Copies of author's previously published articles inserted. / Includes bibliographical references. / vi, 135, [109] leaves, [23] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Studies the structure-function properties of the human cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to generate molecules with novel biological properties. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1995

"May 2002" / Includes bibliographical references (leaves 229-251) / xv, 251 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes the investigation of the alteration of ABH antigen expression on the surface of red blood cells in patients with haematological malignancies. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003

Errata inserted on back end paper. / Bibliography: leaves 226-254. / xviii, 261 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes the development of techniques to genotype and simultaneously assess allele dosage at the ABO locus using PCR and allele-specific restriction enzyme digestion. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1996

Este estudo teve o propósito de validar os diagnósticos de enfermagem da NANDA (2001) \"Disfunção Sexual\" e \"Padrões de Sexualidade Ineficazes\" e de proporcionar uma avaliação objetiva da Sexualidade Humana. A abordagem metodológica de validação adotada foi a de Hoskins (1989): análise de conceito, validação por especialistas e validação clínica, denominada de verificação da incidência das evidências clínicas. A partir da reconstrução dos dois diagnósticos estudados e construção das definições operacionais de suas características definidoras, estes foram validados por 32 enfermeiros considerados peritos nestes diagnósticos, a partir da pontuação recomendada por Fehring (1994). Os resultados demonstraram que no diagnóstico \"Disfunção Sexual\" a definição está adequada ao título, mas merece que se especifique as fases da resposta sexual humana. Quanto às 10 características definidoras propostas, 07 receberam os maiores escores: limitações percebidas impostas pela doença e/ou terapêutica; limitações reais impostas pela doença e/ou terapêutica; alteração no alcance da satisfação sexual; busca de confirmação da qualidade de ser desejável; incapacidade de alcançar a satisfação desejada; percepção de alteração na excitação sexual e percepção de escasso desejo sexual. Ressalta-se que essas duas últimas características foram encontradas na literatura e acrescidas neste diagnóstico. Referente ao diagnóstico \"Padrões de Sexualidade Ineficazes\", a adequação da definição ao título necessitou de ser comprovada pela literatura, pois as sugestões dos enfermeiros peritos que discordaram foram heterogêneas. Quanto às características definidoras, os maiores escores foram atribuídos a dificuldades ou limitações relatadas nos comportamentos ou atividades sexuais, mudanças relatadas nos comportamentos ou atividades sexuais, alterações no desempenho do papel sexual percebido e alteração no relacionamento com pessoas significativas, sendo estas duas últimas foram deslocadas do diagnóstico \"Disfunção Sexual\". Todas as características definidoras do diagnóstico \"Disfunção Sexual\" que receberam escores acima de 0,80 na Validação por Especialistas tiveram incidências acima de 55% no contexto clínico dos pacientes portadores de doenças onco-hematológicas. Porém, referente ao diagnóstico \"Padrões de Sexualidade Ineficazes\", as maiores incidências ocorreram nas características definidoras: dificuldades ou limitações relatadas nos comportamentos ou atividades sexuais e mudanças relatadas nos comportamentos ou atividades sexuais, que constam na NANDA (2001). Conclui-se que os pacientes portadores de neoplasias hematológicas apresentaram comprometimento de uma ou mais fases da resposta sexual humana e mostraram-se preocupados com a influência da doença e do tratamento no seu comportamento sexual, principalmente, no que se refere ao medo de se adquirir uma infecção, resultando na diminuição ou interrupção da sua atividade sexual, após descobrir a doença / This study aimed to validate the NANDA (2001) nursing diagnoses \"Sexual Dysfunction\" and \"Ineffective Sexuality Patterns\" and offer an objective evaluation of Human Sexuality. Our methodological approach of validation was based on Hoskins (1989): concept analysis, expert validation and clinical validation, called verification of clinical evidence incidence. Starting from the reconstruction of the two diagnoses under analysis and the construction of the operational definitions of their defining characteristics, validation was realized by 32 nurses, who are considered experts on these diagnoses, according to the punctuation recommended by Fehring (1994). Results demonstrate that, with respect to the \"Sexual Dysfunction\" diagnosis, the definition is adequate for the title, but human sexual response phases need to be specified. 07 out of 10 defining characteristics obtained the highest score: perceived limitations imposed by disease and/or therapy; actual limitations imposed by disease and/or therapy; alteration in achieving sexual satisfaction; seeking confirmation about being desirable; incapacity to achieve desired satisfaction; perception of altered sexual excitement and perception of scarce sexual desire. We highlight that the last two characteristics were found in literature and added to this diagnosis. The adequacy of the \"Ineffective Sexuality Patterns\" definition to the title had to be proved by means of literature, since the experts nurses displayed heterogeneous suggestions in this respect. The defining characteristics with the highest scores were: reported difficulties or limitations in sexual behaviors or activities; reported changes in sexual behaviors or activities; alterations in achieving perceived sex role and alteration in relationship with significant other. The last two were transferred from the \"Sexual Dysfunction\" diagnosis. All defining characteristics for the \"Sexual Dysfunction\" diagnosis with scores superior to 0.80 in Experts Validation disclosed incidence rates superior to 55% in the clinical context of blood cancer patients. However, with respect to the \"Ineffective Sexuality Patterns\" diagnosis, the highest incidence rates occurred for the following defining characteristics: reported difficulties or limitations in sexual behaviors or activities and reported changes in sexual behaviors or activities, which are listed in NANDA. We conclude that the human sexual response of blood cancer patients was affected in one or more phases. Patients revealed to be worried about the influence of the disease and treatment on their sexual behavior, mainly with respect to the fear of getting an infection, resulting in decreased or interrupted sexual activity after the discovery of the disease

