published_or_final_version / Anatomy / Master / Master of Medical Sciences

Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves [110]-116).

Thesis--Wisconsin. / Vita. Includes bibliographical references.

Submitted by GUSTAVO MUÇOUÇAH SAMPAIO BRANDÃO null (gubrandao@terra.com.br) on 2016-07-11T20:28:32Z No. of bitstreams: 1 Pentasaccharides para o tratamento da trombose venosa profunda - cópia.pdf: 2647553 bytes, checksum: 21a99ea1c79999dd8932b40302271db0 (MD5) / Rejected by Ana Paula Grisoto (grisotoana@reitoria.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo a orientação abaixo: O arquivo submetido está sem a ficha catalográfica. A versão submetida por você é considerada a versão final da dissertação/tese, portanto não poderá ocorrer qualquer alteração em seu conteúdo após a aprovação. Corrija esta informação e realize uma nova submissão contendo o arquivo correto. Agradecemos a compreensão. on 2016-07-12T19:07:50Z (GMT) / Submitted by GUSTAVO MUÇOUÇAH SAMPAIO BRANDÃO null (gubrandao@terra.com.br) on 2016-07-12T21:33:22Z No. of bitstreams: 2 Pentasaccharides para o tratamento da trombose venosa profunda - cópia.pdf: 2647553 bytes, checksum: 21a99ea1c79999dd8932b40302271db0 (MD5) Pentasaccharides para o tratamento da trombose venosa profunda - com ficha catalográfica.pdf: 2703945 bytes, checksum: d9034b6210add676a4f9b7cbf4c31ad3 (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-07-14T16:36:47Z (GMT) No. of bitstreams: 1 brandao_gms_dr_bot.pdf: 2703945 bytes, checksum: d9034b6210add676a4f9b7cbf4c31ad3 (MD5) / Made available in DSpace on 2016-07-14T16:36:47Z (GMT). No. of bitstreams: 1 brandao_gms_dr_bot.pdf: 2703945 bytes, checksum: d9034b6210add676a4f9b7cbf4c31ad3 (MD5) Previous issue date: 2016-05-25 / Pentasaccharides para o tratamento da trombose venosa profunda Questão da revisão: Os novos anticoagulantes da classe dos pentasaccharides podem ser uma alternativa eficaz e segura aos anticoagulantes convencionais utilizados na terapia padrão do tratamento da trombose venosa profunda? Visão geral: Trombose venosa profunda (TVP) é uma doença grave e potencialmente fatal que se caracteriza pela formação aguda de um coágulo de sangue nas veias profundas. Sua incidência aumenta exponencialmente com a idade e estima-se que na população geral, sua incidência seja de 5 casos em 10,000 habitantes. O tratamento padrão se faz por meio de medicamentos anticoagulantes, inicialmente pela administração de medicamentos injetáveis, as heparinas, por 5 a 7 dias e em seguida pelo uso prolongado de medicamentos de uso oral, os antagonistas da vitamina K. Entretanto, o alto risco de sangramento e a necessidade de um rigoroso controle laboratorial, permanecem como importantes limitações à terapia padrão. Os pentasaccharides são anticoagulantes sintéticos que podem apresentar vantagens em relação ao tratamento convencional como um efeito mais previsível, um regime de dosagem mais conveniente, a ausência da necessidade de controle laboratorial, ausência de interações com medicamentos e/ou alimentos, ausência da temida diminuição das plaquetas induzida pela heparina e em muitos casos melhor custo-benefício. Características chaves e resultados: Nossas buscas, realizadas até julho de 2015, identificaram 20 entre 730 registros que representavam 5 estudos elegíveis, compreendendo um total de 6981 pacientes. Os estudos compararam os pentasaccharides fondaparinux, idraparinux e idrabiotaparinux com a terapia padrão (heparina seguida por antagonista da vitamina K). O principal resultado de eficácia foi feito pela avaliação da incidência de qualquer episódio tromboembolismo venoso (novo episódio de TVP ou embolia pulmonar) durante o tratamento. E o principal resultado de danos foi incidência de sangramento. Esta revisão mostrou que os pentasaccharides (fondaparinux, e a dose de 2.5 mg de idraparinux e a dose equivalente de 3.0 mg de idrabiotaparinux) podem ser uma alternativa eficaz e segura a anticoagulação convencional para o tratamento da TVP. Qualidade da evidência: A qualidade da evidência foi considerada moderada a alta. Um único estudo incluído (Persist) poderia ser julgado potencialmente falho devido ao relevante número de pacientes que foram perdidos ou descontinuaram prematuramente o tratamento após a randomização. De forma geral, os estudos incluídos responderam diretamente as perguntas e foram considerados de boa qualidade. Os resultados dos estudos foram consistentes e os efeitos estimados foram precisos. Nós acreditamos que seja improvável que a maioria dos nossos principais resultados de eficácia e danos possam ser modificados por estudos adicionais. Entretanto, estudos futuros com os pentasaccharides de meia vida prolongada (idraparinux e idrabiotaparinux) em baixas doses podem confirmar nossas estimativas com relação a sua não inferioridade em comparação à terapia padrão. / Background: Deep vein thrombosis (DVT) is a severe disorder caused by acute formation of a clot or thrombus in the deep vein system. The incidence of DVT increases with age: from 2 to 3/10,000 in adults aged 30 to 49 years to 20/10,000 in adults aged 70 to 79 years. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Standard treatment is based on antithrombotic therapy, initially with parenteral administration of unfractionated heparin or low molecular weight heparins (LMWH) for five to seven days, then subsequent long-term oral vitamin K antagonists (e.g. warfarin) therapy. However, hemorrhagic complications are a major concern associated with warfarin treatment. Indeed, the hemorrhagic risk of warfarin and the required laboratory control remain the Achilles’ heel of vitamin K antagonist management. The pentasaccharides have characteristics that may be favourable over conventional treatment, including a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions and absence of heparin-induced thrombocytopenia. To date, no systematic review has measured the effectiveness and safety of these drugs in the treatment of DVT. Objectives: To assess the efficacy and harms of pentasaccharides for the treatment of deep venous thrombosis. Search strategy: 1 The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched July 2015) and the Cochrane Register of Studies (last searched July 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations. Selection criteria: We included randomised controlled trials in which people with a DVTconfirmed by standard imaging techniques, were allocated to receive a pentasaccharide (fondaparinux, idraparinux or idrabiotaparinux) for the treatment of DVT. Data collection and analysis: Three review authors (GB, DJ and MS) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion. We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and major (and clinically non-major) bleeding. Other outcomes included all-cause mortality, recurrent DVT, PE, thrombocytopenia, heparin-induced thrombocytopenia syndrome and all other adverse effects induced by the treatments . We calculated all outcomes using a relative risk (RR) with a 95% confidence interval (CI). Main results: We included 5 randomised controlled trials of 6981 participants. Two studies tested fondaparinux, while three tested idraparinux (being one tested idrabiotaparinux). We deemed all included studies to be of high methodological quality and generally low risk of bias. The quality of the evidence was generally graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the RRs. Meta-analysis of two studies (2658 participants) comparing fondaparinux with standard anticoagulation groups showed no difference in the risk of recurrent VTE (RR 0.88, 95% CI 0.60 to 1.29). The RR of bleeding in the initial period of treatment (RR 0.94, 95% CI 0.73 to 1.22) and three months of follow up (RR 0.61, 95% CI 0.36 to 1.01) were similar comparing both interventions. Two studies comparing idraparinux with standard therapy showed no difference in the risk of recurrent VTE during three months (RR 1.51; 95% CI 0.26, 8.90) and (RR 0.79; 95% CI 0.21; 2.91). The treatment with idraparinux clearly showed a bleeding risk with a pattern dose-response. However, at a dose of 2.5 mg idraparinux, there was no significant difference in the risk of bleeding in patients receiving idrapaparinux in comparison to standard therapy during six months of follow up (RR 0.92, 95% CI 0.69 to 1.22). One study contributed with data for the analysis (n=741 participants) that there was no significant difference in the risk of recurrent VTE during six months follow-up between idrabiotaparinux compared with idraparinux (RR 0.71, 95% CI 0.30 to 1.66). The risk of bleeding was also similar comparing the two interventions (RR 0.71, 95% CI 0.49 to 1.04). Authors' conclusions: The pentasaccharides (fondaparinux, the dose of 2.5 mg idraparinux and equimolar dose of 3.0 mg idrabiotaparinux) may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

