Orientador: Denise Pontes Cavalcanti / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-18T22:10:26Z (GMT). No. of bitstreams: 1 Buck_CeciliaOliveiraBarbosa_D.pdf: 3074480 bytes, checksum: d8ed23fbbc34d4773afce0c5bb451361 (MD5) Previous issue date: 2011 / Resumo: Osteocondrodisplasias (OCD) ou displasias esqueléticas são um grupo heterogêneo de doenças genéticas que afetam o crescimento. e o desenvolvimento do esqueleto e possuem alta morbimortalidade associada. Apesar dos avanços recentes no diagnóstico pré-natal e no conhecimento das bases moleculares das OCD, o seu diagnóstico ainda se baseia em anamnese, exame físico e radiografias de esqueleto. A prevalência habitualmente referida de 2,0/10.000, baseada em poucos estudos com populações pequenas, é subestimada. O objetivo deste estudo foi avaliar a epidemiologia das OCD na América do Sul (AS) utilizando uma grande população de mais de 1,5 milhões de nascimentos. Os casos de OCD foram selecionados dos arquivos do ECLAMC (um programa colaborativo de base hospitalar, caso-controle, para vigilância de defeitos congênitos) por dois códigos específicos (75640-OCD e 75650-Osteogenesis Imperfecta). Todos os casos nascidos entre 2000-2007 foram revisados e os diagnósticos finais foram escalonados em quatro níveis de evidência diagnóstica (NED), sendo o NED1 (padrão-ouro) casos com boas radiografias ou estudo molecular confirmando o diagnóstico. No período do estudo, 132 hospitais em 9 paises sul-americanos observaram 1.544.496 nascimentos. Todos os 51.827 controles nascidos no mesmo período foram utilizados para comparação. Excluídos 44 casos, a prevalência geral foi de 3,2/10.000 (IC95% 2,9-3,5) (492 casos em 1.544.496 nascimentos) e 33,6 (25,3-42,3) nos natimortos. Casos letais foram 50% (natimortos e óbito neonatal precoce). O diagnóstico foi referido como pré-natal na maioria dos casos (359-73%). Os grupos de OCD mais frequentes, segundo a classificação internacional, foram: G-1 (FGFR3) - 31%; G-25 (OI) - 23,5%; G-9 (CCP) - 4,5%; G-2 (Colágeno 2) - 4%; G-18 (Bent bones) - 4%. As prevalências das OCD mais comuns foram: OI - 0,74 (0,61-0,89); D. Tanatofórica - 0,47 (0,36-0,59); Acondroplasia - 0,44 (0,33-0,56); D. Campomélica - 0,10 (0,05-0,16). A taxa de mutação/gameta/geração para Acondroplasia foi 1,74 (1,25-2,25) x 10-5. Idade paterna, paridade e consanguinidade foram maiores nos casos que nos controles (31,2 anos X 28,9 anos; 2,6 X 2,3; 5,4% X 1,0%; P < 0,001). Idade materna elevada nos casos em relação aos controles (26,4 anos X 25,4 anos, P < 0,001) não foi confirmada por regressão logística considerando idades paterna e materna e paridade como fatores de risco para OCD (OR=1,63 para idade paterna > 39 anos; 0,79 para idade materna > 34 anos e 1,3 para paridade > 1). Peso e idade gestacional foram menores nos casos que nos controles (2498,1 g X 3198,6 g, P < 0,001), permanecendo a diferença para o peso após estratificação apenas para gestações de 31-35, 36-40 e 41-44 semanas (P<0,001, P<0,001 e P<0,05, respectivamente). A prevalência geral de 3,2/10.000 encontrada parece mais verossímil, sustentada por uma população numerosa e heterogênea, com grande diversidade étnica em sua composição, onde interrupções da gestação não são permitidas. Este estudo também observou uma alta taxa de diagnóstico pré-natal das OCD na AS e confirmou: a elevada morbi-mortalidade associada às OCD, a idade paterna elevada (especialmente nos casos de herança dominante) e altas taxas de consangüinidade nos casos de OCD (especialmente os de herança recessiva) e na população controle da AS / Abstract: Osteochondrodysplasias (OCD) are a heterogeneous group of genetic diseases that affect skeletal growth and development with a high infant morbid-mortality. Despite the great advances in prenatal diagnosis and knowledge of OCD molecular bases in the last twenty years, OCD diagnosis still relies upon anamnesis, clinical examination and skeletal X-rays. The currently accepted birth prevalence rate of OCD (2.0/10,000), based on few studies with small populations, is underestimated. This study aimed to assess OCD epidemiology in South America (SA) based on a large population of more than 1.5 million births. The OCD cases were ascertained from