Ischemic heart disease represents a leading cause of death worldwide. Ischemia denotes an insufficient supply of oxygenated blood to the heart due to occlusion of the coronary vessels. Timely reperfusion, i.e., restoring blood flow to the ischemic part of the heart, limits ischemic damage. However, reperfusion itself induces injury to the heart. This phenomenon is referred as ischemia/reperfusion (I/R) injury. Osteopontin (OPN), also known as cytokine Eta-1, is a cell-secreted extracellular matrix protein. Expression of OPN increases in the heart in response to a variety of pathological conditions. Mice lacking OPN exhibit exaggerated left ventricular dilation in non-reperfused model of myocardial remodeling. Cardioprotective role of OPN has also been demonstrated in a mouse model of repetitive I/R injury for 7 days. The objective of this study was to examine the role of OPN in modulation of systolic and diastolic parameters of the heart following I/R injury in a time-dependent manner. For this study, wild type (WT) and OPN knockout (KO) mice aged ~4 months were subjected to cardiac ischemia by the ligation of left anterior descending coronary artery (LAD). Following 45 min of ischemia, the LAD was reperfused by snipping the ligature. Heart function was measured using echocardiography at baseline, 3, 7, 14, and 27 days following I/R injury. M-mode echocardiographic images were used to calculate the systolic parameters (% fractional shortening [%FS], % ejection fraction [%EF], and end-systolic volume [ESV]), while pulse wave Doppler images were used to calculate diastolic parameter (aortic ejection time; [AET]). Global cardiac function was evaluated using myocardial performance index (MPI; a Doppler-derived index which combines systolic and diastolic functions). At basal levels, most of the systolic and diastolic parameters remained unchanged between the two groups. I/R injury decreased %FS and EF in both groups vs the baseline values at 3, 7, 14 and 27 days post-I/R. However, the decrease in %FS and EF was significantly greater in KO-I/R vs WT-I/R group. ESV was significantly higher in WT mice 7 days post-I/R, and stayed higher 14 and 27 days post-I/R vs baseline. However, the increase in ESV was significantly greater in KO mice 3 day post-I/R, and remained higher vs WT-I/R during the time course. AET was lower in WT group 14 days post-I/R vs baseline. On the other hand, AET was significantly lower in KO group 3, 7, 14 and 27 days post-I/R vs WT-I/R. MPI was higher in WT group 7 days post-IR vs baseline. MPI decreased significantly in WT group 27 days vs 7 days post-I/R. In KO group, MPI was significantly higher than WT mice at baseline, and remained higher 3 and 27 day post-I/R vs WT-I/R. Thus, lack of OPN decreases systolic and diastolic functional parameters of the heart following I/R injury, suggesting a cardioprotective role of OPN in myocardial remodeling post-IR.

Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease. However, they are predisposed to developing cancer or ischemic heart disease, and die 7-8 years earlier than the non-carriers. DNA double-strand breaks activate ATM, and active ATM is known to phosphorylate an extensive array of proteins involved in cell cycle arrest, DNA repair, and apoptosis. The importance of ATM in the regulation of DNA damage response signaling is fairly well-established. This review summarizes the role of ATM in the heart, specifically in cardiac remodeling following β-adrenergic receptor stimulation and myocardial infarction.

Marathon runners are prone to femoral stress fractures due to the high magnitudes and frequencies of lower extremity loads during training. Female runners tend to have a greater incidence of stress fracture compared to male runners. Sex-specific differences in body structure, joint pressure, and muscle activation patterns that influence bone remodeling may cause this observed difference in stress fracture occurrence. The goal of this thesis was to develop a finite element model of the femur during marathon training, then determine if marathon training affected bone properties of male and female runners differently. To achieve this goal, a finite element femur model was integrated with a bone remodeling algorithm. Sex-specific muscle and joint pressure loads corresponding to baseline activity and marathon training were applied to the finite element femur model. Axial strain, density, damage, and remodeling activity were quantified at regions predicted to be at high risk of stress fracture. The major results of this analysis predicted that marathon training increased bone damage at all regions of interest in both males and females, especially at the inferior neck. The model predicted that the superior neck, trochanter, and proximal diaphysis were more severely weakened in females than males after marathon training. While this model cannot directly quantify femoral stress fracture risk, it may be used to predict regions of bone weakness in male and female marathon runners. Future work may be done to improve accuracy of this model by using sex-specific femur geometry and bone remodeling parameters specific to male and female marathon runners. This model may be useful in future applications to study effectiveness of injury preventive methods, such as gait retraining, in reducing bone damage.