Blackberry yellow vein disease (BYVD) is the most important virus disease of blackberry in the Southeastern United States. In order to determine viruses in BYVD-affected plants in Mississippi we tested a total of eighty one symptomatic cultivated and wild blackberries collected from different locations for infections by nine different viruses. All tested viruses were present in diseased samples at various rates, with the exception of Rubus canadensis virus 1. Blackberry yellow vein associated virus is prevalent virus in Mississippi, infecting 70% of tested samples, followed by Tobacco ringspot virus. The second part of this research focused on molecular and phylogenetic studies concerning a putatively new virus species, provisionally referred to as Blackberry virus X and present in approximately 27% of the tested samples. Data generated in this study suggest that BVX is a novel species in the family Betaflexiviridae, with final taxonomic allocation (at the genus level) yet to be determined.

The main use of sildenafil in human medicine is to treat erectile dysfunction. In veterinary medicine, sildenafil is most frequently used to treat pulmonary hypertension. The effects of sildenafil on the portal vasculature in the dog have not been previously evaluated. The purpose of this study was to evaluate the effects sildenafil has on the portal vasculature. The cross-sectional area of the aorta, cross-sectional area of the portal vein, and portal vein velocity were acquired in thirteen dogs prior to administration, 45 minutes, 90 minutes, and 120 minutes after the oral administration of sildenafil for the treatment of pulmonary hypertension. No statistically significant difference was detected between all measured values at all time points. Although this study had a small sample size, sildenafil does not have a significant effect on the size of the portal vasculature. Further studies with a larger sample size will be required to further evaluate the effects.

