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O abuso sexual é uma forma de violência interpessoal que acomete milhões de pessoas em todo o mundo, 20% das mulheres e 2% dos homens relatam passar por algum tipo de abuso sexual durante a vida. O Transtorno de Estresse Pós-Traumático (TEPT) é um dos possíveis resultados do abuso sexual e compromete a qualidade de vida do indivíduo e também suas relações interpessoais, com sintomas de reexperiência, hiperexcitação, esquiva e alterações em cognição e humor. As principais terapias baseadas em evidências para o tratamento de TEPT: Cognitive Processing Therapy e Prolonged Exposure, ambos com base na exposição, apesar de apresentarem dados empíricos e significativos de mudança, apontam até 50% de evasão a terapia, dificuldade de implementação pelo terapeuta e aumento de sintomas pela exposição. Os estudos em Psicoterapia Analítica Funcional (FAP) têm mostrado resultados satisfatórios na compreensão e aprimoramento dos processos de mudanças clínicas com foco na relação terapêutica. Levando em consideração que pessoas com TEPT tendem a apresentar comportamentos de esquivas emocionais, esquivas de relações de intimidade e de confiança e que a FAP tem por objetivo proporcionar mudanças por meio da relação terapêutica, os objetivos do presente estudo foram: 1) investigar os efeitos da FAP como tratamento para pessoas com TEPT por abuso sexual, e 2) os processos de mudança clínica envolvidos na utilização da FAP. Os participantes foram uma terapeuta/pesquisadora, três aferidores de concordância e três clientes adultos. A intervenção ocorreu com delineamento experimental de caso único, com introdução da variável independente (FAP) em diferentes momentos para cada participante, na seguinte disposição: Linha de Base - A - B (delineamento em linha de base múltipla - DLBM). As sessões foram transcritas e categorizadas com uso do Sistema de Categorização da Psicoterapia Analítica Funcional (FAPRS), a fim de encontrar os processos envolvidos nas mudanças clínicas, com foco na relação terapêutica. Já as melhoras do cliente foram analisadas por meio dos instrumentos: Escala de Sintomas de Transtorno de Estresse Pós-Traumático (PCL-C) e Outcome Questionnaire (OQ-45). O padrão comportamental de esquivas de situações que sinalizavam intimidade e vulnerabilidade foi encontrado em todas as participantes por meio da conceituação do caso. Os resultados apontaram que, após a introdução da variável independente (FAP) os comportamentos clinicamente relevantes do tipo problema (CRB1) diminuíram drasticamente e os comportamentos clinicamente relevantes de melhora (CRB2) aumentaram. Ademais, o instrumento FAPRS apontou a potência da Regra 3 (consequenciar diferencialmente) e da Regra 2 (evocar) como os principais processos de mudanças clínicas na FAP. Os efeitos da FAP foram observados também no instrumento PCL-C, com queda dos escores para as clientes que tiveram maior tempo de intervenção FAP, dado corroborado pelos resultados do OQ-45 que também tiveram queda após a introdução da FAP, com exceção da participante exposta à menos sessões com a variável independente (FAP). Dessa forma, esse estudo pontua a eficácia da FAP para o tratamento de vítimas de abuso sexual e o primeiro caso de sucesso na utilização do DLBM em pesquisas de prática clínica / Sexual abuse is a type of interpersonal violence that happens among millions of people worldwide, 20% of women and 2% of men states being a victim of sexual abuse during their lives. Posttraumatic Stress Disorder (PTSD) is one of the possible outcomes of sexual abuse that compromises the life quality of the victim and interpersonal relationships, experiencing symptoms as re-experience, hyperexcitation, avoidance and negative changes in thinking and mood. The main evidence based practice for treatment of PTSD: Cognitive Processing Therapy and Prolonged Exposure, both based on exposure, although they show data of meaningful changes, they point up to 50% of drop-out rates, difficult implementation by therapists and increase of re-experience symptoms. Researches on Functional Analytic Psychotherapy (FAP) have shown satisfactory results related to the knowledge and improvement in the mechanism of change mainly occurring in the therapeutic relationship. Considering that people with PTSD tend to show emotional avoidance, avoidance of intimacy and trust and that FAP has as main goal to provide