No description available.

Myelodysplastic syndrome (MDS) is a group of clonal bone marrow disorders characterized by bone marrow dysplasia with myeloblasts <20%, typically seen in older patients. MDS has a significant risk of transformation to Acute Myeloid Leukemia (AML). We report a case of MDS transformed to AML, with sustained Complete Remission and incomplete count recovery (CRi) with treatment. A 78-year-old male with a 2-year history of leukopenia had a workup including bone marrow biopsy (BMBX) revealing intermediate- risk MDS with 13% blasts (Refractory Anemia Excess Blasts II), deletion 20 on cytogenetics and normal MDS FISH panel. He was categorized as revised IPSS score 4.5 on risk stratification. Patient initiated treatment with hypomethylating agent Azacytidine with subsequent improved BMBX with 7% blasts. He continued Azacytidine with dose reductions due to cytopenia only to develop 14% blasts on another follow up BMBX. He continued successful treatment for over 3 years before developing with 40-50% CD 34+/CD117+ blasts in the bone marrow consistent with transformation to AML. He commenced salvage treatment with Venetoclax and full dose Azacytidine as advanced age and performance status precluded transplant options. Repeat BMBX 4 weeks following Venetoclax showed hypocellular marrow, blasts percentage less than 2% indicating a CRi. Two other subsequent marrow exams have demonstrated sustained CRi twelve months after transformation with continued Venetoclax and Azacytidine administration. Around 30% of MDS patients eventually transform to secondary AML. Azacytidine therapy has significantly improved survival and time to AML transformation in intermediate-2 and high-risk MDS patients. Venetoclax, a BCL-2 inhibitor, in treating AML. Based on the results of the VIALE-A trial, the incidence of CR (complete remission) was higher around 36.7% with Azacytidine-Venetoclax (A-V) compared to 17.9% with Azacytidine. The composite CR (CR+ Cri) was higher in the A-V group, 66.4% compared to 28.3% with Azacytidine group. The median overall survival was 14.7 months in the A-V group compared to 9.6 months in the Azacytidine group. Our patient achieved a CRi with A-V treatment and has demonstrated a durable response beyond 16 months in secondary AML which has a bleak prognosis indicating the promise of this new combination treatment.

