Introduction Non-union (NU) is a fracture that will not unite. With over one million fractures per annum in the UK long bone non-union has serious social and economical implications. There is little epidemiological data available specifically looking at this NU patient cohort. Studies that are bone specific quote rates of non-union as a proportion of their study group but there is no data quantifying the incidence of NU in the population or per fracture. Studies have highlighted risk factors associated with atrophic non-union including age, diabetes, non-steroidals, and cigarette smoking. There is scientific interest regarding how best to classify non-unions and the role of biological agents in treating them. Aims • To quantify the incidence of non-union in a large population and calculate the risk of non-union per fracture according to age, sex and anatomical distribution. • To assess the causes contributing to non-union and outcomes of treatment in a non-union cohort and validate a new non-union scoring system. • To test the treatment potential of a novel molecule (monobutyrin) and a growth factor in a small animal model of non-union. Method • Using the ICD-10 data from the Scottish population as collected by NHS Scotland the incidence of non-union and fractures were calculated. • A cohort of 100 non-union patients were studied for risk factors associated with their non-union, treatment outcome and to assess a new NU classification system. • A rat model of tibial non-union was used to assess the potential of monobutyrin and BMP-2 in treating non-union in an animal model. Results • Fracture non-union is very rarely found in children (1 in 500 fractures) and occurs in up to 1 in 50 adult fractures. Non-union of a fracture has a significantly higher risk in young adults than the elderly by about 3 fold. Osteoporosis may not be a risk for non-union. The tibia and clavicle are the sites with the greatest potential for fracture non-union. • Non-union is multifactorial in two out of three patients. Biomechanical stability, patient host factors and infection must all be considered in every patient. Occult or unexpected recurrent infection is present in up to 10% of patients. When all factors are considered in treatment the outcome is 95% successful with 88% requiring 2 or less procedures to heal the non-union and only a minority requiring adjuvant graft or biological agents. The proposed new classification system is complex and did not clearly identify those patients who would require adjuvant treatment (eg bone grafting or BMP) or those likely to have unsuccessful non-union treatment. • Monobutyrin and BMP-2 when tested on the small animal non-union model did not improve the success rate of union. Conclusions Non-union affects approximately 1000 people per year in Scotland, this figure is not as high as 5-10% of all fractures. It is associated with fractures in young adults and of the clavicle and tibia, treatment can have a very high success rate without the need for adjuvant biological polytherapy when all contributing factors are considered and managed appropriately. A new non-union classification needs to incorporate the multifactorial aspects of non-union without being too complex to use in everyday clinical situations.

Made available in DSpace on 2014-06-11T19:31:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-04-05Bitstream added on 2014-06-13T18:41:38Z : No. of bitstreams: 1 colli_vc_dr_araca.pdf: 1176842 bytes, checksum: 7b5e4f64a86568d1041b8b5218994711 (MD5) / A ação da ocitocina (OT) como regulador direto da massa óssea foi reportada em roedores jovens e este efeito anabólico foi atribuído à ação periférica deste hormônio. O objetivo deste estudo foi investigar a ação periférica de OT no processo de reparo alveolar de ratas Wistar de 12, 18 e 24 meses. Ratas de 12 meses com ciclo estral normal e ratas de 18 e 24 meses em diestro permanente receberam duas injeções intra-peritoniais (12 horas de intervalo) de salina (NaCl 0,15M – grupos controle) ou OT (134g/Kg – grupos tratados). Sete dias após, o incisivo direito foi extraído e as análises foram realizadas com 28 dias de reparo alveolar (35 