changes through therapeutic relationship, the current study aimed to investigate: 1) the effects of FAP, as treatment for victims of sexual abuse with PTSD and 2) the FAP mechanism of change. The participants were a therapist-researcher, three agreement coders and three clients. The study had a single-case experimental design, introducing the independent variable (FAP) in different time for each client, following: baseline - A - B (multiple baseline design MBLD). The sessions were transcribed and coded with Functional Analytic Psychotherapy Rating Scale (FAPRS) aimed to study the therapeutic relationship and to find the mechanism of change. The clients improvements were analyzed through the assessments: Posttraumatic Stress Disorder Checklist (PCL-C) and Outcome Questionnaire (OQ-45). The avoidance patterns that indicated intimacy and vulnerability were found in all clients through the case conceptualization. Results indicated that after the introduction of FAP the clinical relevant problems behaviors (CRBs1) considerably decreased and the clinical relevant improvements behaviors (CRBs2) increased. In addition, the FAPRS assessment indicated that Rule 3 and Rule 2 were the main mechanism of change in FAP. The FAP effects were also analyzed by the OQ-45 and PCL-C assessments that showed decreased scores by the clients who had the longest period of FAP intervention. In conclusion, the current study demonstrated the efficacy of FAP in the treatment of sexual abuse victims and is the first successful study using MBLD in clinical researches

A doença linfoproliferativa pós transplante (DLPT) é a proliferação tecidual secundária mais comum em crianças submetidas a transplante de órgãos sólidos, e representa um espectro de proliferação linfoide clínica e morfologicamente heterogêneo que vai desde uma hiperplasia policlonal indolente até linfomas agressivos. Aproximadamente 80% das DLPT estão associadas ao vírus Epstein Barr (EBV) e é originaria de células B, entre 10 a 15% tem origem em células T e aproximadamente 1% em células natural killer. O status sorológico negativo para EBV pré transplante e o grau de imunossupressão são os fatores de risco de maior relevância para o desenvolvimento desta enfermidade. A apresentação clínica é diversa e sintomas constitucionais podem estar presentes simulando infecção e ou rejeição ao órgão transplantado. A confirmação do diagnóstico por exame histopatológico é, habitualmente, necessária e a hibridização in situ geralmente detecta as partículas de EBV nos tecidos examinados. A melhor opção terapêutica ainda não está definida e atualmente o tratamento consiste na redução da imunossupressão associada ao uso do anticorpo Anti CD20 e ou quimioterapia citotóxica além da terapia celular disponível em alguns centros. Este estudo teve por objetivos avaliar a resposta tumoral ao uso do anticorpo Anti CD20 na DLPT de células B EBV positivas pós transplante de órgãos sólidos, além de associar a neoplasia à eventual inclusão genômica de DNA/EBV na célula neoplásica. Foram analisados retrospectivamente os prontuários de vinte e três pacientes com até 18 anos incompletos admitidos na Unidade de Internação do Serviço de Onco- Hematologia do Instituto da Criança (ICR) e Instituto do Tratamento do Câncer Infantil (ITACI) que desenvolveram DLPT CD20 positiva pós transplante de órgãos sólidos comprovada histologicamente entre 8 de março de 1995 e 13 de agosto de 2011. Todos foram submetidos à redução da imunossupressão, treze receberam Anti CD20 isolado, três Anti CD20 associado à quimioterapia citotóxica e sete pacientes não fizeram uso desta droga. A sobrevida global em dois anos dos pacientes que receberam Anti CD20 foi de 81,45% e quando comparada à sobrevida global de 37,5% dos que não receberam a droga revelou diferença estatística significativa (p=0,02). Todos os pacientes tiveram a detecção da proteína de latência viral de EBV Latent Membrane Protein1 (LMP1) na célula tumoral através da técnica de hibridização in situ realizada em blocos de parafina devidamente armazenados ao diagnóstico. A curta duração do tratamento com o Anti CD20, a toxicidade aceitável em relação às demais alternativas terapêuticas, a possibilidade de seu uso exclusivo, sua eficácia inclusive na doença de histologia agressiva e associação às demais alternativas de tratamento na doença refratária sugerem a inclusão desta droga no arsenal terapêutico atualmente