Introduction: Articular cartilage (AC) is a low friction load bearing material found in synovial joints. The natural repair of damaged tissue is difficult and often requires surgical intervention. With large defects it becomes necessary to match the original tissue geometry. We hypothesized that localized collagen (COL) and/or proteoglycan (PG) remodeling occurs during AC spherical reshaping. The objective of this study was to determine the presence, magnitude and depth dependence of COL and PG remodeling that accompanies AC reshaping. Methods: Full thickness AC blocks (7x7 mm2 surface area) were harvested from the ridges of the patellofemoral groove of immature (1-3 week old) bovine knees. The top 0-1 mm with intact articular surface was sliced off with a vibrating microtome. A 6 mm diameter disk was punched out of the slice and the most anterior edge was notched to mark directionality. The final sample was a 1 mm thick, 6 mm diameter disk with a notch on the most anterior edge. Samples were either not treated (day 0; D0) or allowed to free swell overnight in 20% FBS. Then cultured samples were placed in culture with 20% FBS in either free swelling (FS), static bending with the articular surface concave (concave) or in static bending with the articular surface convex (convex). Wet-weight and opening angle were measured before and 2 hours after removal from culture. Following culture, samples were cut in half in the anterior posterior direction. One half of each sample was frozen and later analyzed for PG, COL and cell content. The other half was fixed for 24-48 hours in 4% paraformaldehyde; samples were then transferred to 20% Hexabrix for 24 hours before imaging by micro-computed tomography (μCT) to assess PG distribution. Following μCT, samples were again placed in 4% paraformaldehyde for 24-48 hours and then prepared for qPLM to assess collagen orientation (α), parallelism index (PI), and area fraction of non-birefringent tissue (AFNBR). Variations were assessed by ANOVA with post hoc tests for significant ANOVA (pResults: Four days of spherical bending significantly changed (pDiscussion: Spherical bending reshapes AC into a cup shape. Trends of decreasing α standard deviation (αSD) with depth in concave samples and increasing αSD with depth in convex samples indicate that COL matrix disorganization is associated with regions of compressive strain. Consequently, further evaluation on the disorganization of the collagen network should be studied to elucidate mechanisms of cartilage reshaping.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13515号 / 論医博第2265号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 湊谷 謙司, 教授 石見 拓, 教授 江木 盛時 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Israel’s spatial imaginary, as an unsettled project, is in constant negotiation, revision, and transmutation. At the heart of this dissertation is an ethnographic endeavor driven by a reading of the past, present, and future of political and religious struggles in Israel/Palestine through an analysis of actors, practices, and material palimpsests of three sites: a French Mandate building and former Syrian military base in the Golan Heights, turned into a boutique hotel by a security entrepreneur; the longed-for and imagined Third Temple in Jerusalem—today’s Temple Mount—a once marginal messianic scheme currently in revival; and the Jaffa Ottoman train station, reopened as a high-end shopping center and later as a light rail station. Through these sites, this dissertation asks how Israel understands itself vis-à-vis its narrative of a biblical past, its present ‘indigenous’ presence, and its vision or imaginaries of the future.

Indiana University-Purdue University Indianapolis (IUPUI) / It has been proposed that the accumulation of microdamage in bone of aging individuals may play a causative and synergistic role in increased fracture incidence. If microdamage production were somehow increased, or reparative remodeling was somehow decreased, the scales may tip towards pathologic fracture. It is known that bisphosphonates increase microdamage accumulation in ribs, lumbar vertebrae, and ilium. The specific aim of this study was to histomorphometrically quantify the microdamage effect of the bisphosphonates alendronate and risedronate therapy on alveolar bone surrounding the first mandibular molar in the dog to determine if this response differs from that in non-bisphosphonate treated dogs. Thirty-four dogs were randomly assigned in two test, and one control groups. Test groups received pharmacologically equivalent doses of either alendronate (11 dogs) or risedronate (11 dogs). The control group (12 dogs) received subcutaneous injections of saline solution. The mandibular right first molar was analyzed for this study. Histomorphometric measurements were made using a x150 Nikon Optiphot-2 fluorescence microscope equipped with brightfield sources (Nikon, Inc.) using the semi-automatic Bioqant digitizing system (R & M Biometrics). There was no significant differences in cortical bone area across treatment groups for any of the regions, nor were any expected. Overall, there was almost twice as much crotical bone found in the Middle (Combined) regions compared with the Coronal (Combined) regions. The precent cortical area was universally high across all treatment groups averaging in the mid-90% range. The Apical region averaged 96.05%, followed by the Coronal region with 95.04% and the Middle