dias após administração de salina ou OT). Os resultados plasmáticos de cálcio e fósforo não diferiram entre os grupos. Os marcadores bioquímicos sistêmicos de formação óssea, fosfatase alcalina (FAL) e osteocalcina (OC), não revelaram diferença significativa de valores na comparação entre grupos controle e tratado de 12 meses, porém esta diferença foi significativa para os dois marcadores quando os animais tratados de 18 e 24 meses foram comparados com os respectivos controles. A análise histomorfométrica e a reação de imunohistoquímica contra OC confirmaram estes resultados mostrando que o tratamento com OT, promoveu maior formação óssea nos animais de 18 e 24 meses. O marcador sistêmico de reabsorção óssea, fosfatase ácida resistente ao tartarato (TRAP) não foi estatisticamente diferente entre animais dos grupos controle e tratado de 12 e 18 meses, porém nos de 24 meses este valor foi significativamente menor nos animais tratados indicando diminuição de reabsorção por ação de OT nos animais desta idade. A imunomarcação para TRAP realizada nos cortes alveolares confirmou os... / The action of oxytocin (OT) as a direct regulator of bone mass has been reported in young rodents and this anabolic effect was attributed to the peripheral action of this hormone. The aim of this study was to investigate the peripheral action of OT in the process of alveolar repair of Wistar rats with 12, 18 and 24 months. Rats of 12 months with normal estrous cycle and rats with 18 and 24 months in permanent diestrus received two intra-peritoneal injections (12 hours apart) of saline (NaCl 0.15 M - control group) or OT (134  g / kg - treated groups). Seven days later, the right incisor was extracted and the analyzes were performed with 28 days of alveolar repair (35 days after administration of saline or OT). The plasma results of calcium and phosphorus did not differ between groups. The systemic biochemical bone formation markers, alkaline phosphatase (ALP) and osteocalcin (OC), revealed no significant difference of values in animals of 12 months, but this difference was significant for both markers when treated animals of 18 and 24 months were compared to controls. The histomorphometric analysis and immunohistochemical reaction against osteocalcin confirmed these results showing that treatment with OT, promoted greater bone formation in animals with 18 and 24 months. The systemic marker of bone resorption, tartrate-resistant acid phosphatase (TRAP) was not statistically different between animals of the control and treated groups of 12 and 18 months, but in 24 months the values were significantly lower in treated animals indicating decreased resorption action of OT in animals of this age. The immunostaining for TRAP performed on alveolar cuts confirmed the results of the results of systemic markers in groups of 12 and 24 months... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:31:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-28Bitstream added on 2014-06-13T19:20:06Z : No. of bitstreams: 1 faria_pep_dr_araca.pdf: 1244848 bytes, checksum: 1c3d78205883be40533349acdfc5ffde (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A combinação de um fármaco fotossensível (FS) ativado por luz (vermelha, infravermelho ou ambas) forma uma das vertentes de aplicação da Terapia Fotodinâmica (TFD), que consiste na administração de um FS que posteriormente é ativado pela irradiação do LED ou Laser junto ao tecido, sendo que o FS ou a luz sozinhas, não apresentam citotoxicidade. O presente estudo teve por objetivos estabelecer o potencial regenerador do tecido ósseo para o reparo em calvária de coelho, utilizando três sistemas de liberação de drogas (DDS) de FS, estimulado pela combinação da fotobiomodulação de sistemas LED operando na faixa do visível e infravermelho. Foram utilizados 48 coelhos New Zealand White divididos em 3 grupos: Grupo LED 24/48 (dezoito coelhos) com aplicações de LED 24/48 horas após a cirurgia, Grupo LED 72/96 (dezoito coelhos) com aplicações de LED 72/96 horas após a cirurgia e Controle (doze coelhos) onde não houve aplicação de LED. Nos grupos experimentais foram realizadas 4 perfurações nas calvárias