Matrix metalloproteinase-2 (MMP-2, gelatinase A, type IV collagenase) is a member of a family of zinc-dependent metalloendopeptidases that functions in the degradation of elastin, collagens, and other components of extracellular matrix (ECM). Both secretion and activation of MMP-2 are elevated in human atherosclerotic lesions and abdominal aortic aneurysms (AAA). In this dissertation project, we sought to test the hypothesis that MMP-2 plays a critical role in both atherosclerosis and AAA. We also sought to determine the detailed mechanism. We first examined the atherosclerosis and AngII-induced AAAs development in MMP-2-/- x apolipoprotein (apoE)-/- mice in vivo. It was surprising that MMP-2 deficiency did not reduce the incidence of AngII-induced AAAs or the size of atherosclerosis in apoE-/- mice. However, the cellular and ECM content of atherosclerotic plaques were modified in MMP-2-/- x apoE-/- mice as compared to MMP-2+/+ x apoE-/- control mice. To explain the apparent paradox between this result and the hypothesis, we investigated the morphological characteristics of the aortic wall of MMP-2-/- mice. We detected an enhanced MMP-9 level in the aortic wall of MMP-2-/- x apoE-/- mice compared with MMP-2+/+ x apoE-/- mice. Interestingly, we also observed more branching of the elastin fibers in aortic wall of MMP-2-/- mice as compared with aorta of wild type mice. We also examined the behavior of macrophages from MMP-2-/- mice. Reduced adhesion, migration, and expression of integrin beta 3 were detected in MMP-2 deficient macrophages compared with wild type macrophages. Lastly, we examined whether MMP-2 deficiency in bone marrow-derived cells may influence AAAs and atherosclerosis using bone marrow transplantation technique. There was a significant reduction of both atherosclerosis development and AAAs formation in mice that were reconstituted MMP-2-/- bone marrow cells. In conclusion, the findings in this dissertation suggest that MMP-2 might play an important role in atherosclerosis and aneurysm through influencing inflammatory cell infiltration.

No description available.

Aging is associated with increased insulin resistance, a condition in which the tissue response to insulin-stimulated glucose uptake is reduced. Insulin resistance is a strong predictor of disease and mortality. Aging is also associated with a decline in physical activity, lower cardiorespiratory fitness (ability to deliver oxygen to active muscles during exercise), and increase in abdominal fat. Both low cardiorespiratory fitness (CRF) and excess abdominal fat are associated with reduced insulin sensitivity in older adults. Improvements in CRF and abdominal obesity through exercise training may be responsible for improvement in insulin sensitivity. Several investigations have reported that changes in CRF and abdominal obesity through exercise are associated with changes in insulin sensitivity. To our knowledge, no prior study has assessed whether change in CRF or abdominal fat alone explains the association between exercise and improvement in insulin sensitivity in older adults. Our findings suggest that improvement in CRF may not explain the exercise-induced change in insulin sensitivity. The improvement in insulin sensitivity from exercise is explained through a decrease abdominal fat that also occurs with exercise. Additionally, improvements in waist circumference, a surrogate measure for abdominal obesity, and body mass index together explained a large portion of exercise-induced change in insulin sensitivity compared to either variable alone. Our findings suggest that exercise combined with a healthy diet will improve insulin resistance, a risk factor for development of type 2 diabetes and cardiovascular disease in older adults. Our findings suggest that the reduction in abdominal obesity is the conduit by which exercise improves insulin sensitivity in older adults. Although CRF is not related to exercise-induced change in insulin sensitivity, change in CRF from exercise has been reported to decrease risk for other health conditions, such as hypertension and all-cause mortality. Our findings suggest that clinicians should measure both waist circumference and body mass index when evaluating the effectiveness of a lifestyle-based treatment strategy for improving insulin resistance and its associated health outcomes in older adults. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2013-09-27 14:53:00.796