disponível / Post-transplant lymphoproliferative disease (PTLD) is the most common secondary tissue proliferation that occurs in children after solid organ transplantation and represents a spectrum of clinical lymphoid proliferation and morphologic heterogeneity that goes from an indolent polyclonal hyperplasia to aggressive lymphomas. Approximately 80% of PTLD is associated with Epstein Barr virus (EBV) and is of B-cell origin, 10 to 15% of T-cells and approximately 1% of natural killer cells. EBV pretransplant seronegativity and the degree of immunosuppression are the most relevant risk factors for developing the disease. Clinical presentation is diverse and constitutional symptoms may simulate infection and/or organ transplanted rejection. Histopathologic examination is usually necessary to confirm diagnosis and, generally, in situ hybridization detects the EBV particles in examined tissues. The best treatment option is yet to be determined and the current treatment consists of immunosuppression reduction associated with the use of anti CD20 antibody and/or cytotoxic chemotherapy besides cell therapy only available in some centers. This study aimed to evaluate tumor response to the use of anti CD20 antibody in positive B-cell EBV PTLD after solid organ transplantation and the association of the neoplasia to the eventual inclusion of genomic EBV/DNA in the tumor cell. We retrospectively analyzed medical records of twenty-three patients under 18 years of age who were admitted to the inpatient unit of Serviço de Onco- Hematologia do Instituto da Criança (ICR) e Instituto do Tratamento do Câncer Infantil (ITACI) who developed histologically proven CD20 positive pediatric PTLD after solid organ transplantation between 8 March 1995 and 13 August 2011. All patients were submitted to immunosuppression reduction, thirteen received isolated Anti CD20, three Anti CD20 associated with cytotoxic chemotherapy and seven patients did not use this drug. The estimated 2-year overall survival rates of patients who received anti CD20 was 81.45% and when compared to the overall survival rates of those who did not receive the drug it was 37, 5%, showing a statistically significant difference (p = 0.02). All patients had the Epstein-Barr virus latency protein (latent membrane protein1 - LMP1) detected in tumor paraffin embedded stored at diagnosis by the in situ hybridization technic. The short duration of the Anti CD20 treatment, its acceptable toxicity compared to other therapeutic alternatives, the possibility of its exclusive use, its effectiveness in aggressive histology disease and the association with other treatment alternatives in refractory disease, suggest this drug inclusion to the currently available therapeutic arsenal

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2016-06-21T17:12:33Z No. of bitstreams: 1 cinthiadias_dissert.pdf: 1995817 bytes, checksum: 27317444195c0604e0ed14f9ac182ee5 (MD5) / Made available in DSpace on 2016-06-21T17:12:33Z (GMT). No. of bitstreams: 1 cinthiadias_dissert.pdf: 1995817 bytes, checksum: 27317444195c0604e0ed14f9ac182ee5 (MD5) Previous issue date: 2015-08-25 / Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP / Introduction: Stem cell therapy is a promising strategy to repair or delay the progression of chronic renal failure (CRF). Induced pluripotent stem cells (iPS) can be a therapeutic alternative due to their differentiation potential. Objectives: 1- To modify genetically stem cells from mice´s fibroblasts with lentiviral vectors containing transcription factors, transforming differentiated cells into iPS; 2- To evaluate the effect of iPS in the experimental IRC progression of IRC induced by 5/6 nephrectomy (CRF-5/6). Materials and Methods: The animals were divided according to the type of cell therapy received from extracted mesenchymal stem cells from bone marrow (MSC) or iPS and compared with CRF group 5/6 without treatment. Assessment of renal function was carried out during baseline and after 60 days. Additionally expression of genes, VEGF, IL-6, TGF-β and IL-10 were quantified in the kidney tissue, and also the analysis of implanted cell migration through the SRY gene. Immunohistochemical study evaluated the expression of CD68, α-SMA, TGF-β, PCNA and VEGF markers. Results: A significant decrease was observed in creatinine variation (p<0.05) and plasma urea (p<0.01) in animals treated with MSC and a 