Esta tese sustenta que as características sociodemográficas, ocupacionais e de situação de saúde constituem fatores de adoecimento ou de proteção para a ocorrência de acidentes de trabalho, alterações musculoesqueléticas e doenças do trabalho em trabalhadores de uma instituição hospitalar. O objetivo geral foi identificar os fatores de proteção e de adoecimento para ocorrência de acidentes de trabalho, alterações musculoesqueléticas e doenças do trabalho em trabalhadores de uma instituição hospitalar. Trata-se de um estudo transversal, cujo cenário foi o Hospital de Clínicas de Porto Alegre (HCPA), no qual foram abordados 288 trabalhadores e seus respectivos prontuários, de 54 ocupações distintas, no período entre 2010 a 2012. Utilizou-se para a coleta o banco de dados da pesquisa aprovada pelo Comitê de Ética e Pesquisa HCPA, sob o registro 11-315. Os dados foram analisados por estatística descritiva e analítica, considerando o nível de significância de 95%, QuiQuadrado e Regressão de Poisson. Na abordagem do trabalhador, verificou-se a prevalência do sexo feminino, maiores de 40 anos, residentes em Porto Alegre, que realizavam atividade física e de lazer, profissionais da área da Enfermagem, e regime de trabalho diurno. Uma menor proporção relatou trabalhar em outra instituição; hospitalizações; acidentes de trabalho; as doenças do trabalho; e doenças crônicas. No prontuário do trabalhador, observou-se o predomínio da admissão inferior a dez anos, risco biológico, risco ergonômico, realização do exame periódico médico, doença crônica e afastamentos laborais. Os acidentes de trabalho, as doenças do trabalho e as alterações musculoesqueléticas tiveram menor prevalência nos registros dos prontuários. Dentre os fatores que potencializam o adoecimento por acidentes de trabalho, identificou-se consumo de tabaco alguma vez na vida (RP=1,80; p=0,010) e o afastamento laboral registrado nos últimos três anos (RP=5,79; p=0,014). As alterações musculoesqueléticas mostraram associação com a situação conjugal sem companheiro (RP=1,69; p=0,005), ter filhos (RP=1,55; p=0,032), e o afastamento laboral nos últimos três anos (RP=2,04; p=0,008). As doenças do trabalho, como fatores de adoecimento, associam-se à mudança da situação conjugal (RP=3,51; p=0,020), risco ergonômico (RP=2,60; p=0,038) e limitação funcional no período de três anos (RP=4,38; p=0,006). Dentre os fatores de proteção, observou-se a associação com a carga horária diária menor que 6 horas e 15 minutos (RP=0,41; p=0,007) e os acidentes de trabalho. Para as doenças do trabalho, a associação protetora ocorreu dentre trabalhadores com risco biológico (RP=0,24; p=0,028) e os que realizam o exame periódico médico (RP=0,36; p=0,015). Os resultados evidenciaram fatores fatores de adoecimento e de proteção à saúde do trabalhador que reforçam a necessidade de articulação de ações que valorizem a co-reponsabilização do trabalhador e da instituição, de modo a se tecerem as estratégias para a prevenção de acidentes de trabalho, alterações musculoesqueléticas e doenças do trabalho. / This thesis sustains that sociodemographic characteristics, occupational and health condition compose illness or protection factors for work accidents occurrence, musculoskeletal disorders and work diseases, considering workers of a hospital institution. The general objective was to identify the protective factors for illness and accidents, musculoskeletal disorders and occupational diseases in workers of a hospital institution. It is a transversal study, whose scenario was the Hospital de Clínicas de Porto Alegre (HCPA), in which 288 workers from 54 different occupations were approached along with their related medical records, in the period between 2010 and 2012. The data collection was performed using the data bank from a former research work approved by the Research Ethics Committee of HCPA, under the record 11-315. The data were analyzed using descriptive and analytical statistics, considering a confidence interval of 95%, chi-square and Poisson regression. At worker approach it was verified the prevalence of females, over 40 years, residents in Porto Alegre, practitioners of physical and relaxing activities, nursing area professionals, and daytime workers. A less portion reported working in a second institution; hospitalizations; work accidents; work diseases; and chronic diseases. It was observed, inside the worker medical record, the predominance of admission lower than ten years, biological risk, ergonomic risk, periodic medical exams, chronic disease and work absence. Work accidents, work diseases and musculoskeletal disorders were observed having low prevalence in workers medical records. Among the factors that leverage the illness by work accidents, it was identified the tobacco consumption at least once in life (RP=1.80; p=0.010) and work absence recorded in the last three years (RP=5.79; p=0.014). Musculoskeletal disorders indicates association with marital status as without partner (RP=1.69; p=0.005), have children (RP=1.55; p=0.032), and work absence in the last three years (RP=2.04; p=0.008). Work diseases, as illness factors, were associated with marital status change (RP=3.51; p=0.020), ergonomic risk (RP=2.60; p=0.038) and functional limitation in the period of three years (RP=4.38; p=0.006). Among protection factors, it was observed an association with working time lower than 6 hours and 15 minutes (RP=0.41; p=0.007) and work accidents. For