Introducción: La cavidad abdominal contiene órganos vitales vulnerables de sufrir lesiones por trauma abdominal. Esta emergencia debe recibir manejo quirúrgico de inmediato, cuya evolución clínica posterior dependerá de varios factores. Objetivo: Determinar las características clínicas del periodo postquirúrgico inmediato y mediato del trauma abdominal en el servicio de cirugía del Hospital San Juan de Lurigancho durante el periodo 2012-2014. Materiales y métodos: Estudio descriptivo, retrospectivo y transversal. Se revisó historias clínicas de pacientes que recibieron manejo quirúrgico de emergencia por trauma abdominal y se hospitalizaron en el servicio de cirugía. Resultados: Se revisó 50 historias clínicas, la edad promedio fue 30.8 años, la mayoría tienen entre 20 y 39 años y 47 fueron varones. 43 pacientes ingresaron por trauma abdominal abierto, 24 de ellos por proyectil de arma de fuego (PAF) seguido de 19 pacientes por arma blanca. 20 pacientes presentaron lesión de colon y 19 pacientes de intestino delgado. 17 presentaron alguna complicación en el postquirúrgico, la mayoría en el periodo mediato. Se presentó 5 casos de fiebre en el postquirúrgico inmediato y 13 en el mediato, el resangrado se presentó en 2 pacientes en cada periodo. Los pacientes se hospitalizaron 12.4 días en promedio. Conclusiones: Las lesiones por PAF fueron los mecanismos más frecuente de trauma abdominal y la mayoría presentaron lesión de colon. La complicación más frecuente fue la infección del sitio operatorio más fiebre. La mitad de los pacientes sometidos a relaparotomía fue por retiro de packing.

Introduction. Inflammatory bowel disease (IBD) is a condition affecting more than 3 million people in Europe and the USA combined. Patients report pain as one of the most severe and debilitating symptoms leading to a lower quality of life. Current analgesics lack efficacy for the treatment of visceral pain or produce unacceptable side effect profiles. New targets are needed. Aims and methods. The aim of this thesis was to examine the activation of primary visceral afferents in C57BL/6 mice in response to biopsy supernatants from paediatric patients with IBD (Crohn's disease and ulcerative colitis) and functional abdominal pain syndrome (FAPS). By comparing the expression of pro-inflammatory and pro-nociceptive mediators in these biopsy samples with patient pain scores and afferent nerve recording activation, we identified putative mediators likely to be responsible for causing pain. The ability of inflammatory mediators to drive visceral nociception was then examined by their exogenous application in recordings of mouse and human visceral nociceptor activity. Results. Nerve activation increased significantly in response to biopsy supernatants from FAPS, CD, and UC patients, when compared to controls. Supernatant IL-8, TNFα, IL-6 and IL-1β, levels were increased in IBD samples compared with control patients. Analysis of mRNA expression also showed high levels of pro-inflammatory cytokines and raised MMP-1, MMP-3, MMP-9, MMP-12, and MMP-19 in IBD samples. The expression of MMP-12 in biopsy samples from Crohn's patients significantly correlated with afferent firing suggesting a causative role. This was confirmed by exogenously application of MMP-12 stimulated afferent firing and sensitised responses to mechanical stimulation and inflammatory mediators. UC samples showed TIMP-1 as an effective inhibitor of afferent firing. Conclusion. Data from this study demonstrates that the bowel of patients with IBD and FAP releases pro-nociceptive mediators which stimulate visceral afferents. MMP's play an important role in the afferent activation mediated by IBD samples suggesting that exploiting the endogenous inhibitor TIMP-1 could be a key target for future therapeutic strategies.