33%-decrease in plasma creatinine levels of animals treated with iPS cells, although non- significant when compared to the control group. The 24-hour proteinuria was significantly reduced only in the iPS group (p<0.0001). Significant improvement was observed in creatinine clearance in both treatments (p<0.04). Disease progression measured by the clearance decline rate was significantly lower only in the MSC group (p<0.05) and the urinary osmolality was similar in both treated groups. There was an increase in the expression of TGF- β gene in iPS group when compared to the control group (p<0.05) and VEGF expression in the groups treated with iPS and MSC (p<0.05). IL-6 and IL-10 showed similar expression levels in both treated groups (p=NS). Immunohistochemical analysis showed fewer macrophages and decreased cell proliferative activity (PCNA) in the iPS group p<0.05. Histological analysis showed a significant decrease in glomerulosclerosis in both treatment groups (p<0.01), tubular atrophy was similar in all groups . Leukocyte infiltration was reduced in both treatments when compared to CRF group. The SRY gene was detected in 5 out of 8 (62.5%) mice that were treated with iPS. After 60 days the tumor formations were observed in animals in which SRY gene was detected. Conclusions: MSC therapy is effective in delaying the progression of CKD. Treatment with iPS also improves some parameters of renal function but this assessment can be difficult since the onset of tumor formations; thus some care is necessary with this type of cells. / Introdução: A terapia com células-tronco (CT) é uma estratégia promissora para reparar ou retardar a progressão da insuficiência renal crônica (IRC). As células-tronco pluripotentes induzidas (iPS) podem ser uma alternativa terapêutica, em virtude de seu potencial de diferenciação. Objetivos: 1) Modificar geneticamente células de fibroblastos de ratos com vetores lentivirais contendo fatores de transcrição, transformando essas células diferenciadas em iPS; 2) Avaliar o efeito das iPS e CTM na progressão da IRC experimental induzida pela nefrectomia 5/6 (CRF5/6). Materiais e Métodos: Os animais foram divididos conforme o tipo de terapia celular recebida (célula-tronco mesenquimal extraída da medula óssea (CTM) ou com iPS) e comparados com o grupo CRF5/6. A avaliação da função renal foi realizada no período basal e após 60 dias. Adicionalmente foi quantificada a expressão dos genes, VEGF, IL-6, TGF-β e IL-10 no tecido renal e estudada a migração das células implantadas contendo o gene SRY. O estudo imunohistoquímico avaliou a expressão de marcadores CD68, α-SMA, TGF-β, PCNA e VEGF. Resultados: Redução significativa foi observada na variação da creatinina (p<0,05) e ureia plasmática (p<0,01) dos animais tratados com CTM e uma diminuição de 33% dos níveis de creatinina plasmática nos animais tratados com células iPS, porém sem significância estatística quando comparada ao grupo controle. A proteinúria de 24 horas foi reduzida somente no grupo iPS (p=0,0001) e houve melhora significativa no clearance de creatinina com ambos tratamentos (p=0,04). A progressão da doença, medida pela taxa de declínio do clearance de creatinina, foi significativamente lentificada somente no grupo CTM (p=0,04) e a osmolalidade urinária foi similar em ambos os grupos tratados. Houve aumento na expressão do gene TGF-β no grupo iPS quando comparado ao grupo controle (p=0,01) e da expressão de VEGF nos grupos tratados com iPS e CTM (p=0,01). IL-6 e IL-10 mostraram níveis de expressão semelhantes em ambos os grupos tratados (p=NS). A análise imunohistoquímica demonstrou menor número de macrófagos e diminuição da atividade proliferativa celular (PCNA) no grupo iPS p<0,05. A analise histológica mostrou diminuição significativa da glomeruloesclerose em ambos grupos tratados (p<0,01), a atrofia tubular foi semelhante nos três grupos. A infiltração leucocitária foi reduzida em ambos os tratamentos, quando comparados ao grupo CRF. O gene SRY foi detectado em 5 de 8 (62,5%) ratos que receberam tratamento com iPS. Após 60 dias foram observadas as formações tumorais nos respectivos animais em que o gene SRY foi detectado. Conclusões: A terapia com CTM é eficiente para retardar a progressão da IRC. Tratamento com iPS também melhora alguns parâmetros da função renal, mas o aparecimento de formações tumorais dificulta essa avaliação e requer cuidados com esse tipo de célula.