work diseases, the protection association occurred among workers with biological risk (RP=0.24; p=0.028) and among ones that underwent periodic medical exams (RP=0.36; p=0.015). Results pointed out factors of illness and worker health protection that reinforces the need of articulated actions and that enhance the co-responsibility of worker and institution, in the way to create strategies to prevent work accidents, musculoskeletal disorders and work diseases. / Esta tesis sostiene que las características sociodemográficas ocupacionales y de situación de salud constituyen factores de generación de enfermedades o de protección para la ocurrencia de accidentes de trabajo, alteraciones musculoesqueléticas y dolencias laborales en trabajadores de una institución hospitalaria. El objetivo general fue identificar los factores de protección y enfermedades en la ocurrencia de accidentes, alteraciones musculoesqueléticas y enfermedades profesionales en los trabajadores de una institución hospitalaria. Se trata de un estudio transversal cuyo escenario fue el Hospital de Clínicas de Porto Alegre (HCPA), en el cual fueron abordados 288 trabajadores y sus respectivos prontuarios, de 54 ocupaciones distintas, en el periodo entre 2010 a 2012. Fue utilizada para la colecta el banco de datos de la pesquisa aprobada por el Comité de Ética y Pesquisa HCPA, sob el registro de 11-35. Los datos fueron analizados por estadística considerando el nivel de relevancia de 95%, Qui-cuadrado y Regresión de Poisson. En el abordaje del trabajador fue verificada la prevalencia del sexo femenino, mayores de 40 años, residentes en Porto Alegre, que realizaban actividad fisica y de ocio, profesionales del área de enfermería y régimen de trabajo diurno. Una menos proporción relató trabajar en otra institución; hospitalización; accidentes de trabajo; las dolencias laborales y crónicas. En el prontuario del trabajador fue observado el dominio de la admisión inferior a diez años, riesgo biológico, riesgo ergonómico, realización de examen médico periódico, enfermedad crónica y alejamientos laborales. Los accidentes de trabajo, las enfermedades laborales y las alteraciones musculoesqueléticas tuvieron menor prevalencia en los registros de los prontuarios. Entre los factores que potencializaron las enfermedades por accidentes de trabajo fueron identificados el consumo de tabaco alguna vez en la vida (RP=1,80; p=0,010) y el alejamiento laboral registrado en los últimos tres años (RP=5,79; p=0,014). Las alteraciones musculoesqueléticas mostraron asociación con la situación conjugal sin compañero (RP=1,69; p=0,005), tener hijos (RP=1,55; p=0,032) y el alejamiento laboral en los últimos tres años (RP=2,04; p=0,008). Las enfermedades de trabajo como factoras de dolencias están asociadas a la mudanza de situación conjugal (RP=3,51; p=0,020), riesgo ergonómico (RP=2,60; 0,038) y limitación funcional en el periodo de tres años (RP=4,38; p=0,006). En lo que respecta a los factores de protección, se observó la asociación con la carga horaria diaria menor que 6 horas y 15 minutos (RP=0,41; p=0,007) y los accidentes de trabajo. Para las dolencias laborales, la asociación protectora ocurrió entre los trabajadores con riesgo biológico (RP=0,24; p=0,028) y los que realizan el examen médico periódico (RP=0,36; p=0,015). Los resultados evidenciaron factores de enfermedades y de protección a la salud del trabajador que refuerzan la necesidad de articulación de acciones que valoren la corresponsabilidad del trabajador y de la institución de manera a generar estrategias para la prevención de accidentes laborales, alteraciones musculoesqueléticas y dolencias laborales.

Esta tese sustenta que as características sociodemográficas, ocupacionais e de situação de saúde constituem fatores de adoecimento ou de proteção para a ocorrência de acidentes de trabalho, alterações musculoesqueléticas e doenças do trabalho em trabalhadores de uma instituição hospitalar. O objetivo geral foi identificar os fatores de proteção e de adoecimento para ocorrência de acidentes de trabalho, alterações musculoesqueléticas e doenças do trabalho em trabalhadores de uma instituição hospitalar. Trata-se de um estudo transversal, cujo cenário foi o Hospital de Clínicas de Porto Alegre (HCPA), no qual foram abordados 288 trabalhadores e seus respectivos prontuários, de 54 ocupações distintas, no período entre 2010 a 2012. Utilizou-se para a coleta o banco de dados da pesquisa aprovada pelo Comitê de Ética e Pesquisa HCPA, sob o registro 11-315. Os dados foram analisados por estatística descritiva e analítica, considerando o nível de significância de 95%, QuiQuadrado e Regressão de Poisson. Na abordagem do trabalhador, verificou-se a prevalência do sexo feminino, maiores de 40 anos, residentes em Porto Alegre, que realizavam atividade física e de lazer, profissionais da área da Enfermagem, e regime de trabalho diurno. Uma menor proporção relatou trabalhar em outra instituição; hospitalizações; acidentes de trabalho; as doenças do trabalho; e doenças crônicas. No prontuário do trabalhador, observou-se o predomínio da admissão inferior a dez anos, risco biológico, risco ergonômico, realização do exame periódico médico, doença crônica e afastamentos laborais. Os acidentes de trabalho, as doenças do trabalho e as alterações musculoesqueléticas tiveram menor prevalência nos registros dos prontuários. Dentre os fatores que potencializam o adoecimento por acidentes de