. Conclusion : Le DTN peut être considéré comme option pour la fixation des SMOT effectués avec un MWO. Des études futures doivent faire attention aux conditions limites ayant un effet sur des critères d’évaluation et des conclusions tirées / Introduction: Supra-malleolar corrective osteotomies (SMOT) are a common surgical procedure for the prevention of early onset of ankle arthritis. The Distal Tibia Nail (DTN; Mizuho®), was previously developed for the reduction of distal tibia fractures. The aim of this project was to identify error sources in biomechanical testing, and to test the feasibility of the DTN for SMOT performed using the medial wedge opening (MWO) technique. Methods: A total of 16 Sawbones® were each implanted with either a DTN or medial distal tibia plate (MDTP; Synthes®), and a MWO simulated. Four testing phases were defined: Phase-0, testing of Sawbones® without implant/osteotomy; Phase-1, samples with MWO and implant; Phase-2, Phase-1 samples with lateral cortex fractured; Phase-3, samples with an A3 type fracture. Stiffness construct and interfragmentary movement (IFM) were analysed. CT scans were taken of the samples at Phases 0 and 1. Results: Up to 80% difference was noticed between Sawbones® samples in Phase-0; in Phases 1 and 2 significant differences were found between stiffness constructs of the implant groups but this amounted to <2 mm IFM. The DTN was significantly more resistant to compression and torsion when supporting an A3 fractures (Phase-3). Elements such as original Sawbones® stiffness construct, implant position, potting material, loading axis, and sample positioning can have a high influence on measured stiffness and bias the results. Conclusion: The DTN is a viable option for the fixation of SMOT performed with a MWO technique. Future studies should pay careful attention to boundary conditions affecting outcomes measures and drawn conclusions

Indiana University-Purdue University Indianapolis (IUPUI) / Objective: Gold standard therapy for chronic limb threatening ischemia (CLTI) is revascularization but in patients in whom below-the-knee bypass is indicated autologous vein conduit may not be available. Contemporary outcomes of distal bypass with suboptimal conduits have not been well described and recent advances in non-surgical therapies raise the question of whether in some cases there is evidence that these should be considered. Methods: Data was obtained from the Vascular Quality Initiative (VQI) registry as well as from a multi-center, randomized clinical trial of cell therapy. Incidence of major amputation after distal bypass was estimated for the VQI cohort by conduit type using non-parametric survival analysis with death as a competing risk. A cox proportional hazards model was then fit to the pooled data in a stepwise fashion with death as a competing risk, including evaluations for appropriate transformation, time dependency and interactions for each included covariate, and hazard ratios were estimated for the risk of major amputation by treatment. Results: At 365 days, the estimated cumulative incidence of major amputation with death as a competing risk is 25% after distal bypass with non-autologous biologic conduit (0.2499, 95% CI 0.2242 - 0.2785), 13% for prosthetic (0.1276, 95% CI 0.1172 - 0.1389) and 9% for GSV (0.0900, 95% CI 0.0848 - 0.0956). The cox proportional hazards model found a significant interaction between age and treatment. Compared to bypass with non-autogenous biologic, the hazard ratios for bypass with GSV were 0.41 (p<0.0001), 0.41 (p<0.0001), 0.42 (p<0.0001) and 0.42 (p<0.0001) respectively at ages 55, 60, 65 and 70 and for bypass with prosthetic were 0.68 (p=0.0043), 0.67 (p=0.0004), 0.65 (p<0.0001) and 0.64 (p<0.0001) respectively and for autologous cell therapy 0.22 (p=0.0005), 0.34 (p=0.0011), 0.52 (p=0.0196) and 0.76 (p=0.3677) respectively. No significant differences were found between best medical management and distal bypass with non-autologous biologic. Conclusion: The risk of major amputation after distal bypass is lowest in patients with GSV conduit and highest following bypass with non-autologous biologic. Using a semi-parametric model, cell therapy was estimated to significantly decrease the risk of amputation compared to distal bypass with non-autologous biologic conduit in younger patients.