com preenchimento aleatoriamente de 1) Base em gel, 2) nanoemulsão carregada com FS, 3) lipossoma em gel com FS e 4) nanopartículas de albumina (BSA) carregada com FS. No grupo controle foram feitas duas perfurações, uma preenchida por osso autógeno e outra com coágulo. Dezesseis animais foram submetidos à eutanásia em cada tempo experimental: 5 dias, 10 dias e 20 dias. Lâminas histológicas foram feitas a partir dos defeitos e o osso neoformado foi mensurado. O uso de FS nos DDS não foi efetivo para abreviar o tempo de reparo ósseo em calvária de coelhos nos inervalos de tempo deste estudo / The combination between photosensitizer substances with laser or LED (light emitting diode) form the photodynamic therapy (PDT) basis that consists of photosensitivity drug activated by low frequency light. This mechanism is used in soft tissue healing process to improve the oxygen tension leading to a fast revascularization. The objective of this study was to evaluate the effects of photosensitivity drugs activated through LED on bone healing process. Fourty eight New Zealand White rabbits were underwent to four bicortical calvaria defects made by 6.0 mm trephine drill. The defects were randomly filled up with (1) Gel, (2) Nanoemulsion + photosensitizer drug, (3) Liposome + photosensitizer drug, (4) NPS (nanostructure polymeric system) + photosensitizer drug. After 24/48 hours or 72/96 hours a LED were applied on all the rabbits. Sixteen animals were sacrificed, respectively, at 5, 10 and 20 days after surgery. Histological slides were prepared from each experimental site for histomorphometry and histological analysis. Bone graft was significant higher bone level in all experimental time points.. At 10 days liposome showed higher bone level than Gel (p=0,0161). However on 20 days, no difference was detected between the materials. The use of photosensitizer drugs activated by LED demonstrated do not achieve the stimulate bone formation on later time points on thsi presente study

Orientador: Carlos Rossa Junior / Banca: Karina Gonzales Silverio Ruiz / Banca: Marcia Pinto Alves Mayer / Banca: Alexandra Ivo de Medeiros / Banca: Luis Carlos Spolidorio / Resumo: As interações microrganismo-hospedeiro se iniciam pela detecção de padrões moleculares associados a microrganismos (MAMPs) por receptores semelhantes à Toll (TLR) e por proteínas com domínio de ligação à nucleotídeos e oligomerização (Nod) na resposta imune inata. No entanto, como a cavidade bucal saudável é continuamente colonizada por microrganismos não patogênicos que também apresentam MAMPs, deve haver um mecanismo endógeno de regulação negativa da resposta do hospedeiro para evitar uma resposta exagerada e desnecessária com consequências negativas ao hospedeiro. Os mecanismos associados à distinção de microrganismos comensais e patogênicos na mucosa bucal são ainda pouco compreendidos. As proteínas Nod foram inicialmente descritas como 'TLRs intracelulares' capazes de reconhecer MAMPs no citosol; no entanto, estudos in vitro indicam que Nod têm papel relevante na regulação da expressão de RANKL e OPG induzidas por antígenos microbianos, bem como na modulação da atividade de vias de sinalização intracelular associadas à expressão de citocinas diretamente relacionadas à regulação do turnover do tecido ósseo. Devido à escassez de informações sobre o papel das proteínas Nod na modulação das interações microrganismo-hospedeiro na mucosa oral e com base nestas informações, nossa hipótese é que as proteínas Nod tem um papel relevante na modulação da reação inflamatória e suas consequências, incluindo a reabsorção do osso alveolar. Para testar esta hipótese, os objetivos específicos propostos foram: avaliar em camundongos knockout para Nod1, Nod2 ou Rip2, através de microtomografia computadorizada e avaliações histológicas descritivas, estereométricas e imunohistoquímicas (TRAP), o papel das proteínas Nod na inflamação e reabsorção óssea associadas à doença periodontal experimental induzida por bactérias inativadas por calor... / Abstract: Recognition of pathogenic bacteria by the host is initially mediated by the innate immune response through detection of microbe-associated