A doença linfoproliferativa pós transplante (DLPT) é a proliferação tecidual secundária mais comum em crianças submetidas a transplante de órgãos sólidos, e representa um espectro de proliferação linfoide clínica e morfologicamente heterogêneo que vai desde uma hiperplasia policlonal indolente até linfomas agressivos. Aproximadamente 80% das DLPT estão associadas ao vírus Epstein Barr (EBV) e é originaria de células B, entre 10 a 15% tem origem em células T e aproximadamente 1% em células natural killer. O status sorológico negativo para EBV pré transplante e o grau de imunossupressão são os fatores de risco de maior relevância para o desenvolvimento desta enfermidade. A apresentação clínica é diversa e sintomas constitucionais podem estar presentes simulando infecção e ou rejeição ao órgão transplantado. A confirmação do diagnóstico por exame histopatológico é, habitualmente, necessária e a hibridização in situ geralmente detecta as partículas de EBV nos tecidos examinados. A melhor opção terapêutica ainda não está definida e atualmente o tratamento consiste na redução da imunossupressão associada ao uso do anticorpo Anti CD20 e ou quimioterapia citotóxica além da terapia celular disponível em alguns centros. Este estudo teve por objetivos avaliar a resposta tumoral ao uso do anticorpo Anti CD20 na DLPT de células B EBV positivas pós transplante de órgãos sólidos, além de associar a neoplasia à eventual inclusão genômica de DNA/EBV na célula neoplásica. Foram analisados retrospectivamente os prontuários de vinte e três pacientes com até 18 anos incompletos admitidos na Unidade de Internação do Serviço de Onco- Hematologia do Instituto da Criança (ICR) e Instituto do Tratamento do Câncer Infantil (ITACI) que desenvolveram DLPT CD20 positiva pós transplante de órgãos sólidos comprovada histologicamente entre 8 de março de 1995 e 13 de agosto de 2011. Todos foram submetidos à redução da imunossupressão, treze receberam Anti CD20 isolado, três Anti CD20 associado à quimioterapia citotóxica e sete pacientes não fizeram uso desta droga. A sobrevida global em dois anos dos pacientes que receberam Anti CD20 foi de 81,45% e quando comparada à sobrevida global de 37,5% dos que não receberam a droga revelou diferença estatística significativa (p=0,02). Todos os pacientes tiveram a detecção da proteína de latência viral de EBV Latent Membrane Protein1 (LMP1) na célula tumoral através da técnica de hibridização in situ realizada em blocos de parafina devidamente armazenados ao diagnóstico. A curta duração do tratamento com o Anti CD20, a toxicidade aceitável em relação às demais alternativas terapêuticas, a possibilidade de seu uso exclusivo, sua eficácia inclusive na doença de histologia agressiva e associação às demais alternativas de tratamento na doença refratária sugerem a inclusão desta droga no arsenal terapêutico atualmente disponível / Post-transplant lymphoproliferative disease (PTLD) is the most common secondary tissue proliferation that occurs in children after solid organ transplantation and represents a spectrum of clinical lymphoid proliferation and morphologic heterogeneity that goes from an indolent polyclonal hyperplasia to aggressive lymphomas. Approximately 80% of PTLD is associated with Epstein Barr virus (EBV) and is of B-cell origin, 10 to 15% of T-cells and approximately 1% of natural killer cells. EBV pretransplant seronegativity and the degree of immunosuppression are the most relevant risk factors for developing the disease. Clinical presentation is diverse and constitutional symptoms may simulate infection and/or organ transplanted rejection. Histopathologic examination is usually necessary to confirm diagnosis and, generally, in situ hybridization detects the EBV particles in examined tissues. The best treatment option is yet to be determined and the current treatment consists of immunosuppression reduction associated with the use of anti CD20 antibody and/or cytotoxic chemotherapy besides cell therapy only available in some centers. This study aimed to evaluate tumor response to the use of anti CD20 antibody in positive B-cell EBV PTLD after solid organ transplantation and the association of the neoplasia to the eventual inclusion of genomic EBV/DNA in the tumor cell. We retrospectively analyzed medical records of twenty-three patients under 18 years of age who were admitted to the inpatient unit of Serviço de Onco- Hematologia do Instituto da Criança (ICR) e Instituto do Tratamento do Câncer Infantil (ITACI) who developed histologically proven CD20 positive pediatric PTLD after solid organ transplantation between 8 March 1995 and 13 August 2011. All patients were submitted to immunosuppression reduction, thirteen received isolated Anti CD20, three Anti CD20 associated with cytotoxic chemotherapy and seven patients did not use this drug. The estimated 2-year overall survival rates of patients who received anti CD20 was 81.45% and when compared to the overall survival rates of those who did not receive the drug it was 37, 5%, showing a statistically significant difference (p = 0.02). All patients had the Epstein-Barr virus latency protein (latent membrane protein1 - LMP1) detected in tumor paraffin embedded stored at diagnosis by the in situ hybridization technic. The short duration of the Anti CD20 treatment, its acceptable toxicity compared to other therapeutic alternatives, the possibility of its exclusive use, its effectiveness in aggressive histology disease and the association with other treatment alternatives in refractory disease, suggest this drug inclusion to the currently available therapeutic arsenal