Made available in DSpace on 2015-04-14T13:33:06Z (GMT). No. of bitstreams: 1 449976.pdf: 1321049 bytes, checksum: d77a12eb76bfeca437aa2b97c8365822 (MD5) Previous issue date: 2013-06-28 / Importance: Obesity has become a major public health problem due to its growing prevalence in recent decades and its comorbidities. Many studies have related abdominal fat to metabolic abnormalities and increased risk of cardiovascular diseases in adults, but there are few studies that have examined these questions in adolescents. Atherosclerotic disease is the major cause of morbidity and mortality around the world. Atherosclerosis has been demonstrated to begin in childhood and measurement of carotid artery intima-media thickness (cIMT) by ultrasonography (US) can be used to evaluate cardiovascular risk in this population. Whether the thickness of arterial wall increases with body mass index (BMI) is still a matter of debate. Objective: The purpose of this study was to assess the association between ultrasound measurements of abdominal fat and automated US measurements of cIMT with anthropometric and laboratory data in a group of adolescents in order to identify potential markers that may be used to control the development of risk factors for cardiovascular disease in adolescents. Patients and Methods: Forty-five patients aged 10 to 17 years were enrolled in this study voluntarily. The subjects were evaluated in a pediatric outpatient clinic at either the Instituto da Crian?a da Universidade de S?o Paulo in S?o Paulo or the Hospital S?o Lucas da Pontif?cia Universidade Cat?lica do Rio Grande do Sul in Porto Alegre. Adolescents were classified as obese or eutrophic according to their body mass index z-score for Brazilian children and adolescents. We determined waist circumference, waist-to-height ratio and conicity index from all subjects. We obtained blood samples from all subjects after 12 hours of fasting to measure glycemia, triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, insulin, and apolipoprotein B levels. We calculated the patients HOMA-IR index, a mathematical model that quantifies insulin resistance based on the formula: HOMA-IR = fasting Insulin (μUI/mL) x fasting glucose (mmol/L) / 22.5. All patients received an ultrasound assessment of subcutaneous tissue, pre-peritoneal fat, and intra-abdominal fat and all of them received an US assessment of the common carotid artery intima-media thickness. Results: Ultrasonographic measures of abdominal fat were found to be associated with anthropometric measurements, glucose level, insulin level, and HOMA-IR (except glucose and maximal pre-peritoneal fat). In our multivariate analysis, body mass index z-score, conicity index, and HOMA-IR remained independently associated with the subjects sum of fat. Only minimal subcutaneous fat associated independently with HOMA-IR. In relation to the vascular US evaluation, cIMT was not associated with sex or BMI z-score. However, cIMT on both the right and the left sides was found to associate positively with height. Additionally, cIMT on the right side was found to associate positively with waist circumference and HOMA-IR, and negatively with apolipoprotein B levels. In our multivariate analysis, only height remained independently associated with cIMT (right and left). Conclusions: Subcutaneous fat may be more useful than visceral fat as a marker for insulin resistance in adolescents. In the US measurements of both cIMT, only height was independently associated with this automated method. Further studies should be conducted on a prospective basis in order to identify potential markers that could be used to prevent the development and progression of cardiovascular pathology in pediatric patients. / Import?ncia: A obesidade tornou-se um importante problema de sa?de p?blica devido ? sua preval?ncia crescente nas ?ltimas d?cadas e suas comorbidades. Muitos estudos t?m relacionado gordura abdominal com anormalidades metab?licas e com aumento do risco de doen?as cardiovasculares em adultos, mas poucos estudos examinaram essas quest?es em adolescentes. A doen?a ateroscler?tica ? a principal causa de morbidade e mortalidade em todo o mundo. A aterosclerose inicia-se na inf?ncia e a medida ultrassonogr?fica da espessura m?dio-intimal carot?dea (EMIC) por ultrassonografia (US) pode ser usada para avaliar o risco cardiovascular nessa popula??o. Ainda ? uma quest?o de debate se a espessura da parede arterial aumenta com o ?ndice de massa corporal (IMC). Objetivo: O objetivo deste estudo foi avaliar a associa??o entre as medidas ultrassonogr?ficas de gordura abdominal e as medidas ultrassonogr?ficas automatizadas da EMIC, com dados antropom?tricos e laboratoriais em um grupo de adolescentes, a fim de identificar potenciais marcadores que possam ser usados para controlar o desenvolvimento de fatores de risco para doen?a cardiovascular. Pacientes e m?todos: Quarenta e cinco pacientes com idade entre 10 e 17 anos foram inclu?dos neste estudo de forma volunt?ria. Os indiv?duos foram avaliados ambulatorialmente no Instituto da Crian?a da Universidade de S?o Paulo, em S?o Paulo, e no Hospital S?o Lucas, da Pontif?cia Universidade Cat?lica do Rio Grande do Sul, em Porto Alegre. Os adolescentes foram classificados como obesos ou eutr?ficos, de acordo com seu escore-z de IMC (adaptado para as crian?as e adolescentes brasileiros). Determinou-se a circunfer?ncia abdominal (CA), a raz?o entre a circunfer?ncia abdominal e estatura (CA:A) e o ?ndice de conicidade (IC) de todos os pacientes. Amostras de sangue foram obtidas de todos os indiv?duos ap?s 12 horas de jejum para medi??o da glicemia, triglicer?deos (TG), colesterol total (COL), HDL-colesterol (HDL), LDL-colesterol (LDL), insulina e apolipoprote?na B (apoB). O ?ndice HOMA-IR (Homeostasis Model Assessment), modelo matem?tico que quantifica a resist?ncia ? insulina por meio da f?rmula: HOMA-IR = Insulina jejum (μUI/mL) x Glicose jejum (mmol/L) / 22,5, foi calculado, e todos os pacientes receberam uma avalia??o ultrassonogr?fica das gorduras (subcut?nea, pr?-peritoneal e intra-abdominal) e da EMIC. Resultados: As medidas ultrassonogr?ficas de gordura abdominal associaram-se com as medidas antropom?tricas, a glicose, a insulina e o HOMA-IR (exceto glicose e gordura pr?-peritoneal m?xima). Na an?lise multivariada, o escore-z do IMC, o IC e o HOMA-IR permaneceram associados de forma independente com o somat?rio de gordura dos pacientes. Apenas a gordura subcut?nea m?nima associou-se de forma independente com o HOMA-IR. Em rela??o ? avalia??o ultrassonogr?fica vascular, a EMIC n?o foi associada com o sexo ou com o escore-z do IMC. No entanto, EMIC de ambos os lados associou-se positivamente com a altura. Al?m disso, EMIC direita associou-se positivamente com CA e com o HOMA-IR e negativamente com os n?veis de apoB. Na an?lise multivariada, apenas a altura permaneceu independentemente associada com EMIC (direita e esquerda). Conclus?es: A gordura subcut?nea pode ser mais ?til do que a gordura visceral como um marcador para a resist?ncia ? insulina em adolescentes. Na aferi??o ultrassonogr?fica da espessura m?dio-intimal carot?dea, apenas a altura foi independentemente associada com esse m?todo automatizado. Estudos adicionais devem ser conduzidos de forma prospectiva, a fim de identificar potenciais marcadores que possam ser utilizados para evitar o desenvolvimento e a progress?o de patologias cardiovasculares em pacientes pedi?tricos.