ECLAMC (a case-control, collaborative hospital-based program for birth defects surveillance) database through two specific codes (75640 for "generic" OCD and 75650 for Osteogenesis Imperfecta). All cases born from 2000 to 2007 were revised and final diagnoses ranked in four diagnostic evidence levels (DEL), being the DEL1 (gold-standard) those cases with good X-rays or DNA test supporting a certain diagnosis. During the 8-year period, 132 hospitals from nine South-American countries examined 1,544,496 births. For comparative analysis, all 51,827 controls born in the same period were used. After excluding 44 cases, overall OCD birth prevalence was 3.2 per 10,000 (95% CI 2.9-3.5) (492 cases per 1,544,496 births) and 33.6 (25.3-42.3) among stillbirths. Lethal cases (stillbirths plus early neonatal death) were 50%. Prenatal ultrasound diagnosis was referred in most cases (359 - 73%). The most frequent OCD groups, according to the international classification, were: G-1 (FGFR3) - 31%; G-25 (OI) - 23,5%; G-9 (SRP) - 4,5%; G-2 (Collagen 2) - 4% and G-18 (Bent bones) - 4%. The prevalence of the main OCD types were: OI - 0.74 (0.61-0.89); Thanatophoric D. - 0.47 (0.36-0.59); Achondroplasia - 0.44 (0.33-0.56); Campomelic D. - 0.10 (0.05-0.16). The mutation rate/gamete/generation for Achondroplasia was 1.74 (1.25-2.25) x 10-5. Paternal age, parity and consanguinity rate were significantly increased in cases compared to controls (31.2 years X 28.9 years; 2.6 X 2.3; 5.4% X 1.0%; P < 0.001). Increased maternal age in cases against controls' (26.4 years X 25.4 years, P < 0.001) was not confirmed by logistic regression including paternal age (OR=1.63 for paternal age > 39 years), parity (OR=1.3 for parity > 1) and maternal age (OR=0.79 for maternal age > 34 years) as risk factors for OCD. Birth weight and gestational age were lower in cases than in controls (2498.1 g X 3198.6 g, P < 0.001), and the difference for birth weight remained significant for gestational ages 31-35, 36-40 and 41-44 weeks after stratification (P < 0.001, P < 0.001 and P < 0.05, respectively). The OCD overall birth prevalence rate of 3.2 per 10,000 found seems more verisimilar, supported by a large and heterogeneous population with great ethnic diversity and without pregnancy terminations. This study also indicates a high rate of prenatal OCD diagnosis in SA and confirms: the high OCD-associated infant morbid-mortality, the increased paternal age (especially for cases with autosomal dominant inheritance) and the high parental consanguinity rates in both OCD cases (especially those with autosomal recessive inheritance) and in SA control population / Doutorado / Genetica Medica / Doutor em Ciências Médicas

A population of stromal cells that retains osteogenic capacity in adult bone (adult bone stromal cells or aBSCs) exists and is under intense investigation in relation to osteogenesis and relevant pathology. aBSCs may be different from their embryonic or neonatal counterparts, and are influenced by species-/age-specific and other factors. Mice heterozygous for a null allele of prkar1a (Prkar1a+/-, a gene encoding for cyclic adenosine mono-phosphate (cAMP)-dependent regulatory subunit of protein kinase A (PKA), developed bone lesions that resembled fibrous dysplasia (FD) originated from cAMP-responsive osteogenic cells. Prkar1a +/- mice were crossed with mice heterozygous for catalytic subunit Calpha (Prkaca+/-), the main PKA activity-mediating molecule and generated mouse model with double heterozygosity for prkar1a and prkaca (Prkar1a +/-Prkaca+/-). Unexpectedly, Prkar1a+/-Prkaca+/- mice developed a large number of osseous lesions starting at 2--3 months of age that varied from the rare chondromas in the long bones and the ubiquitous osteochondrodysplasia of tail vertebral bodies to the occasional sarcoma in older animals. Cells from these lesions were fibroblast- and FD-like, and almost always originated from an area proximal to the growth plate and adjacent to endosteal surface of the periosteum; they expanded gradually in the bone marrow space. These cells expressed osteogenic cell markers, showed higher PKA activity that was mostly type II (PKA-II) and display an alternate pattern of catalytic subunit