En behandlingsmetod för distal radiusfrakur är operation med stift och därefter förses patienten med gipsskena. Stiftextraktion sker efter fem veckor på ortopedmottagningen och patienten har då vanligtvis inte sett hur det ser ut under gipset. Eftersom verksamheten saknar skriftliga riktlinjer får patienterna en kort muntlig information före stiftextraktionen. Bristande information kan förstärka en smärtupplevelse. Syftet var att undersöka skattning av given information och smärta hos patienter som genomgått stiftextraktion efter behandling av distal radiusfraktur. För att besvara studiens syfte valdes en enkätundersökning med strukturerade frågor som metod. Resultatet visade att 25 av totalt 38 patienter upplevde att stiftextraktionen inte var smärtsam. Av de 23 respondenterna som smärtskattade på den numeriska skalan låg 16 patienter på VAS &lt;3. Informationen inför den planerade stifrextraktionen skattades av 28 patienter i en fempunktskala som "bra". Av dessa 28 patienter upplevde 11 stiftextraktionen som smärtsam. De fem patienter som skattade smärta vid stiftextraktion högst, mellan fem och tio på VAS-skalan, upplevde att informationen inför proceduren var "bra". Totalt ansåg fem patienter att informationen var "ganska dålig", dessa smärtskattade VAS 0-1. Fyra av de fem patienter som smärtskattade högst (VAS 5-10) hade intagit analgetika inför stiftextraktionen. Totalt hade drygt hälften av patienter intagit analgetika inför proceduren, företrädesvis Alvedon. Slutsatsen är att ett flertal patienter, 25 av 38 inte upplevde smärta vid stiftextraktion. Av de 23 respondenterna som smärtskattade låg 16 patienter på VAS &lt;3. Övervägande delen av patienterna skattade att de fick bra information inför proceduren. Studien kan inte påvisa någon koppling mellan information och smärtupplevelse men bidrar till att belysa sjuksköterskans viktiga roll att med information främja patientens delaktighet. Fortsatta studier i ämnet vore intressant.

Den vanligaste bettavvikelsen som behandlas bland barn och ungdomar är trångställning. När funktionellt och estetiskt störande trångställning i överkäken ska behandlas kan man vanligtvis ta bort tänder eller flytta de första stora kindtänderna (sexårständerna) bakåt för att sedan göra tandraden jämn. Det finns flera vetenskapliga studier som beskriver behandlingseffekterna av olika tandställningar för att flytta de stora kindtänderna bakåt. Det är oklart vilken typ av tandställning som är effektivast och i allmänhet saknas ett evidensbaserat perspektiv. Det är också oklart vid vilken tidpunkt som det är mest effektivt att flytta sexårständerna bakåt, dvs. före eller efter det att de andra stora kindtänderna kommit på plats i tandbågen. Licentiatavhandlingen är baserad på följande studier: Med randomiserad kontrollerad studiedesign var syftet i Studie I att utvärdera behandlingseffekterna av två olika tandställningar för att flytta överkäkens sexårständer bakåt i tandbågen. Fyrtio patienter randomiserades, 20 till en avtagbar tandställning (extraoralt drag) och 20 patienter till en fast tandställning. Studie II hade syftet att analysera när behandlingen var effektivast, dvs. att tandreglera sexårstanden bakåt innan eller efter att den bakomvarande stora kindtanden kommit på plats i tandbågen. I ramberättelsen utfördes dessutom en systematisk litteraturöversikt med syfte att på ett evidensbaserat sätt utvärdera olika metoders effektivitet i att tandreglera de stora kindtänderna bakåt i tandbågen och att göra en kvalitetsbedömning av de utvalda studierna. Översikten omfattade tidsperioden från januari 1966 t o m april 2008 vilket innebar att bedömningen även inkluderade studierna I och II. Konklusioner: • Fast tandställning var effektivare än avtagbar för att flytta de första stora kindtänderna bakåt i tandbågen. • Sidoeffekter i form av 1-2 mm ökat överbett (förankringsförlust) uppstod vid behandling med fast tandställning medan avtagbar tandställning bidrog till minskat överbett. • Det var mest effektivt att tandreglera sexårstanden bakåt innan den bakomvarande stora kindtanden kommit på plats i tandbågen. • I litteraturen fanns det begränsat bevisvärde för att fast tandställning är mer effektiv än avtagbar för bakåtförflyttning av första stora kindtanden i överkäken och att sidoeffekter (1-2 mm ökat överbett) blir följden av den fastsittande apparaturen. • Det är fortfarande svårt att via litteraturen dra några slutsatser om vilken typ av fast tandställning som är mest effektiv och därför behövs det ännu mer forskning om detta. / Maxillary molar distalization is a frequently used treatment method in cases with crowding associated with dental Class II molar relationship or Class I skeletal relationship. Despite the fact that several studies have been published concerning the treatment outcome of different appliances for distal movement of maxillary molars, it is still difficult to interpret the results and evidence presented in these studies because a variety of study designs, sample sizes and research approaches exists. In view of this, well-designed randomized clinical trials comparing patient compliant and non patient compliant extra- and intraoral appliance as methods of distalizing maxillary first molars is desirable as well as a systematic review of the present knowledge. Furthermore, there is a need for further evaluations and knowledge about the most appropriate time to move maxillary molars distally, i.e. evaluation of movement efficiency including anchorage loss before and after eruption of second maxillary molars. The overall aim of this thesis was to evaluate the outcome measures by distalizing maxillary molars with either the conventional extraoral traction (EOA) or a intraoral fixed appliance (IOA) and also to evaluate the optimal timing of distalizing treatment – either before or after the eruption of the second maxillary molars. This thesis was based on two studies and a systematic review included in the frame story: Paper I was a randomized controlled trial involving 40 patients in orthodontic treatment. The study evaluated and compared the treatment effects of an EOA and an IOA for distal molar movement of maxillary first molars. Paper II was a retrospective study involving 40 patients evaluating the maxillary molar distalization and anchorage loss in two groups, one before (MD 1 group) and one after eruption of second maxillary molars (MD 2 group). The systematic literature search was made in 4 different databases to determine what appliances for distal molar movement of maxillary molars have been evaluated in an evidence based manner and with focus on the most efficient method and outcome of molar movement and anchorage loss. Also, the evidence-based standard of Paper I and II was evaluated. These conclusions were drawn: • The IOA was more effective than the EOA to create distal movement of maxillary first molars, and thus, for the clinician the IOA is the most favourable method. • Moderate and acceptable anchorage loss was produced with the IOA implying increased overjet whereas the EOA created decreased overjet. • The two appliances did not have any considerable corrective effect on Class II skeletal relationships and these appliances shall therefore only be used in cases of moderate dental sagittal discrepancies and arch-length deficiencies. • The most opportune time to move maxillary first molars distally is before eruption of the second molars, since molar movement is then most effective and the anchorage loss lesser. • There is limited level of evidence that intraoral appliance is more efficient than extraoral to create distal movement of maxillary molars and that anchorage loss was produced with the intraoral appliance. • It is still difficult to draw any conclusions as to which of the intraoral appliances that were the most effective, and therefore, more RCTs are desireable.

