Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that aim to develop a disease-modifying therapy that slows the progression of PD. These clinical trials are evaluating the safety and feasibility of an autologous peripheral nerve graft to the substantia nigra in combination with Deep Brain Stimulation (DBS) for the treatment of PD. By grafting peripheral nerve tissue to the Substantia Nigra, the researchers aim to introduce peripheral nerve tissue, which is capable of functional regeneration after injury, to the degenerating Substantia Nigra of patients with PD. The central hypothesis of these clinical trials is that the grafted tissue will slow degeneration of the target brain region through neural repair actions of Schwann cells as well as other pro-regenerative features of the peripheral nerve tissue. This dissertation details analysis of the peripheral nerve tissue used in the above clinical trials with respect to tissue composition and gene expression, both of injury-naive human peripheral nerve as well as the post-conditioning injury nerve tissue used in the grafting procedure. RNA-seq analysis of sural nerve tissue pre and post-conditioning show significant changes in gene expression corresponding with transdifferentiation of Schwann cells from a myelinating to a repair phenotype, release of growth factors, activation of macrophages and other immune cells, and an increase in anti-apoptotic and neuroprotective gene transcripts. These results reveal in vivo gene expression changes involved in the human peripheral nerve injury repair process, which has relevance beyond this clinical trial to the fields of Schwann cell biology and peripheral nerve repair. To assess the neurobiology of the graft post-implantation we developed an animal model of the grafting procedure, termed Neuro-Avatars, which feature human graft tissue implanted into athymic nude rats. Survival and infiltration of human graft cells into the host brain were shown using immunohistochemistry of Human Nuclear Antigen. Surgical methods and outcomes from the ongoing development of this animal model are reported. To connect the results of these laboratory studies to the clinical trial we compared the severity of motor symptoms before surgery to one year post-surgery in patients who received the analyzed graft tissue. Motor symptom severity was assessed using the Unified Parkinson’s Disease Rating Scale Part III. Finally, the implications and future directions of this research is discussed. In summary, this dissertation advances the translational science cycle by using clinical trial findings and samples to answer basic science questions that will in turn guide future clinical trial design.

Immediate Breast Reconstruction Surgery (IBRS) is associated with better quality of life among women who undergo a mastectomy. Despite insurance coverage for IBRS, utilization of IBRS remains low. Data from publicly available sources for 2010-2012 are used to examine the association between hospital characteristics receipt of IBRS by patients. Minority-serving status, low bed size, for-profit ownership, non-teaching status, high competition, low density of plastic surgeons in the market and non-metropolitan location are associated with lower likelihood of receipt of IBRS. Racial and ethnic minorities are less likely to receive IBRS. A mixed effects logistic regression model with interactions between Black/Hispanic race/ethnicity and hospital variables is estimated to examine whether certain hospital characteristics are associated with disparately low receipt of IBRS for racial and ethnic minorities. Minority-serving hospitals located in markets with a higher density of plastic surgeons and higher competition characteristics are associated with disparately low receipt of IBRS for racial and ethnic minorities. In order to reduce racial/ ethnic differences in receipt of IBRS, it is important to understand which factors contribute the most to these differences. Fairlie decomposition is used to examine the contribution of multi-level factors to racial and ethnic differences in receipt of IBRS. Racial and ethnic differences in being Medicaid insured, residing in low-income neighborhoods and receiving care at minority-serving hospitals are the three largest contributors to racial and ethnic differences in receipt of IBRS. The results from this study have significant implications for access to IBRS among racial and ethnic minority patients.

<p>The mortality of thoracic aortic diseases (mainly aneurysms and dissections) is high, even with surgical treatment. Epidemiology and long-term outcomes are incompletely investigated. Stroke is a major complication contributing to mortality, morbidity, and possibly to reduced quality of life. </p><p><i>Study I</i> Increasing incidence of thoracic aortic diseases 1987 – 2002 was demonstrated (n=14229). Annual number of operations increased eight-fold. Overall long-time survival was 92%, 77%, and 57% at 1, 5, and 10 years. Risk of operative and long-term mortality was reduced across time.</p><p><i>Study II</i> 2634 patients operated on the proximal thoracic aorta (Swedish Heart Surgery register) were examined. Aortic valve replacement, coronary revascularization, emergency operation, and age were independently associated with surgical death. Long-term mortality was similar for aneurysms and dissections. Operative mortality was reduced (13.7% vs 7.2%) for aneurysms but remained unchanged (22.3% vs 22.4%) for dissections across time.</p><p><i>Study III</i> 65 patients underwent selective antegrade cerebral perfusion (SACP) uni- or bilaterally. Stroke was significantly more common after unilateral SACP (29% vs 8%, p=0.045), confirmed by propensity score-matched analysis. Subclavian artery cannulation with Seldinger-technique entailed vascular complication in one case (1.5%).</p><p><i>Study IV</i> Near-infrared spectroscopy (NIRS) was used to monitor cerebral tissue saturation (rSO2) during SACP in 46 patients. Lower rSO2 were encountered (1) in patients suffering a stroke (2) with unilateral SACP, and (3) in the affected hemisphere of stroke victims. A decrease of rSO2 by 14 – 21% from baseline increased the risk of stroke significantly.</p><p><i>Study V</i> Quality of life (QoL) in 76 survivors of thoracic aortic surgery was examined with the SF-36 health questionnaire. Except for pain, QoL was reduced in all dimensions. QoL was not affected by acuity of operation. Tendencies of lower QoL after descending aortic operations, after major complications, and with persistent dysfunction were non-significant.</p>

No description available.

