Resumo: Os metabólitos do AA exercem um reconhecido papel na patogênese da doença periodontal. O objetivo deste trabalho foi avaliar o efeito do celecoxib, um inibidor seletivo da enzima cicloxigenase-2 (COX-2), sobre o desenvolvimento de doença periodontal induzida por ligadura em ratos. Após a colocação de ligadura de algodão ao redor dos primeiros molares inferiores direitos, 180 ratos Holtzman foram aleatoriamente subdivididos em 3 grupos experimentais com 60 animais cada, os quais receberam diariamente dose oral de celecoxib 10 mg ou 20 mg/ kg de peso corporal (grupos Ce1 e Ce2, respectivamente) ou, dose oral de 10ml/kg de NaCl a 0,9% (grupo Controle). Aos 3, 5, 10, 18 e 30 dias após o início do experimento, 12 animais de cada grupo experimental foram sacrificados. O tratamento com celecoxib, em ambas as concentrações, reduziu significantemente (p<0.05) a perda óssea alveolar radiográfica aos 5 dias e, diminuiu a intensidade da reabsorção óssea, observada histologicamente, aos 30 dias. Ainda, o celecoxib atrasou o início e, diminui a magnitude, do processo inflamatório agudo. Estes resultados demonstram que a inibição seletiva da COX-2 com o celecoxib, pode interferir com a resposta do tecido periodontal frente à presença de ligadura em ratos. / Abstract: Arachidonic acid metabolites have a recognized role in the pathogenesis of periodontal disease. The purpose of this study was to evaluate the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the progression of periodontal disease in a ligature-induced periodontitis model in rats. After ligature placement in the mandibular right first molars, 180, 6-week-old Holtzman rats were ramdomly assigned to one of the following groups of treatment that consisted in a daily oral dose of 10mg/kg body weight of celecoxib (Ce1), 20mg/kg body weight of celecoxib (Ce2) or 10ml/kg of 0,9%NaCl (Control). At 3, 5, 10, 18 and 30 days later, 12 animals of each group were sacrificed. Treatment with celecoxib significantly (p < 0.05) decreased the radiographic bone loss at 5 days of experiment and, decreased the bone loss activity, histologically observed at 30 days. In addition, celecoxib was shown to delay the onset and to suppress the magnitude of the acute inflammatory process. These results show that selective cyclooxygenase-2 (COX-2) inhibition with celecoxib, can interfer with the periodontal tissue response to ligature placement in rats. / Orientador: Luís Carlos Spolidorio / Coorientador: Elcio Marcantonio Junior / Banca: Joni Augusto Cirelli / Banca: Maria Angela Naval Machado / Mestre