trabalho, identificou-se consumo de tabaco alguma vez na vida (RP=1,80; p=0,010) e o afastamento laboral registrado nos últimos três anos (RP=5,79; p=0,014). As alterações musculoesqueléticas mostraram associação com a situação conjugal sem companheiro (RP=1,69; p=0,005), ter filhos (RP=1,55; p=0,032), e o afastamento laboral nos últimos três anos (RP=2,04; p=0,008). As doenças do trabalho, como fatores de adoecimento, associam-se à mudança da situação conjugal (RP=3,51; p=0,020), risco ergonômico (RP=2,60; p=0,038) e limitação funcional no período de três anos (RP=4,38; p=0,006). Dentre os fatores de proteção, observou-se a associação com a carga horária diária menor que 6 horas e 15 minutos (RP=0,41; p=0,007) e os acidentes de trabalho. Para as doenças do trabalho, a associação protetora ocorreu dentre trabalhadores com risco biológico (RP=0,24; p=0,028) e os que realizam o exame periódico médico (RP=0,36; p=0,015). Os resultados evidenciaram fatores fatores de adoecimento e de proteção à saúde do trabalhador que reforçam a necessidade de articulação de ações que valorizem a co-reponsabilização do trabalhador e da instituição, de modo a se tecerem as estratégias para a prevenção de acidentes de trabalho, alterações musculoesqueléticas e doenças do trabalho. / This thesis sustains that sociodemographic characteristics, occupational and health condition compose illness or protection factors for work accidents occurrence, musculoskeletal disorders and work diseases, considering workers of a hospital institution. The general objective was to identify the protective factors for illness and accidents, musculoskeletal disorders and occupational diseases in workers of a hospital institution. It is a transversal study, whose scenario was the Hospital de Clínicas de Porto Alegre (HCPA), in which 288 workers from 54 different occupations were approached along with their related medical records, in the period between 2010 and 2012. The data collection was performed using the data bank from a former research work approved by the Research Ethics Committee of HCPA, under the record 11-315. The data were analyzed using descriptive and analytical statistics, considering a confidence interval of 95%, chi-square and Poisson regression. At worker approach it was verified the prevalence of females, over 40 years, residents in Porto Alegre, practitioners of physical and relaxing activities, nursing area professionals, and daytime workers. A less portion reported working in a second institution; hospitalizations; work accidents; work diseases; and chronic diseases. It was observed, inside the worker medical record, the predominance of admission lower than ten years, biological risk, ergonomic risk, periodic medical exams, chronic disease and work absence. Work accidents, work diseases and musculoskeletal disorders were observed having low prevalence in workers medical records. Among the factors that leverage the illness by work accidents, it was identified the tobacco consumption at least once in life (RP=1.80; p=0.010) and work absence recorded in the last three years (RP=5.79; p=0.014). Musculoskeletal disorders indicates association with marital status as without partner (RP=1.69; p=0.005), have children (RP=1.55; p=0.032), and work absence in the last three years (RP=2.04; p=0.008). Work diseases, as illness factors, were associated with marital status change (RP=3.51; p=0.020), ergonomic risk (RP=2.60; p=0.038) and functional limitation in the period of three years (RP=4.38; p=0.006). Among protection factors, it was observed an association with working time lower than 6 hours and 15 minutes (RP=0.41; p=0.007) and work accidents. For work diseases, the protection association occurred among workers with biological risk (RP=0.24; p=0.028) and among ones that underwent periodic medical exams (RP=0.36; p=0.015). Results pointed out factors of illness and worker health protection that reinforces the need of articulated actions and that enhance the co-responsibility of worker and institution, in the way to create strategies to prevent work accidents, musculoskeletal disorders and work diseases. / Esta tesis sostiene que las características sociodemográficas ocupacionales y de situación de salud constituyen factores de generación de enfermedades o de protección para la ocurrencia de accidentes de trabajo, alteraciones musculoesqueléticas y dolencias laborales en trabajadores de una institución hospitalaria. El objetivo general fue identificar los factores de protección y enfermedades en la ocurrencia de accidentes, alteraciones musculoesqueléticas y enfermedades profesionales en los trabajadores de una institución hospitalaria. Se trata de un estudio transversal cuyo escenario fue el Hospital de Clínicas de Porto Alegre (HCPA), en el cual fueron abordados 288 trabajadores y sus respectivos prontuarios, de 54 ocupaciones distintas, en el periodo entre 2010 a 2012. Fue utilizada para la colecta el banco de datos de la pesquisa aprobada por el Comité de Ética y Pesquisa HCPA, sob el registro de 11-35. Los datos fueron analizados por estadística considerando el nivel de relevancia de 95%, Qui-cuadrado y Regresión de Poisson. En el abordaje del trabajador fue verificada la prevalencia del sexo femenino, mayores de 40 años, residentes en Porto Alegre, que realizaban actividad fisica y de ocio, profesionales del área de enfermería y régimen de trabajo diurno. Una menos proporción relató trabajar en otra