The mortality of thoracic aortic diseases (mainly aneurysms and dissections) is high, even with surgical treatment. Epidemiology and long-term outcomes are incompletely investigated. Stroke is a major complication contributing to mortality, morbidity, and possibly to reduced quality of life. Study I Increasing incidence of thoracic aortic diseases 1987 – 2002 was demonstrated (n=14229). Annual number of operations increased eight-fold. Overall long-time survival was 92%, 77%, and 57% at 1, 5, and 10 years. Risk of operative and long-term mortality was reduced across time. Study II 2634 patients operated on the proximal thoracic aorta (Swedish Heart Surgery register) were examined. Aortic valve replacement, coronary revascularization, emergency operation, and age were independently associated with surgical death. Long-term mortality was similar for aneurysms and dissections. Operative mortality was reduced (13.7% vs 7.2%) for aneurysms but remained unchanged (22.3% vs 22.4%) for dissections across time. Study III 65 patients underwent selective antegrade cerebral perfusion (SACP) uni- or bilaterally. Stroke was significantly more common after unilateral SACP (29% vs 8%, p=0.045), confirmed by propensity score-matched analysis. Subclavian artery cannulation with Seldinger-technique entailed vascular complication in one case (1.5%). Study IV Near-infrared spectroscopy (NIRS) was used to monitor cerebral tissue saturation (rSO2) during SACP in 46 patients. Lower rSO2 were encountered (1) in patients suffering a stroke (2) with unilateral SACP, and (3) in the affected hemisphere of stroke victims. A decrease of rSO2 by 14 – 21% from baseline increased the risk of stroke significantly. Study V Quality of life (QoL) in 76 survivors of thoracic aortic surgery was examined with the SF-36 health questionnaire. Except for pain, QoL was reduced in all dimensions. QoL was not affected by acuity of operation. Tendencies of lower QoL after descending aortic operations, after major complications, and with persistent dysfunction were non-significant.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 5 uppsatser.

Made available in DSpace on 2015-07-22T20:50:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-25. Added 1 bitstream(s) on 2015-08-11T03:25:36Z : No. of bitstreams: 1 Publico-045.pdf: 1293717 bytes, checksum: aa77a18d9ad66fac463c08766304abf5 (MD5) / Objetivo: avaliar os resultados anatômicos, funcionais e complicações do tratamento do prolapso da parede vaginal anterior com tela de submucosa de intestino delgado suíno (SIS) e com colporrafia anterior. Pacientes e Métodos: estudo prospectivo e randomizado para comparação do uso de tela de SIS e de colporrafia tradicional. As mulheres foram avaliadas no pré-operatório e com seis meses após a cirurgia. Os parâmetros utilizados foram: sistema de quantificação do prolapso genital (POP-Q), questionário de qualidade de vida validado (P-QoL) e complicações. Os dados foram analisados pelo teste de Mann-Whitney e Qui-quadrado para avaliação da homogeneidade entre os grupos. A seguir, utilizamos o teste t-Student pareado ou teste t-Student de amostras independentes. O estudo foi aprovado pelo Comitê de Ética Local e registrado no ClinicalTrials com o número NCT00827528. Resultados: os resultados representam a análise de 29 pacientes no grupo com tela de SIS e 27 no grupo com colporrafia tradicional. Os grupos foram semelhantes consoante idade, índice de massa corpórea, paridade, estádio do prolapso, cirurgia prévia para prolapso, presença de incontinência urinária de esforço, pontuação no questionário de qualidade de vida e medidas dos pontos anatômicos no pré-operatório. Com seis meses de seguimento, a taxa de cura anatômica no grupo com tela foi de 86,2% comparada com 59,3% no grupo da colporrafia, pelo critério da Sociedade Internacional de Continência (ICS). Não houve diferença de sucesso anatômico entre as técnicas quando consideramos a subdivisão do estádio II. A média do ponto Ba, pré-operatória, no grupo com tela foi de +2,07 cm e +2,22 cm na colporrafia e, no pós-operatório, de -1,93 cm (p<0,001) e de -1,37 cm (p<0,001), respectivamente. O NNT (Número Necessário a Tratar) foi 4. Ambos os procedimentos melhoraram de forma significativa as medidas de qualidade de vida. Contudo, o grupo com tela não demonstrou diferença quando comparado ao da colporrafia tradicional. Houve 4 pacientes com sangramento excessivo no grupo SIS, embora nenhuma requereu hemotransfusão. Observamos maior número de complicações no grupo SIS (20 vs 9; p=0,01) e maior tempo cirúrgico (48,3 min ±16,1 vs 30,3min ±19,4; p=0,001). O