Evidências científicas têm apontado para inúmeros benefícios do consumo baixo/moderado de cerveja sobre a saúde dos indivíduos. Uma recente meta-análise com mais de 290.000 pessoas confirma a redução no risco de doenças cardiovasculares tanto para o vinho, como também para a cerveja, desde que consumido em doses baixas ou moderadas. A essas substâncias têm se atribuído efeitos antioxidantes e anti-inflamatórios, bem como ações na função vascular. Uma vez que as doenças periodontais apresentam uma natureza infecto-inflamatória, é lícito supor que o consumo de cerveja possa trazer benefícios para os tecidos periodontais. Para isso, o presente estudo abordou de forma prospectiva a ação da cerveja rica ou não em lúpulo sobre a perda óssea alveolar (POA) em modelo animal. Para isso, 64 ratos Wistar machos com 60 dias foram utilizados, divididos em 8 grupos experimentais. Após a eutanásia, o padrão de destruição óssea foi avaliada morfometricamente nos diferentes grupos experimentais Para os grupos submetidos a indução de POA por meio de ligadura, menores médias de destruição periodontal foram encontradas nos grupos expostos a cerveja, especialmente no que se refere a face palatina (p<0.01) e a média de POA no dente (p<0.01). Já na comparação entre os grupos que não sofreram indução de POA, a média de destruição periodontal foi estatisticamente menor somente na face palatina do grupo que recebeu cerveja com alto teor de lúpulo (p=0.01), quando comparada ao controle. Além disso, os ratos expostos a cerveja com alto teor de lúpulo apresentaram uma menor ocorrência de periodontite quando comparado aos demais grupos experimentais. Concluiu-se que o consumo de cerveja enriquecida com lúpulo parece trazer um efeito protetor sobre a POA induzida ou não por meio de ligadura em modelo animal. Além disso, a presença de lúpulo na cerveja pode ser benéfica na diminuição da ocorrência de periodontite experimental. / Effects of a low/moderate consumption of beer on human health has been reported. A recent meta-analysis confirms an important reduction in cardiovascular risk as much for wine as for a beer. Vascular improvement and antioxidant/anti-inflammatory effects should be related with this point. Periodontal diseases have an infectious-inflammatory nature. Therefore, beer consumption can benefits the periodontal health. For that, the aim of the present study was assessed the effect of beer enriched with hops on alveolar bone loss (ABL) in animal model. Sixty-four, 60-days-old, male Wistar rats in 8 experimental groups were stratified. After euthanasia, the ABL in the different experimental groups was evaluated. The groups that were not ligature-induced presented less ABL in beer group, especially regarding the palatal face (p <0.01) and mean of ABL in the tooth (p <0.01). In the comparison between groups that did not undergo ABL induction by ligature, mean periodontal destruction was statistically lower in the group that received beer with high hops concentration (p = 0.01) when compared to control group. In addition, the rats that were exposed to beer with high hops concentration to experienced less occurrence of periodontitis than others groups. It can be concluded that the consumption of beer enriched with hops seems protect to ABL induced or not by ligature. In addition, lower occurrence of experimental periodontitis was experienced in the enriched hops beer group.

A medicina periodontal vem mostrando uma associação entre a doença periodontal (DP) e doenças sistêmicas. Entretanto, são poucos os estudos que têm focado no impacto da hipertensão arterial sistêmica na progressão da periodontite. A relação entre estas duas patologias envolve o processo de inflamação, uma vez que a hipertensão está associada à disfunção endotelial. O objetivo deste estudo foi avaliar, morfometricamente, se a hipertensão afeta a progressão da DP através do aumento da perda óssea alveolar mesmo após a remoção da ligadura. Utilizando-se um modelo de periodontite induzida por ligadura, 20 ratos hipertensos (Spontaneously Hypertensive Rats - SHR) e 20 ratos normotensos (Wistar Kyoto - WKY) foram distribuídos nos seguintes grupos: WKY-C, WKY-DP, SHR-C e SHR-DP (C grupo controle e DP grupo com doença periodontal). Nos grupos com DP os 1°s molares inferiores receberam ligadura com fio de algodão no início do experimento. Após 10 dias, metade dos animais de cada grupo foi sacrificada e a outra metade teve suas ligaduras removidas. No 21° dia (11 dias após a remoção das ligaduras), os animais restantes foram sacrificados. As mandíbulas tiveram seu tecido mole removido e foram submetidas à análise morfométrica, medindo-se a distância entre a crista óssea alveolar e a junção cemento-esmalte (COA-JCE, mm) em todos os grupos. Aos 10 dias, os grupos com DP mostraram uma perda óssea maior (p<0.05) que seus controles (SHR-DP = 0.72 ± 0.05; SHR-C = 0.39 ± 0.04; WKY-DP = 0.75 ± 0.04 e WKY-C = 0.56 ± 0.04). Após a remoção das ligaduras, a perda óssea acumulada foi superior (p<0.05) àquela aos 10 dias com ligadura, apenas no grupo SHR-DP (0.94 ± 0.13 mm). Foram observados 32% de perda óssea adicional após a remoção das ligaduras no grupo SHR-DP e apenas 17% no grupo WKY-DP. Os ratos SHR (83% e 102%) apresentaram um padrão de perda óssea diferente e mais severa que os WKY (32% e 26%) comparando-se com seus respectivos controles, tanto aos 10 quanto principalmente aos 21 dias. Enquanto que a perda óssea nos WKY tendeu a diminuir após a remoção das ligaduras, os SHR apresentaram uma progressão da perda óssea no 21° dia. Portanto, pode-se especular que a hipertensão está associada com uma perda óssea alveolar mais severa, mesmo após a remoção das ligaduras, e que pode perpetuar a progressão da periodontite. / Periodontal medicine has been showing an association between periodontal disease (PD) and systemic diseases. However, few studies have focused on the impact of hypertension on the progression of periodontitis. The correlation of both conditions involves the inflammatory process, once hypertension is associated to endothelial dysfunction. The purpose of this study was to evaluate morphometrically whether hypertension affects PD progression by enhancing bone loss even after ligature removal. Using a ligature-induced periodontitis model, 20 Spontaneously Hypertensive Rats (SHR) and 20 normotensive rats (Wistar Kyoto - WKY) were assigned to one of the following groups: WKY-C, WKY-PD, SHR-C and SHR-PD (C control group, and PD periodontitis group). On PD groups, the first mandibular molar received a cotton ligature at baseline. After 10 days, 5 animals of each group were sacrificed and the ligatures of the other animals were removed. On the 21th day (11 days without ligatures), the remaining animals were sacrificed. The jaws were defleshed and the distances between the alveolar bone crests and the cementoenamel junctions (ABC-CEJ, mm) were measured in all groups. After 10 days, the PD groups showed more bone loss (p<0.05) than the controls (SHR-PD = 0.72 ± 0.05; SHR-C = 0.39 ± 0.04; WKY-PD = 0.75 ± 0.04 and WKY-C = 0.56 ± 0.04 mm). After ligature removal, the culmulative bone loss was worse (p<0.05) than that one at 10 days with ligature only in SHR-PD group (0.94 ± 0.13 mm). It was observed 32% of additional bone loss in SHR-PD group and only 17% in WKY-PD. The SHR animals (83% and 102%) showed a different and more severe pattern of bone loss than WKY (32% and 26%) related to their respectively controls, at 10 and mainly at 21 days. After ligature removal, bone loss in WKY group tended to diminish, while SHR showed a progressive bone loss in 21° day. Therefore, it may be speculated that the hypertensive condition is associated with an advanced bone loss even after ligature removal that may perpetuate the progression of periodontitis.