BACKGROUND: Though direct oral anticoagulants (DOACs) have become a standard of care in the treatment of acute deep vein thrombosis (DVT), it is our observation that physicians tend to initiate heparin or low-molecular-weight heparin, hereafter called “heparin”, for the treatment of extensive DVT or phlegmasia cerulea dolens (PCD). This might be due to a perception that heparin might relieve DVT-related symptoms more quickly than DOACs. Whether these assumptions are true has not been evaluated. METHODS: We conducted a survey of thrombosis specialists in North America to explore the practical management of anticoagulant therapy in patients with extensive DVT, and the underlying reasons for the selection of heparin over DOACs. A cross-sectional, web-based survey was distributed to thrombosis specialists who are members of four thrombosis societies. RESULTS: Eighty-nine respondents provided consent. Most respondents selected DOACs over heparin in a case scenario representing mild DVT-related symptoms and limited thrombus involvement (81% vs. 19%). Most respondents selected heparin over DOACs in a case scenario representing early stage PCD (84% vs.16.3%) or a patient with high bodyweight (72% vs. 28%). In a case scenario representing extensive DVT, 57.4% of the respondents selected heparin, whereas, 42.6% selected DOACs. In the respondents who selected heparin over DOACs, the major reason was that heparin might relieve DVT-related symptoms more quickly because of its anti-inflammatory effects. DISCUSSION: Severity of DVT-related symptoms, thrombus extent, and bodyweight play a role in the selection of anticoagulant therapy. Despite a lack of evidence to support the hypothesis with respect to which anticoagulant is superior, most thrombosis specialists selected heparin over DOACs in patients with severe DVT-related symptoms and extensive thrombus involvement. Observation of variations in the selection of anticoagulant therapy for the treatment of extensive DVT also indicates that clinical trials in this patient population are needed. / Thesis / Master of Science (MSc)

Over seven million Americans suffer from Chronic Venous Insufficiency (CVI), a painful and debilitating disease that affects the superficial and deep veins of the legs. Problems associated with CVI include varicose veins, bleeding, ulcerations, severe swelling, deep vein thrombosis, and pulmonary embolism, which may lead to death. The presence of CVI results from damaged (incompetent) one-way vein valves in leg veins. These valves normally allow forward flow of blood to the heart, and prevent blood from pooling at the feet. However, incompetent valves allow reflux of blood, causing clinical problems. There are few effective clinical therapies for treating CVI. Vein valve transplantation is a surgical option for treatment. However, it is often difficult to find suitable donor valves. Very few prosthetic valves developed in the past have demonstrated sufficient clinical or mechanical functionality. Persistent problems include thrombus formation, leaking valves, and valves that do not open at physiologic pressure gradient. The primary objective of this research was to develop a clinically relevant functional prosthetic vein valve. The novel prosthetic valve is flexible, biocompatible, has low thrombogenecity, and is easy to manufacture. It was designed to address well-defined consumer needs and functional design requirements. The valve was required to 1) withstand 300 mmHg of backpressure with leakage less than 1.0 mL/min, 2) open with a pressure gradient less than 5 mmHg, and 3) meet criteria 1 and 2 after 500,000 cycles of operation. The valve met these design requirements in bench testing. The valve can open with a pressure gradient of 2.6 0.7 mmHg, and can withstand 300 mmHg with leakage less than 0.5 mL/min. The valve remained functional after opening and closing over 500,000 times. The valve presented in this research is operationally functional, and is a potential solution for treating venous incompetence in CVI patients.

Chronic Venous Insufficiency (CVI) is a condition in present in almost 27% of adults in which an insufficient amount of blood is pumped back to the heart due to damaged or poorly apposed one-way valves in the leg veins. During forward flow, vein valves allow blood to return to the heart while posing very little resistance to the flow. During gravity-driven reverse flow, normal valves close and prevent blood from flowing backward through the valve. Incompetent, or damaged, vein valves cannot prevent this reverse flow and lead to a pooling of blood at the feet. CVI is a painful disease presents itself in various ways, including varicose veins, ulcerations of the lower extremities, and severe swelling. Current therapies and treatments include compressive stockings, destruction or removal of affected veins, valve repair, and valve transplants. The implantation of prosthetic vein valves is a future treatment option that does not require an invasive surgery, human donor, or lengthy hospital stay. While no prosthetic vein valves are currently commercially available, this thesis describes the design, verification, and validation of a novel prosthetic vein valve. Verification tests include CFD simulations, functional tests, mechanical tests, and in vitro thromogenicity tests. The validation of the device was done through an animal study in sheep external jugular veins. CFD analysis verified that shear rates within the valve support its lower thrombogenicity as compared to a previous vein valve. Benchtop tests demonstrate superiority in short-term patency over a previous polymer valve. In a sheep study, patency was shown at 6 weeks, surpassing many autograft valves and showing great potential to meet the goal of 3 month patency in sheep.

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