Abdominal aortic aneurysms are a focal dilation of the aorta which can be potentially life threatening if left untreated. Endovascular aneurysm repair (EVAR) is a noninvasive treatment that can reduce the mortality rate when compared to the standard open repair. Yet, EVAR is associated with other complications that can arise such as migration, endoleaks, or device related failures. These complications drive the need for reinterventions which have been shown to occur more frequently with EVAR than with open repair. The long term fixation and sealing characteristics of these devices is likely related to the nature of its apposition to the aortic wall. Currently there is little understanding of these mechanics and factors in how the device performs at the time of deployment. A computational model that reflects the compressive nature of an endovascular graft is beneficial in investigating these mechanics. The aims of the study are; 1) formulate an experimental methodology that captures the radial compressive nature of the stent graft, 2) develop a parameterized finite element model of the stent structure, and 3) compare the compressive behavior this model against the acquired experimental data. A 2 mil polyethylene sleeve was used to transfer a compressive vacuum pressure from the sleeve onto 10 independent stent grafts. The loading-unloading pressure was cycled from 0 to -50 mmHg (complete collapse) over 5 minutes. A pressure transducer and optical micrometer were used to capture the vacuum pressure and diameter relationship. All ten grafts compressed in a similar elliptical shape configuration. Commercial software was leveraged to construct a parameterized model of the stent geometry. All crest and trough vertex locations of the sinusoidal stent structure were validated within 1 mm of a measured value. A dynamic quasi-static computational simulation was completed that included large deformations and contact between the sleeve and stent as well as self-contact in the sleeve. Our results show that the model is representative of the experiments and can be used to interrogate how a stent graft will perform during certain stages of deployment and immediately after deployment with some caution in regard to the stated limitations.

Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival. Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance. About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening. This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population. AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis. It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway. Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024). A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA. Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006. The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms. Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined. From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.

SAMMANFATTNING Buksmärtor är en av de vanligaste orsakerna till att människor söker sjukvård. Historiskt sett har smärtlindring till patienter med buksmärta varit restriktiv. Otillräcklig smärtlindring kan bero på rädsla för att smärtlindrande läkemedel ska dölja viktiga kliniska tecken som kan leda till diagnostiska svårigheter. Syfte: Att undersöka i vilken omfattning ambulanssjuksköterskan smärtlindrar patienter med buksmärta, i vilken utsträckning patienter smärtskattas samt om det föreligger någon skillnad mellan män och kvinnor när det gäller administrering av smärtlindrande läkemedel och omfattning av smärtskattning prehospitalt. Metod: En retrospektiv jämförande deskriptiv journalgranskning med kvantitativ ansats. Ett konsekutivt urval gjordes och sammanlagt granskades 200 journaler, varav 100 omfattade kvinnor och 100 omfattade män. Resultat: 21 % (n=42) av patienterna smärtlindrades. Det fanns ingen statistisk signifikans som visade att kvinnor och män smärtlindrades i olika omfattning. Det var 34,5 % (n=69) av patienterna som smärtskattades, och ingen skillnad mellan könen påvisades. Denna studie är av betydelse för specialistsjuksköterskor och andra personalkategorier som omhändertar patienter med buksmärta. Studien bidrar med kunskap som kan leda till att det prehospitala omhändertagandet av patienter med buksmärta utvecklas och förbättras. / ABSTRACT Abdominal pain is one of the most common reasons for seeking medical care. Historically, pain relief in patients with abdominal pain has been restrictive. Causes of inadequate pain relief could be fear that analgesics will mask important clinical signs that can lead to diagnostic difficulties. Aim: To investigate to what extent patients with abdominal pain receive analgesics, the extent to which patients’ pain is rated and if there is any difference between men and women in the administration of analgesics and the extent of prehospital pain measurement. Method: A retrospective comparative descriptive medical record review with quantitative data. A consecutive selection was made and a total of 200 medical records were reviewed, 100 involved women and 100 involved men. Result: 21 % (n=42) of the patients were given analgesics. Men and women were treated equally in terms of pain relief. There were 34,5 % (n=69) of the patients who were asked to estimate their pain, and no difference between sexes was detected. This study is relevant to healthcare professionals who treat patients with abdominal pain. The result of this study can be used in the development and the improvement of the prehospital care of patients with abdominal pain.

SammanfattningSyftet med föreliggande systematiska litteraturstudie var att undersöka om ingreppet total abdominal hysterektomi (TAH) påverkade kvinnors sexualitet. Ett andra syfte var att granska huruvida kvinnors psykiska välmående förändrades efter operationen. För att klarlägga problemen insamlades artiklar via databaserna Blackwell Synergy, CINAHL, Elin och Pubmed. Sammanlagt 18 artiklar bedömdes med granskningsmodeller utarbetade efter bedömningsmallar av Forsberg och Wengström (2003) för artiklar med kvantitativ respektive kvalitativ ansats. Inalles 13 artiklar bedömdes såsom godkända (G) och 5 artiklar såsom väl godkända (VG). Av 18 studier rapporterades i 10 artiklar förbättrad sexualitet. Det betyder upplevelsen av bättre orgasm, ökad sexuell tillfredställelse eller lust. Beträffande psykiska symptom rapporterades ökat välbefinnande och bättre livskvalitet i 3 artiklar samt minskad ångest och depression i 5 av artiklarna. Resultaten diskuterades i termer av vikten av informerat samtycke i samråd med hälso- och sjukvårdspersonal vid fattandet av beslutet att avstå från livmodern.