We describe a patient who developed hemolysis and methemoglobinemia due to rasburicase (RBU) and was found to have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This is a rare clinical scenario that provides valuable insight into complex diagnosis and management of these life-threatening complications. A 59-year-old male presented to the VA Medical Center with 11 days of epigastric abdominal pain radiating to the back and flank, associated with bloating and lower extremity edema. He was transferred to our facility for percutaneous nephrostomy tube (PCN) placement for renal dysfunction (creatinine 5.5). Computed tomography (CT) scan of the abdomen and pelvis revealed 17 cm retroperitoneal mass engulfing major vessels, involving right renal hilum and ureter with moderate-severe right hydronephrosis. CT guided biopsy of the mass showed intermediate-large malignant cells that were CD20, CD23, BCL2 and BCL6 positive; CD10 and MUM1 negative. Fluorescent in-situ hybridization resulted after discharge to reveal no MYC rearrangement, confirming a diagnosis of diffuse large B-cell lymphoma. Positron-emission tomography CT revealed extensive retroperitoneal lymphadenopathy with pelvic extension into internal and external iliac vessels, encasing aorta, inferior vena cava and anteriorly displacing pancreas and bowel and contiguous involvement of the right kidney with hypermetabolic activity. Moderate right sided pleural effusion was also seen. Creatinine improved with PCN. Uric acid was 10.3 with lactate dehydrogenase (LDH) 953. The patient received RBU for tumor lysis syndrome (TLS). However, pulse oximetry showed an oxygen saturation of 70-80%, though the patient had only mild dyspnea. CT pulmonary embolism (CTPE) showed segmental PE. Therapeutic lovenox was initiated. He underwent thoracentesis with symptomatic improvement but continued to desaturate on pulse oximetry. Arterial blood gas on 100% oxygen via non-rebreather revealed methemoglobin of 4.5% without hypoxemia. LDH worsened to 1668 with low haptoglobin and direct hyperbilirubinemia, suggestive of hemolysis. G6PD was deficient at 0.8 U/g. Treatment was conservative with cautious use of red cell transfusions and supplemental oxygen. Due to hyperbilirubinemia, chemotherapy was started with dose-adjusted etoposide, prednisone, oncovin, cyclophosphamide, and rituximab - with adriamycin withheld upfront. As hemolysis improved the patient received dose-reduced adriamycin. RBU is a recombinant urate oxidase used in managing TLS. It converts uric acid to allantoin, producing hydrogen peroxide, which oxidizes hemoglobin to methemoglobin. G6PD deficiency decreases cellular ability to reduce glutathione and thus detoxify hydrogen peroxide. This causes life-threatening methemoglobinemia and hemolysis. Methylene blue is contraindicated due to the risk of worsening hemolysis in G6PD deficiency. Methemoglobinemia is typically treated in such cases with exchange transfusion or hyperbaric oxygen therapy.

Cette thèse est consacrée au développement de modèles mathématiques de l'hématopoïèse et de maladies du sang. Elle traite du développement de modèles hybrides discrets continus et de leurs applications à la production de cellules sanguines (l'hématopoïèse) et de maladies sanguines telles que le lymphome et le myélome. La première partie de ce travail est consacrée à la formation de cellules sanguines à partir des cellules souches de la moelle osseuse. Nous allons principalement étudier la production des globules rouges, les érythrocytes. Chez les mammifères, l'érythropoïèse se produit dans des structures particulières, les îlots érythroblastiques. Leur fonctionnement est régi par de complexes régulations intra et extracellulaire mettant en jeux différents types de cellules, d'hormones et de facteurs de croissance. Les résultats ainsi obtenus sont comparés avec des données expérimentales biologiques ou médicales chez l'humain et la souris. Le propos de la deuxième partie de cette thèse est de modéliser deux maladies du sang, le lymphome lymphoblastique à cellules T (T-LBL) et le myélome multiple (MM), ainsi que leur traitement. Le T-LBL se développe dans le thymus et affecte la production des cellules du système immunitaire. Dans le MM, les cellules malignes envahissent la moelle osseuse et détruisent les îlots érythroblastiques empêchant l'érythropoïèse. Nous développons des modèles multi-échelles de ces maladies prenant en compte la régulation intracellulaire, le niveau cellulaire et la régulation extracellulaire. La réponse au traitement dépend des caractéristiques propres à chaque patient. Plusieurs scénarios de traitements efficaces, de rechutes et une résistance au traitement sont considérés. La dernière partie porte sur un modèle d'équation de réaction diffusion qui peut être utilisé pour décrire l'évolution darwinienne des cellules cancéreuses. L'existence de “pulse solutions”, pouvant décrire localement les populations de cellules et leurs évolutions, est prouvée / The thesis is devoted to mathematical modeling of hematopoiesis and blood diseases. It is based on the development of hybrid discrete continuous models and to their applications to investigate production of blood cell (hematopoiesis) and blood diseases such as lymphoma and myeloma. The first part of the thesis concerns production of blood cells in the bone marrow. We will mainly study production of red blood cells, erythropoiesis. In mammals erythropoiesis occurs in special structures, erythroblastic islands. Their functioning is determined by complex intracellular and extracellular regulations which include various cell types, hormones and growth factors. The results of modeling are compared with biological and medical data for humans and mice. The purpose of the second part of the thesis is to model some blood diseases, T cell Lymphoblastic lymphoma (T-LBL) and multiple myeloma (MM) and their treatment. TLBL develops in the thymus and it affects the immune system. In MM malignant cells invade the bone marrow and destroy erythroblastic islands preventing normal functioning of erythropoiesis. We developed multi-scale models of these diseases in order to take into account intracellular molecular regulation, cellular level and extracellular regulation. The response to treatment depends on the individual characteristics of the patients. Various scenarios are considered including successful treatment, relapse and development of the resistance to treatment. The last part of the thesis is devoted to a reaction-diffusion model which can be used to describe Darwinian evolution of cancer cells. Existence of pulse solutions, which can describe localized cell populations and their evolution, is proved