expression, and surprisingly possessed higher cAMP levels. In addition, markers of bone synthesis and lysis were increased. Gene expression profiling not only confirmed an early (progenitor) osteoblastic nature for these cells but also showed a signature that was indicative of mesenchymal-to-epithelial (MET) transition and increased Wnt signaling, particularly the brachyury expression. These studies show that a specific subpopulation of aBSCs can be stimulated in adult bone by PKA-II and altered Calpha activity, generating the only available germline mutant mouse model of a disorder that has similarities to human FD. Along with previous data, these studies also suggest that the effects of cAMP signaling on osteogenesis and stromal cell maintenance and proliferation in mice are age-, bone-, site- but also PKA-type and catalytic subunit-specific. / Parts of the work have been published in Proceedings of the National Academy of Sciences of the United States of America 2010; 107(19):8683--8. / Tsang, Kit Man. / Advisers: Constantine A. Stratakas; Kwak-Pui Fung. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 144-183). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Indiana University-Purdue University Indianapolis (IUPUI) / Bone growth can be impaired due to disease, such as osteoporosis. Currently, intermittent parathyroid hormone (PTH) treatment is the only approved therapy in the United States for anabolic bone growth in osteoporosis patients. The anabolic effects of PTH treatment are due, at least in part, to modulation of the Wnt/β-catenin pathway. Activation of the Wnt/ β-catenin pathway using a small molecule inhibitor of GSK3β was previously shown to increase markers of bone formation in vitro. Our study utilized a zebrafish model system to study Wnt activated fin regeneration and bone growth. Wnt signaling is the first genetically identified step in fin regeneration, and bony rays are the main structure in zebrafish fins. Thus, zebrafish fin regeneration may be a useful model to study Wnt signaling mediated bone growth. Fin regeneration experiments were conducted using various concentrations of a GSK3β inhibitor compound, LSN 2105786, for different treatment periods and regenerative outgrowth was measured at 4 and 7 days post amputation. Experiments revealed continuous low concentration (4-5 nM) treatment to be most effective at increasing regeneration. Higher concentrations inhibited fin growth, perhaps by excessive stimulation of differentiation programs. In situ hybridization experiments were performed to examine effects of GSK3β inhibitor on Wnt responsive gene expression. Experiments showed temporal and spatial changes on individual gene markers following GSK3β inhibitor treatment. Additionally, confocal microscopy and immunofluorescence labeling data indicated that the Wnt signaling intracellular signal transducer, β-catenin, accumulates throughout GSK3β inhibitor treated tissues. Finally, experiments revealed increased cell proliferation in fin regenerates following LSN 2105786 treatment. Together, these data indicate that bone growth in zebrafish fin regeneration is improved by activating Wnt signaling. Zebrafish Wnt signaling experiments provide a good model to study bone growth and bone repair mechanisms, and may provide an efficient drug discovery platform.

Indiana University-Purdue University Indianapolis (IUPUI) / Signal Transducer and Activator of Transcription 3 (STAT3) is known to be related to bone metabolism. Mutation of STAT3 causes a rare disorder in which serum levels of IgE are elevated. This causes various skeletal problems similar to osteoporosis. To examine the effect of STAT3 in the osteoclast, we obtained two osteoclast specific STAT3 knockout mouse models: one using the CTSK promoter to drive Cre recombinase and another using a TRAP promoter. Examination of these mice at 8 weeks of age revealed a decreased trabecular bone volume in CTSK specific STAT3 knockout mice along with a slight decrease in osteoclast number in both CTSK and TRAP specific STAT3 knockout females. We also noticed changes in bone mineral density and bone mechanical strength in females. These data suggest that STAT3 plays a part in the function of the osteoclast.