No / The study investigated the role of endothelin (ET) and the ET receptor subtypes ETA and ETB in mediating longitudinal contraction in the mouse proximal and distal colon. Cumulative concentration¿response curves to a range of ET agonists (ET-1, ET-2, ET-3, (Ala1,3,11,13) ET and IRL 1620) were established by administering concentrations ranging from 0.01nM to 0.3¿M. Concentration¿response curves to ET-1, which exhibits a high affinity for both ETA and ETB receptor subtypes, were also established in the presence of the ETA antagonist BMS 182874 and the ETB antagonist IRL1038. The addition of the selective ETA receptor antagonist BMS 182874 caused a rightward shift of the concentration¿response curve to ET-1 in both sections of the colon. The ETB receptor antagonist IRL1038 (0.3¿1¿M) did not significantly effect the response to ET-1 in the proximal colon but caused a significant decrease in response towards higher concentrations ranges (3nM) in the distal colon. A comparison of the concentration¿response curves to ET-1, ET-2 and ET-3 showed a rank order of potency ET-1ET-2ET-3 in the proximal colon and ET-1ET-2ET-3 in the distal colon. The selective ETB receptor agonists, (Ala1,3,11,13) ET and IRL 1620 did not produce any response in the proximal sections of the colon but produced a smaller contraction in the distal segments. The data indicate that ET can contract the proximal tissues of the mouse colon predominantly via ETA receptors and in the distal tissues via ETA and ETB receptors.

No description available.