Acute Myeloid Leukemia (AML) is a potentially fatal disease, more common in an elderly population. The American Cancer Society estimates 21,450 new cases of AML and 10,920 deaths from AML in the United States in 2019. This malignancy originating in the Bone Marrow (BM), usually presents with peripheral blood (PB) abnormalities. Rarely, AML, particularly monoblastic variants can present with extramedullary disease. Here we describe a case of AML presenting with diffuse lymphadenopathy and a biopsy revealing myeloid sarcoma. A 53 years old male developed diffuse lymphadenopathy. Failure of outpatient empiric antibiotic treatment prompted right cervical lymph node biopsy. Lymph node architecture was distorted by the presence of malignant monocytic myeloid cells. Both the peripheral blood and bone marrow were involved by AML with monocytic features. The monoblasts count was 14% in PB and 24% in BM and the promonocyte count was 12% in PB and 26% in BM. Complete Blood Count showed total white blood cell count of 31,700, hemoglobin 11.8, monocytes 22.5% and platelets 122,000. Flow cytometry of the bone marrow demonstrated a blast population with positive expression of cMPO, CD33, CD13, CD11b, HLA-DR, CD64, CD14 and CD4; and negative for CD34, CD117, nTdT, cCD3, cCD79a. Fluorescence in situ hybridization study was positive for MLL gene rearrangement. Molecular study was positive for IDH1 mutation, and negative for IDH2, RUNX1, FLT3 mutations. Further laboratory analysis was significant for lactate dehydrogenase 346, uric acid 8.6, prothrombin time 13.6, INR 1.2, partial thromboplastin time 33.5 and fibrinogen 293. Computed tomography of chest, abdomen, pelvis with contrast revealed extensive adenopathy with enlarged bilateral supraclavicular, bilateral axillary, mediastinal, bilateral hilar, upper abdominal, periaortic retroperitoneal, pelvic and inguinal lymph nodes. Hepatosplenomegaly was also reported. The term Myeloid Sarcoma (MS) is used when leukemic cells are present outside the bone marrow and peripheral blood. MS tends to oocur more commonly in middle aged males (male-to-female ratio, 2:1, median age, 56 years). The Mayo Clinic Experience of 96 cases demonstrated 27% of patients had no bone marrow involvement, and 69% of patients had primary bone marrow disease. Extramedullary involvement can occur prior to, simultaneously, or after bone marrow involvement. Just as in our case this is an important feature for clinicians to remember so that they may recognize this rare entity early.