Text in Afrikaans / Summaries in English and Afrikaans / This study aims to investigate the relation between a crane operator in a slab handlingarea's experience of his/her work environment and occupational health. A study of the literature leads one to the conclusion that the nature of crane operators' work environment may cause health problems. According to the literature crane operators are high risk cases regarding musculoskeletal disorders. The empirical study affirms that there are risk factors present in the crane operator's work environment, which may influence his/her occupational health. It is statistically proven that there is a meaningful difference between crane operators with a negative experience of the work environment and crane operators with a positive experience of the work environment, and the amount of illnesses experienced by crane operators as well as their general health. Recommendations are made regarding training, adjustability and flexibility of the work station, job rotation, job expansion and enrichment, and social contact. / Die doel van die studie is om die verband tussen 'n kraanoperateur in 'n platblokhanteringsarea se ervaring van sy/haar werksomgewing en beroepsgesondheid te ondersoek. Die literatuurstudie lei tot die gevolgtrekking dat die aard van kraanoperateurs se werksomgewing aanleiding kan gee tot gesondheidsprobleme. Volgens die literatuur is kraanoperateurs hoerisikogevalle ten opsigte van spierskeletstelselbeserings. Die empiriese studie bevestig dat daar risikofaktore voorkom in die kraanoperateur se werksomgewing wat sy/haar beroepsgesondheid kan be"invloed. Statisties is bewys dat daar 'n betekenisvolle verskil is tussen kraanoperateurs met 'n negatiewe ervaring van die werksomgewing en kraanoperateurs met 'n positiewe ervaring van die werksomgewing en die hoeveelheid siektetoestande wat kraanoperateurs ervaar, en die algemene gesondheid van kraanoperateurs. Aanbevelings om risikofaktore te beheer word gemaak ten opsigte van opleiding, verstelbaarheid en buigbaarheid van die werkstasie, posrotasie, posverbreding en - verryking, en sosiale kontak. / Industrial Psychology / M. Com (Industrial Psychology)

Text in Afrikaans / Summaries in English and Afrikaans / This study aims to investigate the relation between a crane operator in a slab handlingarea's experience of his/her work environment and occupational health. A study of the literature leads one to the conclusion that the nature of crane operators' work environment may cause health problems. According to the literature crane operators are high risk cases regarding musculoskeletal disorders. The empirical study affirms that there are risk factors present in the crane operator's work environment, which may influence his/her occupational health. It is statistically proven that there is a meaningful difference between crane operators with a negative experience of the work environment and crane operators with a positive experience of the work environment, and the amount of illnesses experienced by crane operators as well as their general health. Recommendations are made regarding training, adjustability and flexibility of the work station, job rotation, job expansion and enrichment, and social contact. / Die doel van die studie is om die verband tussen 'n kraanoperateur in 'n platblokhanteringsarea se ervaring van sy/haar werksomgewing en beroepsgesondheid te ondersoek. Die literatuurstudie lei tot die gevolgtrekking dat die aard van kraanoperateurs se werksomgewing aanleiding kan gee tot gesondheidsprobleme. Volgens die literatuur is kraanoperateurs hoerisikogevalle ten opsigte van spierskeletstelselbeserings. Die empiriese studie bevestig dat daar risikofaktore voorkom in die kraanoperateur se werksomgewing wat sy/haar beroepsgesondheid kan be"invloed. Statisties is bewys dat daar 'n betekenisvolle verskil is tussen kraanoperateurs met 'n negatiewe ervaring van die werksomgewing en kraanoperateurs met 'n positiewe ervaring van die werksomgewing en die hoeveelheid siektetoestande wat kraanoperateurs ervaar, en die algemene gesondheid van kraanoperateurs. Aanbevelings om risikofaktore te beheer word gemaak ten opsigte van opleiding, verstelbaarheid en buigbaarheid van die werkstasie, posrotasie, posverbreding en - verryking, en sosiale kontak. / Industrial Psychology / M. Com (Industrial Psychology)