tempo de internação hospitalar foi de 3,3 e 3,2 dias, respectivamente. Não houve casos de infecção ou de erosão da tela. Conclusão: As cirurgias para o prolapso genital resultam em melhora significativa da qualidade de vida. Observamos melhor cura anatômica do ponto Ba com tela, de acordo com o critério da ICS. Consoante os parâmetros de qualidade de vida não houve diferença entre as técnicas. Houve maior número de complicações no grupo com tela. / Objective: the aim of this study was to evaluate anatomical, functional results and complications of small intestine submucosa (SIS) graft compared to traditional anterior repair in surgical treatment of anterior vaginal wall prolapse. Methods: This is a randomized and prospective study to compare the SIS graft with traditional colporrhaphy (TC) in surgical treatment of anterior vaginal prolapse. Subjects were randomized to SIS (n=29) or to TC (n=27) and compared preoperatively and at 6 months postoperatively. We used pelvic organ quantification system (POP-Q), a validated prolapse quality of life questionnaire (P-QoL) and possible complications. Data were compared using the Mann–Whitney test or a chi-squared test to determine that there were no significant intergroup differences. This then enabled us to use the independent samples t-test or the paired Student’s t-test. This study was approved by Local Ethics Committee and register at ClinicalTrials NCT00827528. Results: the outcomes represent the analysis of 29 patients in SIS group and 27 in traditional repair. Both groups were paired by age, parity, body mass index, stage of anterior prolapse, previous surgery for prolapse, presence of incontinence, POP-Q measurements and quality of life preoperatively. At 6-month follow-up, SIS group have 86.2% anatomic cure comparing with 59.3% in traditional repair, using the International Continence Society (ICS) patterns. We did not report differences between the techniques when we divided the stage II. The mean point Ba preoperatively in SIS group was +2.07 cm and +2.22 cm in traditional repair and postoperatively -1.93 cm (p<0.001) and -1.37 cm (p<0.001), respectively. The NNT (Number Need to Treat) was 4. Both operations significantly improved prolapse quality-of-life severity measures. Although SIS group did not showed significant improvement in quality-of-life parameters measured in comparison to traditional repair. Excessive bleeding occurred in 4 patients in SIS group although none required blood transfusion. We reported more complications in SIS group (20 vs 9, p=0.01) and longer surgical time (48.3min ±16.1 vs 30.3min ±19.4; p=0.001). The average hospital length was 3.3 and 3.2 days, respectively. We did not reported infections or erosion of the mesh. Conclusions: Surgery for vaginal prolapse results in marked improvement in prolapse quality of life. We could see that SIS repair improved point Ba measurement significantly using the ICS patterns. Regarding quality-of-life parameters we did not observe significant differences in both techniques. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2015-12-06T23:02:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2001 / Qualidade dos ensaios clinicos aleatorios em Cirurgia Plastica. Contexto. A avaliacao da qualidade dos ensaios clinicos aleatorios e importante, pois a observacao dos erros e falhas nos permite evita-los no planejamento. conducao, analise e publicacao de futuros estudos. E e fundamental para se determinar o grau de confiabilidade dos resultados dos estudos publicados. Objetivo. Avaliar a qualidade dos ensaios clinicos aleatorios em Cirurgia Plastica. A hipotese testada foi a de que os estudos sao de ma qualidade. Tipo de estudo. Estudo descritivo com a avaliacao realizada por dois pesquisadores, de maneira independente, seguida de uma reuniao de consenso. Selecao da amostra. Ensaios clinicos aleatorios em Cirurgia Plastica, com sigilo de alocacao descrito adequadamente, realizado por/ou com a participacao de pelo menos um cirurgiao plastico, foram identificados atraves da busca eletronica nas bases de dados LILACS, MEDLINE, EMBASE e CCTR. Variavel estudada. Qualidade dos ensaios clinicos aleatorios, por meio da Lista de Delphi, de uma escala de qualidade (JADAD et al., 1996) e de cinco itens complementares. Resultados. Dos 139 estudos publicados como ensaios clinicos aleatorios, 63 por cento (88/139) nao descreveram o sigilo de alocacao, em 17 por cento (23/139) o sigilo de alocacao foi inadequado e 20 por cento (28/139) descreveram o sigilo de alocacao adequadamente. Dos 28 ensaios clinicos aleatorios, com sigilo de alocacao descrito