Each year, thousands of femoral and tibial internal fracture repairs are performed by orthopedic surgeons in the United States. Internal fixation of long bones using intramedullary nails (IMN) has decreased incidence of non-union, allowed shorter hospitalization time, and earlier weight bearing for the patient compared to other fixation methods. Orthopedic surgeons have expressed that one of the most difficult parts of this intramedullary nailing of long bones, is locating and drilling the interlocking screw holes. IMN interlocking requires the surgeon to locate the holes in the nail, center the drill, and advance the bit through the bone to meet them. Many novel procedures and devices have been developed to assist the surgeon in distal locking of intramedullary nails, but have some disadvantages. These can include the need for extensive x-ray exposure, expensive x-ray equipment, high power consumption, active electronics in vivo, soft tissue damage, which all lead to inaccurate screw placement. For these reasons, a new prototype device for locating and drilling IMN distal interlocking holes has been developed. This prototype device uses magnetic sensors to locate a permanent magnet placed at a know distance from the IMN interlocking hole. A drill sleeve may be attached to the targeting sensors so that when they are aligned with the target magnet, the drill sleeve is aligned with the axis of the interlocking hole to be drilled. This new prototype device has significant advantages over existing devices, including the following. It has no active or passive electronics in vivo, no x-ray imaging is needed for targeting, while allowing real time feedback of alignment. It is a percutaneous technique, which can be adapted for use with existing IMN's. The new prototype also has low power requirements allowing battery operation, a single target magnet with unique axisymmetric field and novel magnet orientation, and adjustable sensitivity. Additionally, the new device allows visual, audible, or tactile positioning feedback. This prototype magnetic targeting device can improve orthopedic surgeons' ability to target and drill distal IMN interlocking screw holes. This device may allow shorter surgery, decreased x-ray exposure, and fewer complications for the surgeon and patient. / Master of Science

O uso da ultrassonografia na anestesia regional teve um crescimento vertiginoso nos últimos anos, devido ao grande progresso na resolução das imagens ultrassonográficas, permitindo a visibilização não só de vasos, mas de raízes nervosas e nervos periféricos. O objetivo do presente trabalho consistiu na avaliação ultrassonográfica do plexo braquial pela via axilar, bem como a identificação dos nervos em relação a artéria axilar. Foram utilizados 50 animais da espécie canina, sem distinção de raça, sexo e idade. Em todos os animais administrou-se propofol (3 mg/kg) através de um acesso venoso pré-instalado. Os animais foram mantidos sonolentos, porém facilmente despertáveis durante todo o procedimento. Após posicionamento do animal e iniciada a avaliação ultrassonográfica com a identificação das estruturas vasculares e nervosas, foi introduzida uma agulha eletricamente isolada guiada por estimulador de nervo periférico, obtendo-se, assim, resposta motora adequada para cada nervo visualizado por meio de uma corrente estimuladora de 0,5 mA. O exame teve como objetivo identificar a artéria axilar e os nervos radial, mediano e ulnar, e anotar suas posições. Para relacionar os nervos à artéria axilar, a região a ser estudada foi dividida em quatro setores. Em todos os pacientes estudados foram identificados os nervos: mediano localizado na região craniolateral (setor 4) em 8% dos pacientes e na região craniomedial (setor 1) em 92%; nervo radial na região craniomedial (setor 1) em 2% dos pacientes, caudomedial (setor 2) em 92% e caudolateral (setor 3) em 6%; nervo ulnar encontrado na região craniolateral (setor 4) em 2% dos animais e na região craniomedial (setor 1) em 98%. Diante dos resultados, conclui-se que a artéria axilar, na abordagem estudada, facilita a identificação e posicionamento dos nervos com o auxílio do estimulador de nervos periféricos e da ultrassonografia. / The use of ultrasonography in regional anesthesia has grown rapidly in recent years, due to the great progress in the resolution of ultrasound images, allowing the visualization not only of vessels, but of nerve roots and peripheral nerves. The objective of the present study consisted in the ultrasonography evaluation of the brachial plexus by the axillary way, as well as the identification of the nerves in relation to the axillary artery. Fifty animals of the canine species were used, without distinction of race, sex and age. Propofol (3 mg/kg) was given in all animals via pre-installed venous access. The animals were kept drowsy but easily aroused throughout the procedure. After the positioning of the animal and the ultrasound evaluation with the identification of the vascular and nervous structures, an electrically isolated needle guided by a peripheral nerve stimulator was introduced, thus obtaining adequate motor response for each nerve visualized through a stimulating current of 0.5 mA. The objective of the test was to identify the axillary artery and the radial, median and ulnar nerves, and note their positions. To relate the nerves to the axillary artery, the region to be studied was divided into four sectors. In all the patients studied, nerves were identified: median located in the craniolateral region (sector 4) in 8% of patients and in the craniomedial region (sector 1) in 92%; radial nerve in the craniomedial region (sector 1) in 2% of patients, caudomedial (sector 2) in 92% and caudolateral (sector 3) in 6%; ulnar nerve found in the craniolateral region (sector 4) in 2% of the animals and in the craniomedial region (sector 1) in 98%. In view of the results, it was concluded that the axillary artery, in the approach studied, facilitates the identification and positioning of the nerves with the aid of the peripheral nerve stimulator and the ultrasonography.