institución; hospitalización; accidentes de trabajo; las dolencias laborales y crónicas. En el prontuario del trabajador fue observado el dominio de la admisión inferior a diez años, riesgo biológico, riesgo ergonómico, realización de examen médico periódico, enfermedad crónica y alejamientos laborales. Los accidentes de trabajo, las enfermedades laborales y las alteraciones musculoesqueléticas tuvieron menor prevalencia en los registros de los prontuarios. Entre los factores que potencializaron las enfermedades por accidentes de trabajo fueron identificados el consumo de tabaco alguna vez en la vida (RP=1,80; p=0,010) y el alejamiento laboral registrado en los últimos tres años (RP=5,79; p=0,014). Las alteraciones musculoesqueléticas mostraron asociación con la situación conjugal sin compañero (RP=1,69; p=0,005), tener hijos (RP=1,55; p=0,032) y el alejamiento laboral en los últimos tres años (RP=2,04; p=0,008). Las enfermedades de trabajo como factoras de dolencias están asociadas a la mudanza de situación conjugal (RP=3,51; p=0,020), riesgo ergonómico (RP=2,60; 0,038) y limitación funcional en el periodo de tres años (RP=4,38; p=0,006). En lo que respecta a los factores de protección, se observó la asociación con la carga horaria diaria menor que 6 horas y 15 minutos (RP=0,41; p=0,007) y los accidentes de trabajo. Para las dolencias laborales, la asociación protectora ocurrió entre los trabajadores con riesgo biológico (RP=0,24; p=0,028) y los que realizan el examen médico periódico (RP=0,36; p=0,015). Los resultados evidenciaron factores de enfermedades y de protección a la salud del trabajador que refuerzan la necesidad de articulación de acciones que valoren la corresponsabilidad del trabajador y de la institución de manera a generar estrategias para la prevención de accidentes laborales, alteraciones musculoesqueléticas y dolencias laborales.

Breast cancer, osteoporosis, and coronary heart disease (CHD) are three major threats to women’s health. Postmenopausal women with breast cancer are also at high risk for osteoporosis and CHD. Adjuvant tamoxifen therapy is not only an effective treatment for breast cancer, but has been shown to have a beneficial effect on bone and the cardiovascular system. Although tamoxifen has been convincingly demonstrated to be able to preserve bone mineral density (BMD), an unexpected increase of risk of fractures in patients treated with tamoxifen has been reported. The findings of the association of tamoxifen and CHD from previous studies were either borderline or inconsistent. To clarify the discrepancy between BMD and fractures and test the potential beneficial effect of tamoxifen on CHD, I conducted a series of retrospective studies in postmenopausal women with breast cancer who participated in the Cancer Surveillance in HMO Administrative Data (IMPACT study) or the Study of Osteoporotic Fractures (SOF). In patients who participated in the IMPACT study, I demonstrated that the association of tamoxifen and fracture incidence varied at different skeletal sites. Although the association of tamoxifen and fractures in the spine (HR=0.40, 95% CI: 0.09-1.85), wrist (HR=2.49, 95% CI: 0.88-7.06), and total body (HR=0.87, 95% CI: 0.49-1.55) was inconclusive, tamoxifen was associated with an apparent reduction of the risk of hip fracture (HR=0.41, 95% CI: 0.17-1.03, p=0.0565). Importantly, the pattern of observed association of tamoxifen with the risks of fractures among postmenopausal women with breast cancer is consistent with its widely reported preserving effect on bone mineral density. Using SOF data, I found that the association between BMD and fractures in women with breast cancer varied at different skeletal sites, and type of BMD measured. Non-specific BMD was not associated with hip fracture (HR=1.12; 95% CI: 0.78, 1.59). Site-specific BMD was more likely linked with hip fracture (HR=1.43, 95% CI: 0.99, 2.08) while change in BMD did not predict hip fracture (HR=1.05; 95% CI: 0.63, 1.72). The association of spine morphometric fracture with either non-specific or spine-specific BMD was similar (OR=1.40; 95% CI: 1.04, 1.90; OR=1.35, 95% CI: 0.99, 1.85, respectively). Overall, the association of BMD and fracture in elderly women with breast cancer is weak. Only site-specific BMD appears to have a consistently modest association with fractures in the corresponding skeletal sites. In the IMPACT study population, compared to patients without tamoxifen, the overall incidence of CHD in tamoxifen-treated patients was lower (adjusted HR=0.60, 95% CI: 0.40-0.88). For each year of tamoxifen use, there was a statistically significant decrease in the risk of CHD (HR=0.90, 95% CI: 0.82-0.98). Further analyses categorized by length of tamoxifen use showed that an apparent association with a decreased CHD risk was found in patients who received tamoxifen for two to five years (HR=0.54, 95% CI: 0.33-0.86). No association was detected after the discontinuation of tamoxifen therapy. In summary, I detected a possible benefit associated with tamoxifen on fractures in the hip, the most common fracture site. I also found that BMD did not predict osteoporotic fractures well in postmenopausal women with breast cancer. In addition, I demonstrated that tamoxifen was associated with a reduced risk of CHD in postmenopausal women with breast cancer in a dose-dependent manner. An apparent benefit was found in those patients who received tamoxifen therapy for at least two years.