This work is concerned with the characterization of mesenchymal stem cells (MSC) specifically from bone marrow samples derived from patients with osteoarthritis (OA). The multilineage potential of mesenchymal stem cells as well as their ease of exvivo expansion makes these cells an attractive therapeutic tool for applications such as autologous transplantation and tissue engineering. Bone marrow is considered a source of MSC. However, there is a general assumption that the occurrence of MSCs and their activity in bone marrow diminishes with age and disease. This prompted us to isolate and identify multipotential and self-renewing cells from patients with the degenerative disease osteoarthritis, with the view of using these cells for autologous cell therapies. It is therefore of great potential benefit to investigate the isolation and characterization of stem cell/progenitors from bone marrow samples of patients with osteoarthritis in greater detail. We employed a single cell clone culture method in order to develop clonal cell populations from three bone marrow samples and characterized them based on their proliferation and differentiation capabilities. The clonal populations were grouped into fast-growing and slow-growing clones based on their proliferation rates. The fastgrowing clones displayed 20-30% greater proliferation rate than the slow-growing clones. The study also revealed that the proliferation rates were directly proportional to their differentiation capacities. Most of the fast-growing clones were found to be tripotential for osteogenic, chondrogenic and adipogenic lineages, whereas the slow growing clones were either uni or bipotential. Flow cytometry analysis for the phenotype determination using putative MSC surface markers did not reveal any difference between the two clonal populations indicating a need for further molecular studies. Two approaches were employed to further investigate the molecular processes involved in the existence of such varying populations. In the first method gene expression studies were performed between the fast-growing (n=3) and slow-growing (n=3) clonal populations to identify potential genetic markers associated with cell 'sternness' using the Stem Cell RT2 ProfilerTM PCR Array comprising a series of 84 genes related to stem cell pathways. Ten genes were identified to be commonly and significantly over represented in the fast-growing stem cell clones when compared to slow-growing clones. This included expression of transcripts beyond MSC lineage specification such as SOX2, NOTCH1 and FOXA2 which signified that stem cell maintenance requires a coordinated regulation by multiple signalling pathways. The second study involved an extensive protein expression profiling of the fast growing (n=2) and slow growing (n=2) clonal populations using off-line Two Dimensional Liquid Chromatography (2D-LC)/Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry (MS). A total of 67 proteins were identified, of which 11 were expressed at significantly different levels between the subpopulations. Protein ontology revealed these proteins to be associated with cellular organization, cytokinesis, signal transduction, energy pathways and cell stress response. Of particular interest was the differential presentation of the proteins calmodulin, tropomyosin and caldesmon between fast- and slow-growing clones. Based on their reported roles in the regulation of cell proliferation and maintenance of cell integrity, we draw an association between their expression and the altered status in which the subpopulations exist. Based on our observations, these proteins may be prospective molecular markers to distinguish between the fast-growing and slow-growing subpopulations. In summary, this study demonstrated the existence of potential stem cells of therapeutic importance in spite of a supposedly smaller stem cell compartment in patients with osteoarthritis. Furthermore, the differentially expressed genes between the sub-populations highlight the 'sternness' of the potential clones, an observation supported by the expression of proteins which act as effective modulators in the maintenance of cell integrity and cell cycle regulation. This study provides a basis for more detailed investigations in search of selective cell surface markers

Current research on HIV therapy is diverse and multi-disciplinary. Engineers however, were late in joining the research movement and as such, engineering literature related to HIV chemotherapy is limited. Control engineers in particular, should have risen to the challenge, as it is apparent that HIV chemotherapy and control engineering have a lot in common. From a control theoretic point of view, HIV chemotherapy is control of a time varying nonlinear dynamical system with constrained controls. Once a suitable model has been developed or identified, control system theoretical concepts and design principles can be applied. The adopted control approach or strategy depends primarily on the control objectives, performance specifications and the control constraints. In principle, the designed control system can then be validated with clinical data. Obtaining measurements of the controlled variables however, has the potential to hinder effective control. The first part of this research focused on the application of control system analytical tools to HIV/AIDS models. The intention was to