region with 93.80%. The number of labeled osteons per cortical area in the alendronate and risedronate groups both tended to be lower relative to the control group (0.92/mm2 and 0.93/mm2 vs. 1.26mm2, respectively), but were not significantly different. On average, the coronal regions had nearly three times the LOn/CtAr as the Middle and Apical regions (1.90/mm2 vs. 0.63/mm2 and 0.57/mm2 respectively). Only in one region was MAR statistically higher in the Coronal (1mm) region, relative to all other regions compared. The Middle region demonstrated a low MAR. The WTh was significantly higher in the risedronate and alendronate groups than that of the control group for the Coronal region. This illustrates that with respect to the bisphosphonates, there is more formation and less resorption. In one region of a significantly lower WTh for the alendronate group relative to the risedronate group was noted. This implies a more potent inhibition in the risedronate treated groups. The WTh for the entire Coronal was statistically lower than every Middle measurement, but was not different than observed in the Apical region. This would tend to signify that in the Coronal, the turnover rate is more of a rapid nature, and therefore the osteons are not as large, while in the Apical, there were so many missing values due to the low rate of turnover, the numbers are skewed to the low end. In the Coronal (Combined) region, the risedronate (108.79 days) group exhibiting a significantly higher FP than the alendronate (62.88 days) and the control (56.13 days) groups. This would imply an increased potency of risedronate over alendronate. Regionally, the FP was significantly lower in the Coronal, relative to Middle or Apical. This is consistent with a more rapid turnover in the Coronal regions observed earlier. The Acf for alendronate (6.41/mm2 per day) and risedronate (5.69/mm2 per day) both tended to be lower by approximately 40% when compared with the control group (10.11/mm2 per day). Overall, the Acf for the Coronal region was 14.15/mm2 per day vs. 2.98/mm2 per day for the Middle and 9.13/mm2 per day for the Apical regions. This shows a significantly increased amount of turnover events taking place not just in the Coronal region, but in the region immediately adjacent to the tooth in the Coronal region. In no region did bone formation differ significantly when treated with bisphosphonates. The Coronal (1mm) region was statistically greater than every region it was measured against, individual and combined. Based on this observation, the second hypothesis that within the first molar alveolar site, bisphosphonate therapy with alendronate, and risedronate would inhibit remodeling more in the coronal region than in the middle and apical region, is rejected. When measuring microdamage accumulation (CrDn), only in the Middle (1mm) region was a significant difference across treatment groups notes. There were no other statistical differences across groups for any other regions. This observation demonstrates that bisphosphonate treatment does not increase the accumulation of microcracks in the dentate alveolar bone. Therefore, the first hypothesis that within the dentate mandible, bisphosphonate therapy with alendronate and risedronate would increase microdamage accumulation around the first molar compound to control, is rejected. When CrDn was compared by region, significant differences were noted. As expected, the Coronal (1mm) region demonstrated a significantly increased CrDN compared with the Apical and Middle regions. Coupled with the information that the BFR is increased in the Coronal and Middle (1-3mm) regions would argue for a reparative function of remodeling in the Coronal and outer Middle regions, which is in response to microdamage accumulation. Significant differences were observed in the Middle (1mm) and Middle (Combined) regions, with the alendronate group demonstrating an increased CrSDn relative to control. There was no statistical difference across treatment groups for any of the regions studied. When compared by regions, the Coronal (1mm) was statistically higher than all regions it was measured against. The Middle regions demonstrated elevated CrSDn relative to the apical region, which displayed the lowest CrSDn values of all regions. One final measure of microdamage is mean crack length. There were no statistically significant differences across any groups for any regions. The only significant differences, when observed across regions, was in reference to the Middle (1mm) region, which was significantly larger than the Coronal (1mm), Coronal (Combined), and the Middle (1-3mm) region. Otherwise, there is no observable trend, and no significant difference between regions. In conclusion, this study found that there was no an increase in microdamage in the dentate mandible of the dogs with bisphosphonate therapy, thereby rejecting the first hypothesis. While there were isolated regions of remodeling inhibition, the hypothesis that bisphosphonate therapy would inhibit remodeling more in the coronal region than in the middle and apical region is rejected. Therefore, based on the findings of this study, we conclude that bisphosphonates do inhibit remodeling in the dentate alveolus generally, but inhibition is not localized to any particular region. Finally, the administration of bisphosphonates do not result in an increase in microdamage accumulation in the dentate alveolus of dogs.