Background: Patient reports of pain and function are used to inform the need for and timing of total knee replacement (TKR) and evaluate TKR outcomes. This dissertation compared measurement properties of commonly-used patient surveys in TKR and explored ways to develop more efficient knee-specific function measures. Methods: 1,179 FORCE-TJR patients (mean age=66.1, 61% female) completed questionnaires before and 6 months after TKR. Patient surveys included the knee-specific Knee injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and generic SF-36 Health Survey. Tests of KOOS and WOMAC measurement properties included evaluations of scaling assumptions and reliability. Item response theory methods were used to calibrate 22 KOOS function items in one item bank; simulated computerized adaptive tests (CAT) then were used to evaluate shorter function scores customized for each patient. Validity and responsiveness of measures varying in attributes (knee-specific versus generic, longer versus shorter, CAT versus fixed-length) were compared. Results: KOOS and WOMAC scales generally met tests of scaling assumptions, although many pain items were equally strong measures of pain and physical function. Internal consistency reliability of KOOS and WOMAC scales exceeded minimum levels of 0.70 recommended for group-level comparisons across sociodemographic and clinical subgroups. Function items could be calibrated in one item bank. CAT simulations indicated that reliable knee-specific function scores could be estimated for most patients with a 55-86% reduction in respondent burden, but one-third could not achieve a reliable (≥ 0.95) CAT score post-TKR because the item bank did not include enough items vi measuring high function levels. KOOS and WOMAC scales were valid and responsive. Short function scales and CATs were as valid and responsive as longer KOOS and WOMAC function scales. The KOOS Quality of Life (QOL) scale and SF-36 Physical Component Summary discriminated best among groups evaluating themselves as improved, same or worse at 6 months. Conclusions: Results support use of the KOOS and WOMAC in TKR. Improved knee-specific function measures require new items that measure higher function levels. TKR outcomes should be evaluated with a knee-specific quality of life scale such as KOOS QOL, as well as knee-specific measures of pain and function and generic health measures.

Osteoclast-mediated focal articular bone erosion is a hallmark of rheumatoid arthritis, a disease of inflammation-induced bone loss. Inflammation in the bone microenvironment enhances osteoclast differentiation leading to bone erosion. Simultaneously, inflammation also inhibits osteoblast-mediated bone formation, further contributing to the net loss of bone. Previous studies have shown a paucity of mature osteoblasts at eroded bone surfaces correlating with suppression of bone formation and upregulation of antagonists of the Wnt pathway, a signaling cascade essential for osteoblast lineage commitment. Despite these observations, the exact pathogenesis of impaired bone formation in the setting of inflammation is not clearly understood. This dissertation aims to delineate the mechanisms by which inflammation suppresses osteoblast differentiation and activity in inflammatory arthritis. Specifically, this research elucidates how inflammation-induced alterations in the Wnt and bone morphogenetic protein (BMP) osteogenic signaling pathways contribute to bone loss and formation at distinct inflammatory microenvironments within the bone. Secondly, the means by which cellular mediators, including lymphocytes and macrophages, facilitate bone erosion and formation was addressed. Taken together, the research in this dissertation underscores the relationship between inflammation-induced bone loss and alterations in osteogenic signaling. Using an innovative murine inflammatory arthritis model, this study definitively demonstrates that resolving inflammation promotes osteoblast-mediated bone formation. Repair of erosions correlates with upregulation of synovial expression of Wnt10b, a Wnt agonist, and downregulation of sFRP1 and sFRP2, Wnt antagonists. This work also directly evaluates the contribution of sFRP1 to inflammation-induced bone destruction. Furthermore, this research demonstrates that expression of BMP3, a negative regulator of BMP signaling, is upregulated in osteoblasts by IL-17, a pro-inflammatory cytokine. BMP3-expressing osteoblasts are also observed at erosion sites in murine arthritis. Lastly, evaluation of the mediators of inflammation-induced periosteal bone formation implicates BMP2 as a means by which inflammation may positively regulate osteoblast function. This dissertation further elucidates the role of T cells and macrophages in the erosion and formation processes, respectively. In the absence of lymphocytes, bone erosion occurred normally, demonstrating that RANKL-expressing lymphocytes are not absolutely required for the bone erosion. Preliminary studies also suggest that M2 macrophages are potential mediators of bone formation via the expression of BMP2. In conclusion, this dissertation explores the ability of inflammation to act as a rheostat, which controls the fate of bone by modulating not only osteoclast differentiation, but also osteogenic signaling pathways and cellular mediators in the bone microenvironment. The soluble mediators and cell types identified in this research highlight novel mechanisms by which inflammation may regulate osteoblast activity within the bone microenvironment. Collectively, these data imply that strict control of inflammation may be necessary in order to create an anabolic environment that preserves bone architecture in diseases of inflammation-induced bone loss.