molecular pattern (MAMPs) by Toll-like receptors (TLR) and Nucleotide-oligomerization domain (Nod) proteins. Since the oral cavity, as well as other mucosal surfaces, is continuously colonized with non-pathogenic bacteria that also present MAMPs, there has to be an endogenous negative regulatory mechanism in place to prevent an overt host response with deleterious consequences. Specifically in the oral mucosa, it is not clear how the immune system is able to quickly distinguish between commensal and pathogenic bacteria and tailor the host response. Nod proteins were initially described as 'intracellular TLRs' that recognize MAMPs associated with bacteria invading the cytosol; however these proteins have been shown to modulate the activation of various signaling pathways involved in the expression of inflammatory genes, including p38 MAPK and NF-κB in concert with TLR stimulation. There is paucity of information on the in vivo role of Nod proteins in the modulation of host-microbe interactions in the oral mucosa. Based on this information, our hypothesis is that Nod proteins play an important role in the modulation of the inflammatory reaction associated with periodontal diseases and its consequences, including alveolar bone resorption. To test this hypothesis, we propose the following specific aims: Assess the role of Nod proteins in the inflammation and bone resorption in experimentally-induced periodontal disease Describe the influence of Nod proteins on the cytokine and signaling networks associated with periodontal disease. / Doutor

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / The bisphosphonate tiludronic acid (TIL) presents anti-resorptive and anti-inflammatory properties and it has not been evaluated in the association periodontitis-diabetes mellitus (DM) to date. The purpose of this study was to evaluate the effects of local administration of TIL on experimental periodontitis (EP) in rats with streptozotocin (STZ)-induced DM. On day 1, thirty two rats received STZ injection. The animals were divided into groups (n=8): DM/C (Control), DM/EP, DM/EP/TIL1 and DM/EP/TIL3. In groups EP, a ligature was placed around the cervical area of mandibular first molars at day 8. In groups DM/EP/TIL1 and DM/EP/TIL3, TIL solutions of 1 and 3 mg/kg body weight, respectively, were injected into the buccal gingival margin of mandibular first molars every other day. Animals were euthanized at day 18. Histomorphometric analyses were performed. Data were statistically analyzed (p<0.05). Group DM/EP/TIL3 presented reduced alveolar bone loss and attachment loss when compared with group DM/EP (p<0.05). Within the limits of this study, it can be concluded that i) the local administration of TIL solutions presented a protective effect on tissue destruction in EP in diabetic rats and ii) the dosage of TIL may influence its effects. / O bisfosfonato Ãcido tiludrÃnico (TIL) apresenta propriedades antirreabsortivas e anti-inflamatÃrias e ainda nÃo foi estudado na associaÃÃo periodontite-diabetes mellitus (DM). O objetivo deste estudo foi avaliar os efeitos da administraÃÃo local do TIL na periodontite experimental (PE) em ratos com DM induzido por streptozotocina (STZ). No 1 dia, trinta e dois ratos receberam injeÃÃo de STZ. Os animais foram divididos nos grupos (n = 8): DM/C (Controle), DM/PE, DM/PE/TIL1 e DM/PE/TIL3. Nos grupos PE, uma ligadura foi colocada na Ãrea cervical dos primeiros molares inferiores no 8 dia. Nos grupos DM/PE/TIL1 e DM/PE/TIL3, soluÃÃes de TIL (1 e 3 mg/kg de peso corporal, respectivamente) foram injetadas na margem gengival vestibular dos primeiros molares inferiores em dias alternados. Os animais foram submetidos à eutanÃsia no 18 dia. AnÃlises histomorfomÃtricas foram realizadas. Os dados foram estatisticamente analisados (p<0,05). O grupo DM/PE/TIL3 apresentou perda Ãssea alveolar e perda de inserÃÃo reduzidas quando comparado com o grupo DM/PE (p<0,05). Dentro dos limites deste estudo, pode-se concluir que i) a administraÃÃo local de soluÃÃes de TIL apresentou um efeito protetor na destruiÃÃo tecidual na PE em ratos diabÃticos e ii) a dosagem de TIL pode influenciar seus efeitos.