ROT-projekt allmänt är ganska återkommande i Sverige och utomlands. Till exempel spenderas drygt 38% av alla investeringar inom bostadsmarknaden på antingen renovering eller ombyggnation. Dessa projekt brukar ha många svårigheter och risker, bland annat oförutsägbarhet, bristfälliga handlingar/ritningar, många intressenter, hantering av kvarsittande hyresgäster samt grannar, brist på erfarenhet hos de olika parterna, mm… Tyvärr har dessa svårigheter varit en stor utmaning för byggentreprenörer under en lång period och väldigt få forskningar har försökt lösa dessa problem och optimera ombyggnationsprocessen. Det här examensarbetet kommer att försöka optimera ROT-projekt med hjälp av Lean och med fokus på standardisering. Författaren av detta examensarbete skulle nästan våga påstå att den här studien är väldigt unikt i sitt slag och kan räknas som ett pilotprojekt för tillämpning av standardisering inom ROT-projekt. För det här syftet har författaren samarbetat med en traditionell byggentreprenör där han fick vara med i ett ROT-projekt (fasadrenovering, byte av fönster, byte av värmestamm, mm…). Vissa arbetsmoment inom det ROT-projektet var repetitiva och då har kunnat metodstandarder tillämpas och resultatet av tillämpningen studerats och analyserats i denna rapport. Författaren har även intervjuat verksamma personer från byggentreprenörsidan samt beställarsidan och även en hyresgäst för att kunna jämföra resultaten från de äldre studierna om Lean och standardisering med hur tillämpas standardisering inom ROT-projekt. Resultatet från detta examensarbete visade att standardiseringen bidrar till att minska oförutsägbarheten inom ROT-projekt och hjälper byggentreprenören att ta fram en träffsäker tidplan samt budget. Det bidrar även till att uppnå den önskade kvalitén på det utförda arbetet samt minimera slöserierna inom byggbranschen som uppskattas till 30% av den totala produktionskostnaden. Resultaten visade också att det finns en stor brist på kunskap på hur kan Lean, särskilt standardisering tillämpas inom ROT-projekt. Resultaten har även visat att standardiseringen och det kontinuerliga förbättringsarbetet av standarderna inte leder till en bestående förbättring som fallet är när man sysslar med nyproduktion. Utan att de nya överraskningarna som drabbar produktionen leder till en viss försämring av resultatet, vilket gör att förbättringen inte blir bestående. Detta var säkert ett bevis på att det är dags att börja forska om tillämpningen av Lean och standardisering inom ROT-projekt, för de nuvarande studierna är baserade på nyproduktion och resultaten från dessa studier går inte att använda när man sysslar med ROT-projekt. Slutligen vill författaren gärna att forskarna börjar titta mer på det området och hoppas att det här examensarbetet blir som ögonöppnare för de. Författaren hoppas även att universitet och högskolor börjar undervisa separata ämnen som handlar om ROT-projekt och dess utmaningar och möjligheter. ROT-projekt är återkommande projekt som inte påverkas av konjunkturläget och branschen behöver säkert nyexaminerade ingenjörer som är kompetenta för att driva dessa projekt. / Renovation and remodeling projects in general are quite recurring in Sweden and abroad. For example, just over 38% of all investments in the housing market are spent on either renovation or remodeling. These projects usually have many difficulties and risks, including unpredictability, deficient documents / drawings, many stakeholders, managing of remaining tenants and neighbors, lack of experience on the part of the various parties, etc.… Unfortunately, these difficulties have been a major challenge for construction contractors for a long period and very little research has attempted to solve these problems and optimize the remodeling process. This thesis will try to optimize renovation and remodeling projects with the help of Lean and with a focus on standardization. The author of this thesis would almost dare to say that this study is unique in its kind and can be counted as a pilot project for the application of standardization in renovation and remodeling projects. For this purpose, the author has collaborated with a traditional building contractor where he was involved in a renovation and remodeling project (facade renovation, replacement of windows, replacement of heating installation, etc.…). Some work within the remodeling project were repetitive and then it was possible to apply method standards and the results of the application were studied and analyzed in this report. The author has also interviewed active people from the construction contractor side as well as the client side and a tenant to be able to compare the results from the older studies on Lean and standardization with how standardization is applied within renovation and remodeling projects. The results from this thesis showed that the standardization helps to reduce the unpredictability within renovation and remodeling projects and helps the construction contractor to develop an accurate schedule and budget. It also contributes to achieving the desired quality of the work performed and minimizing the waste in the construction industry, which is estimated at 30% of the total production cost. The results also showed that there is a great lack of knowledge on how Lean can be applied, especially standardization within renovation and remodeling projects. The results have also shown that the standardization and the continuous improvement of the standards do not lead to a permanent improvement, as is the case when dealing with new production. The new surprises that affect production leading to a certain deterioration of the result, which means that the improvement will not be consisting. This certainly proof that it is time to start researching the application of Lean and standardization in renovation and remodeling projects, because the current studies are based on new production and the results from these studies cannot be used when working with renovation and remodeling projects. Finally, the author would like the researchers to start looking more at that area and hope that this thesis will be an eye opener for them. The author also hopes that universities and colleges will start teaching separate subjects about renovation and remodeling projects, their challenges and opportunities. renovation and remodeling projects are recurring projects that are not affected by the economic situation and the industry certainly needs newly graduated engineers who are competent to run these projects.

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