adequadamente, 25 por cento nao descreveram a geracao da sequencia de alocacao, 82 por cento nao descreveram as perdas e exclusoes, 68 por cento nao descreveram se os grupos eram comparaveis, 50 por cento nao especificaram os criterios de inclusao e exclusao, 68 por cento nao apresentaram as medidas de variabilidade e as estimativas dos pontos para a variavel primaria, 61 por cento nao apresentaram uma analise por intencao de tratar. Na pontuacao pela escala de qualidade (JADAD et al., 1996), 71 por cento (20/28) receberam dois ou menos pontos. Conclusao. Os ensaios clinicos aleatorios em Cirurgia Plastica sao de ma qualidade / Quality of randomized clinical trials in Plastic Surgery. Context. The valuation of the quality of the randomized clinical trials is important since the observation of the mistakes and failures allows us to avoid them during planning, performing, analysis and publishing of future studies. It is fundamental in order to determine the reliability degree of the results of the published studies. Objective. To evaluate the quality of randomized clinical trials in Plastic Surgery. The hypothesis tested was the one stating that the studies are low quality ones. Type of study. Descriptive study with the valuation performed by two appraisers, in an independent way, followed by a consensus meeting. Study selection. Randomized clinical trials in Plastic Surgery, with allocation concealment suitably described, performed by/or with the participation of, at least, one plastic surgeon, were identified through electronic search in the basis of LILACS, EMBASE, MEDLINE and CCTR data. Studied variable. Quality of the randomized clinical trials, through Delphi List, through a quality scale (JADAD et al., 1996) and five complementary items. Results. From 139 studies published as randomized clinical trials, 63% (88/139) didn’t describe allocation concealment, in 17% (23/139) it was unsuited and 20% described it suitably. From 28 randomized clinical trials with allocation concealment suitably described, 25% didn’t describe the formation of the allocation sequence, 82% didn’t describe the loss and exclusion, 68% didn’t describe if the groups were comparable, 50% didn’t specify the inclusion and exclusion criteria, 68% didn’t present the variability measures and the points estimation for a primary variable, 61% didn’t present an analysis for a treating intention. In the punctuation by the quality scale (JADAD et al., 1996), 71% (20/28) got two or less points. Conclusion. The randomized clinical trials in Plastic Surgery are low quality ones. / BV UNIFESP: Teses e dissertações

NOD mice model human type 1 diabetes and have been used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. Costimulation blockade-based tolerance protocols that induce prolonged skin and permanent islet allograft survival in non-autoimmune mice have failed in NOD mice. To investigate the underlying mechanisms, we generated NOD hematopoietic chimeras. We were able to show that dendritic cell maturation defects seen in NOD mice are partially corrected in mixed hematopoietic chimeras. Furthermore, skin allograft survival was dependent upon the phenotype of the bone marrow donor, demonstrating that in the NOD the resistance to tolerance induction resides in the hematopoietic compartment. In addition, we studied congenic NOD mice bearing insulin dependent diabetes (Idd) loci that reduce diabetes incidence. The incidence of diabetes is reduced in NOD.B6 Idd3 mice, and virtually absent in NOD.B6 Idd3Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice is prolonged as compared to NOD mice, and in NOD.B6 Idd3Idd5 mice islet allograft survival is similar to that achieved in C57BL/6 mice. Alloreactive CD8 T cell depletion in NOD mice treated with costimulation blockade is impaired, but is partially restored in NOD.B6 Idd3 mice, and completely restored in NOD.B6 Idd3Idd5 mice. Idd3 results from variations in Il2 gene transcription. We hypothesized insufficient levels of IL-2 in NOD mice contributes to impaired deletion of alloreactive CD8 T cells and shortened islet allograft survival. We observed using synchimeric mice that co-administration of exogenous IL-2 to NOD mice treated with costimulation blockade led to deletion of alloreactive CD8 T cells comparable to that in C57BL/6 mice and prolonged islet allograft survival. However, some Idd loci impaired the induction of transplantation tolerance. These data suggest that Idd loci can facilitate or impair induction of transplantation tolerance by costimulation blockade, and that Idd3 (IL-2) is critical component in this process.