O objetivo deste trabalho foi comparar o prognóstico de sobrevida da graduação histológica após efeito da quimioterapia (graus I versus II de Huvos), visando também identificar fatores prognósticos no que diz respeito à sobrevida livre de recidiva local (SLRL), sobrevida livre de metástase (SLM) e sobrevida global (SG), em pacientes portadores de osteossarcoma primário não metastático ao diagnóstico. Vinte e quatro entre 45 pacientes admitidos no Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo IOT/HC/FMUSP, entre 2000 e 2004, foram eleitos para o estudo, segundo os critérios de inclusão e exclusão utilizados. As probabilidades de sobrevida acumuladas foram feitas pela técnica de Kaplan-Meier e os índices I e II de HUVOS comparados pelos testes de Log Rank. A análise multivariada foi feita pela técnica de regressão logística com modelo de risco proporcional de COX e a validade estatística estabelecida para valores de p<0,05. Os graus I e II de Huvos, quando comparados, não foram considerados de valor prognóstico em nenhuma das sobrevidas estudadas (SLRL, SLM e SG). Os fatores adversos que influenciaram o risco de recidiva local e a sobrevida global, na análise univariada foram: subtipo histológico diferente do osteoblástico (p=0,017) e o tamanho tumoral maior que 15 cm (p=0,048). Em relação à SLM o subtipo não osteoblástico (p=0,007) teve um pior prognóstico. O subtipo histológico manteve sua significância na análise multivariada em todas as sobrevidas estudadas / The purpose of this study was to compare the prognostic of survivor of histologic graduation post chemotherapy (Huvos´s grade I versus II), aiming to identify prognostic factors concerning to local recurrence free survival (LRFS), metastases free survival (MFS) and overall survival (OS) in patients with nonmetastatic primary osteosarcoma. This study included 24 patients registred in the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil, from 2000 to 2004. Survivor rates were calculed using Kaplan-Meier method. Huvos´s grade (I e II) were compared using the Log Rank test. Cox proportional hazards model was used for multifatorial analysis. Statistical significance was defined as a p value less than 0, 05. The Huvos´s grade I versus II was not significant factor for LRFS, MFS or OS. The adverse factors for LRFS and OS in univariate analysis were nonosteoblastic histologic subtypes (p=0,017) and large tumor (p=0,048). For MFS nonosteoblastic histologic subtypes (p=0,007) had worse prognostic. The histologic subtypes maintained their significance in multivariate testing on all studied survivor

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O presente estudo conduzido na FZEA/USP, teve por finalidade avaliar os efeitos do flúor provenientes do fosfato de rocha e do fluoreto de sódio na fluorose dental de ovinos. Foram utilizados 21 carneiros Santa Inês, os quais foram submetidos a três tratamentos com duração de 140 dias. Os tratamentos foram: Tratamento B: Dieta Controle (fosfato bicálcico) com 13,2 mg de flúor/Kg M.S.; Tratamento F: Dieta suplementada com 98,5 mg de flúor proveniente do fluoreto de Sódio; Tratamento R: Dieta suplementada com 94,5 mg de flúor proveniente do fosfato de rocha. No inicio e a cada 28 dias os carneiros eram pesados e colhidas amostras de sangue para dosagem sérica de flúor e no final do experimento, os animais foram abatidos para colheita de amostras de costela e dentes, para determinação dos teores de F. e análise histológica. Os animais suplementados com fosfato de rocha apresentaram níveis séricos de F superiores ao grupo controle, mas inferiores aos suplementados com flúor de fluoreto de sódio (p<=0,05). Ao final do experimento (40 dias), houve uma tendência (p<=0,08) dos animais da dieta controle ganharem mais peso que os suplementados com flúor do fluoreto de sódio. A suplementação da dieta durante 140 dias com 98,5mg de flúor proveniente do fluoreto de sódio ou com 94,5 mg de F proveniente do fosfato de rocha foi suficiente para aumentar significativamente o teor de F nos ossos. Não foi verificada alteração histológica nos molares de ovinos erupcionados aos 10 meses. / The present study was conducted at FZEA/USP and had the purpose to evaluate the effects of fluorine in rock phosphate and sodium flouride in sheep. Twenty one Santa Inês rams were submitted to three treatments during 140 days. The treatments were: Treatment B: Control diet dicalcium phosphate with 13,2 mg of fluorine/kgDM; Treatment F: Supplemented diet with 98,5 mg of fluorine from sodium fluorine ; Treatment R: Supplemented Diet with 94,5 mg of fluorine from rock phosphate. In the beginning and each 28 days the animals were weighted and blood samples were collected for analyses of fluorine serum concentration. By the end of the experiment, the animals were slaughtered to collect samples of ribs and teeth to determine the fluorine content and for histologic. The supplemented animals with rock phosphate presented higher fluorine serum levels than the control group, but lower than the supplemented ones with fluorine from sodium fluoride (p<=0,05). In the end of the experiment (140 days) there was a tendency (p<=0,08) of the animals control diet to put on more weight than the supplemented with fluorine from sodium fluoride. The supplementation of the diet during 140 days with 98,5 mg of fluorine from sodium fluoride or with 94,5 mg of fluorine from rock phosphate it was enough for a significative increasing in the fluorine concentration in the bones. No histological alteration was detected in the ovine molars broken out while they were 10 months.