The purpose of this observational cross-sectional study was to assess the oral health of children between the ages of 6 to 18 with neutropenia attending the Marrow Failure and Myelodysplasia Program at The Hospital for Sick Children and compare the results to healthy control patients attending the Children’s Clinic, Faculty of Dentistry, University of Toronto. Fifteen patients with neutropenia and 26 healthy controls participated in this study. Patients with neutropenia reported an increased incidence of mouth sores and bleeding gums while brushing. However, clinical examination showed no statistical differences in the presence of ulcerations, gingival recession, tooth mobility, gingival inflammation or plaque and calculus levels. The dmft/t and DMFT/T scores were lower for the group with neutropenia, but only the dmft/t score was significant. This data suggests that patients with neutropenia that are being treated by a haematologist do not experience any more severe oral problems than healthy dental patients.

The purpose of this observational cross-sectional study was to assess the oral health of children between the ages of 6 to 18 with neutropenia attending the Marrow Failure and Myelodysplasia Program at The Hospital for Sick Children and compare the results to healthy control patients attending the Children’s Clinic, Faculty of Dentistry, University of Toronto. Fifteen patients with neutropenia and 26 healthy controls participated in this study. Patients with neutropenia reported an increased incidence of mouth sores and bleeding gums while brushing. However, clinical examination showed no statistical differences in the presence of ulcerations, gingival recession, tooth mobility, gingival inflammation or plaque and calculus levels. The dmft/t and DMFT/T scores were lower for the group with neutropenia, but only the dmft/t score was significant. This data suggests that patients with neutropenia that are being treated by a haematologist do not experience any more severe oral problems than healthy dental patients.

Thesis--University of Oklahoma. / Bibliography: leaves 97-101.

Thesis--University of Oklahoma. / Bibliography: leaves 76-79.