Dentre os países da América Latina, o Brasil é o país que mais recebe doações de sangue em volume, alcançando mais de 3,5 milhões de bolsas anualmente só na hemorrede pública. Para que possam ocorrer as transfusões e processamento de hemoderivados é mandatória a realização de testes para detecção de agentes patológicos. Neste cenário está inserido o Instituto de Biologia Molecular do Paraná (IBMP) que, em parceria com a FIOCRUZ, é responsável pelo fornecimento do kit NAT destinado a detecção dos vírus da imunodeficiência humana (HIV), hepatite C (HCV) e hepatite B (HVB) à hemorrede pública brasileira. Visando implementar melhorias e novas tecnologias aos processos existentes, o Instituto adquiriu a licença para utilização da técnica de gelificação na produção de kits para diagnóstico. Esta técnica propõe a estabilização de biomoléculas sem afetar sua funcionalidade, proporcionando a redução de custos de produção, além de possibilitar que os kits sejam armazenados e transportados à temperatura ambiente, aspecto fundamental para simplificar sua cadeia logística e viabilizar a distribuição destes produtos em áreas remotas do Brasil e do mundo. No entanto, ainda há escassez de trabalhos que avaliem aspectos financeiros da implementação desta técnica na indústria. Cabe salientar ainda que a realização de testes em campo seria complexa e demandaria um alto investimento. Uma alternativa para realizar este tipo de avaliação é pelo uso de simulação computadorizada do processo. As ferramentas de simulação possibilitam avaliar diferentes cenários, obtendo dessa forma informações imprescindíveis para melhoria operacional e para tomada de decisões. Neste trabalho, são avaliados os impactos da implementação da técnica de gelificação no custo direto de produção de insumos para diagnóstico por meio de simulação discreta usando o software FlexSim®. Dados obtidos a partir de dezesseis cenários simulados usando a nova tecnologia foram comparados com registros históricos do IBMP na produção de insumos para diagnóstico pelo processo convencional. Dentre os cenários avaliados, seis atenderam às restrições impostas pelo processo e em todos foi possível verificar a redução nos custos diretos, que variou de 3,73% até 5,41% em relação às condições atuais. As reduções de custo ocorreram principalmente devido a reduções nos custos com matéria-prima, que alcançaram economia de 4,1% e nos custos com mão de obra, dada redução do número de operadores no processo. Ademais, os resultados indicam que a implementação da tecnologia propicia melhor aproveitamento da estrutura física da planta sem que ocorra saturação de linhas de processamento. Portanto, baseado em modelos de simulação, este trabalho demonstra a viabilidade do emprego da tecnologia de gelificação no IBMP em termos de custo direto de produção de insumos para diagnóstico. / Among Latin American countries, Brazil is the one that receives more blood donations in volume, reaching up to 3.5 million blood bags in the public blood donation network annually. In order to enable transfusions and processing of blood-derived products, it is mandatory to test the blood against pathologic agents. In association with the Oswaldo Cruz Foundation (FIOCRUZ), the Molecular Biology Institute of Paraná (IBMP) supplies the kit NAT for the detection of the human immunodeficiency, hepatitis B and C viruses (HIV, HBV and HCV) to the Brazilian public blood donation network. Aiming at the implementation of improvements and the introduction of new technologies to its processes, the Institute acquired a license to use the gelification technique in the production of diagnostic kits. The gelification technique proposes the stabilization of biomolecules without harming their functionality, while reducing production costs and allowing the products to be stored and transported at room temperature. It is a key aspect to simplify the logistics chain used to distribute the kit, allowing it to reach World`s remote areas. However, there is still a lack of published studies evaluating financial aspects of the implementation of this technique in the industry. It is worth emphasizing the cost to conduct field experiments of this kind of implementation. One alternative for such an evaluation is by the use of process computer simulation. Simulation tools could be used to analyze different scenarios, providing valuable information for process improvement and decision-making. In this work, the impacts of the gelification technique implementation in the direct production cost of reagents for diagnostic were evaluated using discrete simulation with FlexSim®. Data obtained from sixteen simulated scenarios deploying gelification were compared with historic records of the production of reagents for diagnosis using the conventional process at IBMP. Six of the sixteen evaluated scenarios satisfied the restrictions imposed by the process and all of them indicated a reduction of direct production costs, varying from 3.73% to 5.41% when compared to current conditions. The cost reduction is mainly associated to lower expenses with raw materials, representing savings of up to 4.1% and to the reduction in the number of operators needed. Additionally, results indicate that the implementation of the new technology leads to a better use of the physical structure of the production facility without saturating processing lines. Therefore, based on simulation models, this work shows that the employment of the gelification technology in the manufacturing process of diagnostic reagents at IBMP is viable in terms of direct production costs.