gain some insights into the HIV infection dynamics from a control theoretic perspective. The issues that needed to be addressed are: Persistent virus replication under potent HAART, variability in response to therapy between individuals on the same regimen, transient rebounds of plasma viremia after periods of suppression, the attainment, or lack thereof, of maximal and durable suppression of the viral load. The questions to answer were: When are the above mentioned observed responses to therapy most likely to occur as the HIV infection progresses, and does attaining one necessarily imply the other? Furthermore, the prognostic markers of virologic success, the possibility of individualizing therapy and timing the initiation of antiretroviral therapy such that the benefits of therapy are maximized, are matters that were also investigated. The primary objective of this thesis was to analyze models for the eventual control of the HIV infection. HIV therapy has multiple and often conflicting objectives, and these objectives had to be prioritized. The intention of the proposed control strategy was to produce practical solutions to the current antiretroviral problems. To this end, the second part of the research focused on addressing the HIV/AIDS control issues of sampling for effective control given the invasive nature of drawing blood from a patient and the derivation of drug dosage sequences to strike a balance between maximal suppression and toxicity reduction, when multiple drugs are concomitantly used to treat the infection. / Thesis (PhD)--University of Pretoria, 2006. / Electrical, Electronic and Computer Engineering / Unrestricted

In-home family therapy has become one of the most common options of treatment for providing services to families who do not typically utilize a private clinic (Lawson, 2005; Reiter, 2000; Yorgason, McWey, & Felts, 2005). Researchers have given some attention to the topic of home-based therapy and to general supervision, but little attention has focused on the actual supervision experiences of home-based therapy providers. This phenomenological study explored the supervision experiences of seven past and current in-home therapists: marriage and family therapists (MFTs) and social workers (MSWs). Semi-structured interviews were conducted with the participants, and data was analyzed to develop structured descriptions and meanings via highlighted “significant statements” that described the participants’ experiences (Kvale, 2007). The participants’ descriptive accounts were categorized as 1) in-home therapy descriptions, 2) factors affecting in-home therapy supervision, and 3) effective and ineffective supervisory practices. Implications of the research findings suggested that clinicians’ needs and expectations related to safety, burn out, and supervisory knowledge were often unmet. Supervisory practices that appeared significantly effective were 1) developing trusting supervisor-supervisee relationships, 2) reviewing models and clinical application collaboratively, and 3) actively prioritizing clinician safety and burn out prevention.

No description available.

Background: The focus of this study was to investigate how producing human bone marrow (hBM) derived mesenchymal stromal cell (MSC) extracellular vehicles (EVs) in a high purity isolation system would affect their established characterization criteria and address the validity of these methods of EV production. Additionally, we set out to functionally characterize the hBM-MSC-EVs for their identified immunomodulatory ability while also assessing the presence of novel MSC-EV marker NRP1 identified by our group to further affirm its validity as a functional MSC-EV identity marker. Methods: Each hBM-MSC-EV donor was cultured in a hollow-fiber bioreactor system in non-stimulating serum/xeno-free conditions for 25 days to produce EVs persistently under quiescent conditions to characterize the hBM-MSC-EVs in their native form. EVs were isolated by traditional PEG-based precipitation for preliminary characterization to monitor bioreactor production wherein they were characterized using multimodal tangential flow filtration coupled with fast protein liquid chromatograph (FPLC) size exclusion/high-affinity purifications to obtain the final highly purified EV sample. Additionally, functional analysis of their immunomodulatory ability, EVs and MSCs were incubated with activated peripheral blood mononuclear cells (PBMCs) as an in-vitro model to evaluate their potency. Results: The hBM-MSC-EVs produced from the bioreactor system showed consistent characterization in accordance with the MISEV2018 establish criteria. We were also able to demonstrate their functional ability by observing statistically significantly immunomodulatory ability of activated PBMCs equivalent to native MSC ability. We were also able to validate the present of NRP1 on all hBM-MSC-EV samples produced confirming its validity as a MSC-EV marker. Conclusion: The significance of the results obtained from this study confirms the production of MSC-EV using a bioreactor and high purity isolation for obtaining consistent MSC-EVs for downstream investigation. Additionally, we were able to demonstrate the significance of MSC-EVs on MSC signaling for immunomodulation by showing equivalent functional potency when tested in-vitro. These results contribute to further understanding the biological attributes of MSC-EVs and contribute to the validation of currently established characterization guidelines.