Many common cancers have a predisposition for bone metastasis. Tumor occupation of bone is both destructive and a source of debilitating pain in cancer patients. As a result, cancer-induced bone pain (CIBP) is the single most common form of clinical cancer pain. Opioids remain the golden standard for the management of CIBP; however, >30% of cancer patients do not experience adequate pain relief with opioids. Furthermore, clinical reports have suggested that opioids can exacerbate bone loss and increase the likelihood of skeletal-related events. To date, there is no known direct mechanism for opioid-induced bone loss (OIBL). We hypothesized that opioid off-target activation of toll-like receptor 4 (TLR4), an innate immune receptor that is expressed in bone, mediates an increase bone loss and associated CIBP. In the 66.1-BALB/cfC3H murine model of breast cancer bone metastasis, TLR4 expression is upregulated in tumor-burdened bone. Chronic morphine treatment exacerbated spontaneous and evoked pain behaviors in a manner paralleled by bone loss: we identified an increase in spontaneous fracture and osteolysis markers including serum collagen-type I (CTX) and intramedullary receptor activator of nuclear κ-B ligand (RANKL). Administration of (+)naloxone, a non-opioid TLR4 antagonist, attenuated both exacerbation of CIBP and morphine-induced osteolytic changes in vivo. Morphine did not alter tumor burden in vivo or tumor cell growth in vitro. Importantly, morphine produced the in vitro differentiation and activation of osteoclasts in a dose-dependent manner that was reversible with (+)naloxone, suggesting that morphine may contribute directly to osteolytic activation. To improve opioid management of CIBP, we then posited and evaluated three novel adjunct therapeutic targets: cannabinoid receptor-2, adenosine 3 receptor and sphingosine-1-phosphate receptor 1. These pharmacological targets were identified as having a multiplicity of anti-cancer, osteoprotective and/or neuroprotective effects in addition to analgesic efficacy in chronic pain. Targets were tested in the 66.1-BALB/cfC3H model of CIBP and demonstrated to have stand-alone efficacy as antinociceptive agents. Taken together, this work provides a cautionary evaluation of opioid therapy in cancer-induced bone pain and seeks to mitigate opioid side effects through the identification of innovative adjunct therapies that can ultimately improve quality of life in patients suffering from cancer pain.

<p>S. 1-50: sammanfattning, härtill 6 uppsatser.</p> / digitalisering@umu

Mechanical unloading has deleterious effects on the musculoskeletal system and results in significant reductions in bone density, mass, and strength, which do not fully recover even years after returning to weightbearing. For example, the rate of bone loss in microgravity is 10-fold more rapid than the rate of loss seen in elderly Caucasian females, the population group most predisposed to osteoporosis. This raises concern with individuals who are exposed to multiple bed rest periods or crewmembers who make repeated missions. Exercise offers a way to reduce or reverse these effects. Dual-energy X-ray absorptiometry (DXA) densitometry and bone mineral density (BMD) alone are generally insufficient for capturing the complex changes in bone mass, structure, and integrity and not an accurate predictor of fracture risk. Therefore, it is essential to measure the mechanical properties of bone tissue directly using animal models. The hindlimb unloaded (HU) rat model is a well-established ground-based analog for studying bone response to disuse and effects of spaceflight. The current study is one of the very few that has measured longitudinally densitometric and mechanical properties of bone after repeated simulated microgravity and long-term recovery at multiple anatomic sites in skeletally mature rats. The specific aims were to characterize 1) loss and recovery dynamics of bone following a period of unloading, 2) bone response after a second exposure to 28 days of HU, following an initial 28 days of HU and a recovery period equal to twice the duration of initial exposure, and 3) effects of resistance exercise during recovery period following an initial HU exposure and its effects on a subsequent exposure. In general, our data showed that bone response to unloading and recovery is site-specific. More specifically, we found that: 1) the rat proximal tibia metaphysis modeled the loss and discordant recovery dynamics as seen in the International Space Station (ISS) crewmembers proximal femur better than the rat femoral neck; 2) the initial exposure to HU has minimal effect on the subsequent HU exposure, and detrimental effects of the second HU exposure were milder than the initial due to reduced mechanosensitivity of the bone; 3) exercise significantly enhanced recovery following the initial HU exposure, and losses during the second exposure were not affected by exercise in most cases.