Ectopic calcification can cause pain and limit mobility. Studies suggest that circadian genes may play a role in the calcification process. Core circadian genes Clock, Npas2, and Bmal1 are transcription factors that form CLOCK:BMAL1 or NPAS2:BMAL1 transactivator complexes that drive the rhythmic expression of circadian oscillator genes and output genes. Circadian oscillator genes Period1-3 and Cryptochrome1-2 encode proteins that form transcription repressor complexes that feedback to inhibit CLOCK/NPAS2:BMAL1 activity, thus completing the feedback loop that is the basis of the molecular circadian clockwork. Arrhythmic Bmal1-/- mice exhibit site-specific, age-dependent arthropathy. While studying the circadian phenotype of Clock-/-;Npas2m/m double mutant mice, we discovered that these double mutant mice develop site-specific arthropathy similar to the arthropathy described in Bmal1-/- mice. Based on the circadian clockwork mechanism, we hypothesized that CLOCK/NPAS2:BMAL1 transactivator complexes drive the expression of a gene (or genes) that prevents age-dependent arthropathy. To investigate Clock-/-;Npas2m/m double mutant mouse arthropathy, we evaluated mutant mice using X-ray, micro-computed tomography, and histology, and found that Clock-/-;Npas2m/m double mutant mice exhibit age-dependent, site-specific arthropathy that phenocopies that of Bmal1-/- mice. The costosternal junction and calcaneal tendon are most prominently affected, in that calcification of those tissues is detectable as early as 4-5 weeks and 11-12 weeks, respectively. The arthropathic lesions in these tissues consist of calcium phosphate vii deposits, and in Bmal1-/- costosternal junction calcifications, the deposits contain calcium pyrophosphate dihydrate crystals. Mechanical stress, disregulation of centrally-regulated circadian rhythms, and systemic serum mineral imbalances likely do not contribute to this pathology. In vitro micromass cultures generated from Clock-/-;Npas2m/m double mutant mouse embryonic fibroblasts do not exhibit irregular chondrocyte differentiation compared to wild-type cultures, suggesting that chondrocyte cell-autonomous mechanisms are insufficient to induce this arthropathy. Analysis of Clock-/-;Npas2m/m double mutant intersternebral tissue RNA did not reveal significant changes in chondrocyte or calcification-related gene expression. Histological stains showed an absence of osteoblasts and osteoclasts around costosternal junction calcifications, suggesting that these cell types are not contributing to this pathology. Instead, chondrocytes are localized to the costosternal junction but there were no significant changes in the distribution of chondrocyte markers in this tissue, as evaluated by immunohistochemistry. These findings suggest that Clock or Npas2, and Bmal1, regulate ectopic calcification through a combination of systemic and local factors, and that the cells affected by Clock and Npas2, or Bmal1, disruption are a subset of the cells distributed in specific tissues that develop age-dependent arthropathy. The significance of these findings is that “circadian genes” play a role in the regulation of ectopic calcification in a non-oscillator capacity. Understanding this new mechanism by which ectopic calcification is controlled could lead to novel approaches for the treatment of some human calcification diseases.

<p>The risk of fracture is higher in adults with type 2 diabetes compared to controls without type 2 diabetes, despite normal or higher than normal bone mineral density (BMD). In addition to BMD, bone strength depends on other factors such as structural and material <em>bone qualities</em>, which are not accounted for in BMD measurements. The objective was to determine whether structural and material <em>bone qualities</em> are different in adults with type 2 diabetes compared to controls without type 2 diabetes. First, a cross-sectional study was undertaken using MRI to investigate distal radius trabecular bone microarchitecture, a structural <em>bone quality.</em> In women with type 2 diabetes, trabecular bone holes were larger compared to controls, which is important because greater trabecular bone hole size is related to reduced bone strength. Next, a two year prospective study was conducted with the participants involved in the cross-sectional study to determine whether changes in trabecular bone microarchitecture are different in women with type 2 diabetes compared to controls. There was a greater increase in the number of trabecular bone holes in women with type 2 diabetes compared to controls, which provides early evidence of trabecularization of cortical bone in women with type 2 diabetes. In the third study, quantitative backscattered electron imaging (qBEI) was used to derive bone mineralization density distribution (BMDD) outcomes for bone samples from adults with and without type 2 diabetes to compare material <em>bone quality. </em>There was evidence of elevated bone calcium concentration and reduced mineralization heterogeneity in bone samples from adults with type 2 diabetes compared to controls, which may contribute to bone brittleness. In summary, differences in structural and material <em>bone qualities </em>identified in this body of work provide explanations for elevated fracture risk in adults with type 2 diabetes.</p> / Doctor of Science (PhD)