abstract: College students are a niche of young adults, characterized by abnormal sleeping habits and inactive lifestyles. Many students entering college are as young as 18 years old and graduate by 22 years old, a window of time in which their bones are still accruing mineral. The purpose of this cross-sectional study was to determine whether sleep patterns and physical activity observed in college students (N= 52) 18-25 years old at Arizona State University influenced bone biomarkers, osteocalcin (OC) and N-terminal telopeptide of type 1 collagen (NTX-1) concentrations. Students completed various dietary and health history questionnaires including the International Physical Activity Questionnaire short form. Students wore an actigraphy watch for 7 consecutive nights to record sleep events including total sleep time, sleep onset latency and wake after sleep onset. Total sleep time had a significant, negative correlation with OC (r = -0.298, p-value =0.036) while sleep onset latency had a significant, positive correlation with NTX-1 serum concentration (r = 0.293, p-value = 0.037). Despite correlational findings, only sleep percent was found to be significant (beta coefficient = 0.271 p-value = 0.788) among all the sleep components assessed, after adjusting for gender, race, BMI and calcium intake in multivariate regression models. Physical activity alone was not associated with either bone biomarker. Physical activity*sleep onset latency interactions were significantly correlated with osteocalcin (r = 0.308, p-value =0.006) and NTX-1 (r = 0.286, p-value = 0.042) serum concentrations. Sleep percent*physical activity interactions were significantly correlated with osteocalcin (r = 0.280, p-value = 0.049) but not with NTX-1 serum concentrations. Interaction effects were no longer significant after adjusting for covariates in the regression models. While sleep percent was a significant component in the regression model for NTX-1, it was not clinically significant. Overall, sleep patterns and physical activity did not explain OC and NTX-1 serum concentrations in college students 18-25 years old. Future studies may need to consider objective physical activity devices including accelerometers to measure activity levels. At this time, college students should review sleep and physical activity recommendations to ensure optimal healthy habits are practiced. / Dissertation/Thesis / Masters Thesis Nutrition 2019

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases, the genetic basis is unknown. Via whole-exome sequencing and linkage analysis, we determined the most likely causative mutations in four families. While the mutations are in three different genes – FBLIM1, PLCG2 and PIP; all three genes are involved in Fcγ signaling and osteoclast activation. In a large cohort of 61 individuals with CRMO, we performed gene and pathway based association analysis using the 1000 genomes participants of European ancestry as controls. One gene from the family-based analyses, ANO6, was significantly enriched for rare variants in our cohort of cases. ANO6 is involved in P2RX7- mediated inflammasome activation and in the regulation of bone mineralization. While no pathways were enriched for rare variants in the CRMO cohort after genome-wide correction, four pathways were significantly enriched for rare variants in the control samples, indicating a protective effect of the variants. The second most significant pathway, activation of chaperone genes by XBP1s, is relevant to CRMO pathogenesis as XBP1s is a transcription factor that attenuates ER stress, and regulates the expression of genes involved in RANKL signaling and bone remodeling. An association analysis using a larger set of cases followed by functional validation of candidate genes is necessary to confidently declare the mutations isolated in the work presented here to be pathogenic. Our preliminary findings suggest that mutations in genes involved in both the inflammatory response and bone remodeling underlie the pathogenesis of CRMO.