La douleur est une réponse normale qui nous permet de réagir en réponse à un trauma ou une situation qui pourrait potentiellement causer du tort à notre corps. Cette expérience désagréable n’est pas seulement physiologique, mais elle est aussi psychologique, émotionnelle et socio-culturelle. C’est ce qui la rend aussi complexe et subjective. Lorsque les mécanismes de modulation de la douleur ne fonctionnent plus normalement, ces douleurs peuvent devenir chroniques et être très handicapantes pour les patients. Dans cette étude, nous nous sommes plus particulièrement focalisés sur certaines maladies musculosquelettiques présentant de la douleur chronique telles que l’encéphalomyélite myalgique (EM), la fibromyalgie (FM) et l’arthrose ou l’ostéoarthrite (OA). L’EM et la FM sont deux maladies complexes et hétérogènes qui ont plusieurs symptômes qui se chevauchent. L’EM se caractérise généralement par de la fatigue chronique qui n’est pas soulagée par le repos et par des malaises après-effort (PEM). Alors que la FM se caractérise davantage par de la douleur chronique musculaire et articulaire. Puis, l’OA est une maladie débilitante où les patients ont une dégradation progressive du cartilage articulaire causant de la douleur chronique qui est davantage localisée au niveau des joints articulaires atteints. Actuellement, il n’existe pas de biomarqueurs idéaux pour mesurer le niveau de douleur pour ces maladies dont l’étiologie reste incertaine. Toutefois, une étude récente a démontré une diminution de l’expression du gène MFAP3 au niveau des cellules mononuclées du sang périphérique (PBMC) chez des individus présentant des états de douleur élevée à la suite d’un syndrome post-traumatique. Ce gène code pour une protéine appelée protéine associée aux microfibrilles 3 (MFAP3), qui participent dans plusieurs processus biologiques dont l’assemblage des microfibrilles, l'élastinogenèse et l'homéostasie tissulaire, et pourrait aussi être une protéine clé impliquée dans l’inhibition de la douleur. L’objectif de cette étude est de mieux comprendre le rôle de la protéine MFAP3 et son implication dans la douleur dans ces différentes pathologies. L’expression du gène MFAP3 a été mesurée dans les PBMC de patients atteints d’EM, de FM, d’OA et de sujets sains (HC) et a été corrélée aux niveaux de douleur des patients. Une recherche in silico nous a permis d’identifier des récepteurs membranaires impliqués dans la douleur et pouvant interagir physiquement avec la protéine MFAP3 dont le récepteur HTR3A (le récepteur à sérotonine 3A). La spectroscopie cellulaire diélectrique a été utilisée pour valider cette interaction dans des cellules Jurkat (lymphocytes T humains immortalisés) dans des conditions standards. Il a été observé que la protéine MFAP3 inhibait la réponse induite par la stimulation de ce récepteur. Cette recherche pourrait éventuellement conduire au développement de nouvelles thérapies pour traiter la douleur associée à ces maladies musculosquelettiques. / Pain is a normal response that allows us to react in response to trauma or in situations that are dangerous or could potentially harm our body. This unpleasant experience is not only physiological, but it is also psychological, emotional, and socio-cultural. This is what makes it so complex and subjective. When pain modulation mechanisms no longer function normally, pain can become chronic and be very disabling for patients. In this study, we particularly focused on some musculoskeletal diseases presenting chronic pain such as myalgic encephalomyelitis (ME), fibromyalgia (FM) and osteoarthritis (OA). ME and FM are two complex and heterogeneous diseases that exhibit several overlapping symptoms. ME is characterized by a chronic fatigue that is not relieved by rest and post-exertional malaise (PEM), whereas FM is rather characterized by more chronic muscle and joint pain. In regard to OA, this debilitating disease leads to a progressive degradation of articular cartilage joints resulting in chronic pain which is more localized in the affected joints. Currently, there are no ideal biomarkers to measure pain level for these diseases and their etiology remains unclear. However, a recent study demonstrated a decrease in MFAP3 gene expression in peripheral blood mononuclear cells (PBMC) in individuals presenting high pain states following a post-traumatic syndrome. This gene encodes a protein called Microfibril-associated protein 3 (MFAP3), which participates in several biological processes including microfibril assembly, elastinogenesis and tissue homeostasis, and could also be a key protein involved in pain inhibition. The objectives of this study were to better understand the role of the MFAP3 protein and its involvement in pain in these different pathologies. MFAP3 gene expression was measured in PBMCs from patients with ME, FM, OA and healthy subjects (HC) and correlated with their pain levels. In silico research allowed us to identify membrane receptors involved in pain that can physically interact with the MFAP3 protein, including the HTR3A receptor (Serotonin receptor 3A). Cellular dielectric spectroscopy was used to validate this interaction in Jurkat cells (immortalized human T lymphocytes) under standard conditions. It was observed that MFAP3 inhibits the response induced by this receptor stimulation. This research could eventually lead to the development of new therapies to treat pain associated with these musculoskeletal diseases.

INTRODUÇÃO: A infecção pelo vírus C é um grande problema de saúde pública e tem se tornado a principal indicação de transplante de fígado. Com uma distribuição universal, é a segunda doença crônica viral mais frequente no mundo. No entanto, a hepatite C crônica é mais que uma doença hepática. Pacientes com infecção crônica pelo HCV podem desenvolver um grande número de manifestações extra-hepáticas independentemente da gravidade da doença hepática. Há muitas doenças reumatológicas associadas à infecção pelo HCV, incluindo artralgia, mialgia e artrite. MÉTODOS: Um estudo transversal desenvolvido entre os pacientes atendidos no Ambulatório de Hepatites da Divisão de Clínica de Moléstias Infeciosas e Parasitárias do HCFMUSP, na cidade de São Paulo, no período de 2004 a 2008, selecionou 243 pacientes que preencheram os critérios de inclusão e assinaram o termo de consentimento após esclarecimentos sobre a pesquisa. Foi realizada uma entrevista com os pacientes, em que foram coletadas informações demográficas, epidemiológicas e clinico-laboratoriais. Foram realizados exames laboratoriais, bioquímicos, hematológicos, imunológicos, PCR, HCV, RNA quantitativo e genotipagem do HCV. A avaliação das características da infecção pelo HCV (epidemiológica, histológica, virológica), associada às manifestações extra-hepáticas clínicas reumatológicas (aquelas com prevalência > 10%) e laboratoriais (com prevalência > 5%), foi realizada utilizando-se as análises univariada e multivariada (regressão logística). Odds ratios (OR) ajustados e intervalos de confiança de 95% (IC 95%) foram derivados do coeficiente do modelo logístico multivariado final. Todas as análises foram realizadas com o pacote estatístico SPSS. RESULTADOS: Dos 243 pacientes estudados, pudemos determinar a provável forma de infecção em 147 (60,49%). Dos 147 pacientes, 93 (38,27%) sofreram transfusão sanguínea prévia, 10 (4,11%) tinham histórico de uso droga injetável há mais de 1 ano, 15 (6,17%) tinham antecedente de uso do droga inalatória há mais de 1 ano, 11 (4,52%) eram profissionais da saúde com histórico de acidente com material perfuro-cortante, 10 (4,11%) realizaram tatuagem e 8 (3,29%) tinham parceiro portador de hepatite C crônica. Nessa análise, 148 (60,9%) dos pacientes com hepatite C crônica apresentaram queixa de artralgia, 145 (59,7%) apresentaram queixa de mialgia, 144 (59,3%), de cansaço. A artrite esteve presente em 50 (20,57%) dos pacientes avaliados nesse estudo. Dentre estes pacientes, o envolvimento foi predominantemente poliarticular em 36 (72%) deles, acometendo grandes e pequenas articulações, simultaneamente, em 29 (58%). Idade maior que 50 anos, dor nas costas e crepitação em articulações mostraram-se fatores associados à artrite. Observou-se que sexo feminino, tabagismo importante e fibrose hepática avançada (F3 e F4) foram fatores associados à artralgia. Sexo feminino e tabagismo importante foram fatores associados à mialgia. CONCLUSÃO: Foi encontrada elevada prevalência de manifestações musculoesqueléticas entre os pacientes portadores de hepatite C crônica deste serviço. Os fatores de risco mais frequentes para a presença das manifestações extra-hepáticas foram sexo feminino e idade maior que 50 anos. Os autoanticorpos, embora freqüentes, não mostraram significância estatística com relação às principais manifestações musculoesqueléticas analisadas. Infiltrado inflamatório hepático e nível de transaminases também não apresentaram significância estatística / INTRODUCTION: C virus infection is a major public health problem and has become the leading indication for liver transplantation. With a worldwide distribution, is the second most common chronic viral worldwide. However, chronic hepatitis C is more than a liver disease. Patients with chronic HCV infection may develop a large number of extra hepatic manifestations regardless of the severity of liver disease. There are many rheumatic diseases associated with HCV infection including arthralgia, myalgia and arthritis. METHODS: A cross-sectional study carried out among patients treated in outpatient Hepatitis Clinical Division of Infectious and Parasitic Diseases of the HC-USP, in São Paulo, in the period from 2004 to 2008, selected 243 patients who met the inclusion criteria and signed the consent form after clarification of the research. An interview was conducted with patients which were collected demographic, epidemiological and clinical-laboratory. Laboratory tests were carried, biochemical, hematological, immunological, quantitative PCR HCV RNA and HCV genotyping. The evaluation of the characteristics of HCV infection (epidemiological, histological, virological) associated with extrahepatic manifestations rheumatology clinics (those with prevalence > 10%) and laboratory (with prevalence > 5%) were performed using univariate and multivariate analysis (regression logistics). Odds ratios (OR) and adjusted confidence intervals of 95% (95% CI) were derived from the ratio of the final multivariate logistic model. All analyzes were performed with the SPSS statistical package. RESULTS: Of the 243 patients studied were able to determine the likely form of infection in 147 (60.49%). Of the 147 patients, 93 (38.27%) had previous blood transfusion, 10 (4.11%) had a history of injection drug use for more than 1 years, 15 (6.17%) had prior use of the drug is inhaled over 1 year, 11 (4.52%) were health professionals with a history of accidents with sharp objects, 10 (4.11%) underwent tattooing and 8 (3.29%) had a partner with hepatitis C chronic. In this analysis, 148 (60.9%) of patients with chronic hepatitis C complained of arthralgia, 145 (59.7%) complained of myalgia, 144 (59.3%) of fatigue. Arthritis was present in 50 (20.57%) of the patients evaluated in this study. Among patients with arthritis of this study, involvement was predominantly polyarticular in 36 (72%) of them, affecting large and small joints simultaneously in 29 (58%). Age greater than 50 years, back pain and crepitus in the joints proved to be factors associated with arthritis. We observed that female smoking important and advanced liver fibrosis (F3 and F4) were associated with arthralgia. Female gender and smoking were important factors associated with myalgia. CONCLUSION: We found a high prevalence of musculoskeletal manifestations among patients with chronic hepatitis C of this service. The most common risk factors for the presence of extra hepatic manifestations were female and older than 50 years. The autoantibodies, although frequently not statistically significant compared with the major musculoskeletal manifestations analyzed. Inflammatory infiltrate and liver transaminase levels did not show statistical significance

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 6 uppsatser.