Bisphosphonates for metastatic bone disease in lung cancer

Bisphosphonates have proven effectiveness in preventing skeletal-related events (SREs) in advanced breast cancer, prostate cancer and multiple myeloma. The purpose of this study was to assess efficacy of bisphosphonates in preventing SREs, in controlling pain, and in increasing life expectancy in lung cancer patients with bone metastases.^ We performed an electronic search in MEDLINE, EMBASE, Web of Science, and Cochrane library databases up to April 4, 2010. Hand searching and searching in clinicaltrials.gov were also performed. Two independent reviewers selected all clinical trials that included lung cancer patients with bone metastases treated with bisphosphonates. We excluded articles that involved cancers other than lung, patients without bone metastasis and treatment other than bisphosphonates. Outcome questions answered were efficacy measured as overall pain control, overall improvement in survival and reduction in skeletal-related events or SREs (fracture, cord compression, radiation or surgery to the bone, hypercalcemia of malignancy). The quality of each study was evaluated using the Cochrane Back Review group questionnaire to assess risk of bias (0-worst to 11-best). Data extraction and quality assessments were independently performed by two assessors. Meta-analyses were performed where more than one study with similar outcomes were found.^ We identified eight trials that met our inclusion criteria. Three studies evaluated zoledronic acid, three pamidronate, three clodronate and two ibandronate. Two were placebocontrol trials while two had multi-group comparisons (radiotherapy, radionucleotides, and chemotherapy) and two had different bisphosphonate as active controls. Quality scores ranged from 1-4 out of 11 suggesting high risk of bias. Studies failed to report adequate explanation of randomization procedures, concealment of randomization and blinding. Metaanalysis showed that patients treated with zoledronic acid alone had lower rates of developing SREs compared to placebo at 21 months (RR=0.80, 95% CI=0.66-0.97, p=0.02). Meta-analyses also showed increased pain control when a bisphosphonate was added to the existing treatment modality like chemotherapy or radiation (RR=1.17, 95% CI=1.03-1.34, p=0.02). However, pain control was not statistically significantly different among various bisphosphonates when other treatment modalities were not present. Despite improvement in SRE and pain control, bisphosphonates failed to show improvement in overall survival (Difference in means=109.1 days, 95% CI= -51.52 – 269.71, p=0.183).^ Adding biphosphonates to standard care improved pain control and reduced SREs. Biphosphonates did not improve overall survival. Further larger studies with higher quality are required to stengthen the evidence.^ Keywords/MeSH terms Bisphosphonates/diphosphonates: generic, chemical and trade names.^

Delayed Thrombus Resolution and Fibroproliferative Vascular Wound Healing From Deficiency of Type III Collagen: a Paradoxical Mechanism for Tissue Fragility

Vascular Ehlers-Danlos syndrome is a heritable disease of connective tissue caused by mutations in COL3A1, conferring a tissue deficiency of type III collagen. Cutaneous wounds heal poorly in these patients, and they are susceptible to spontaneous and catastrophic rupture of expansible hollow organs like the gut, uterus, and medium-sized to large arteries, which leads to premature death. Although the predisposition for organ rupture is often attributed to inherent tissue fragility, investigation of arteries from a haploinsufficient Col3a1 mouse model (Col3a1+/-) demonstrates that mutant arteries withstand even supraphysiologic pressures comparably to wild-type vessels. We hypothesize that injury that elicits occlusive thrombi instead unmasks defective thrombus resolution resulting from impaired production of type III collagen, which causes deranged remodeling of matrix, persistent inflammation, and dysregulated behavior by resident myofibroblasts, culminating in the development of penetrating neovascular channels that disrupt the mechanical integrity of the arterial wall. Vascular injury and thrombus formation following ligation of the carotid artery reveals an abnormal persistence and elevated burden of occlusive thrombi at 21 post-operative days in vessels from Col3a1+/- mice, as opposed to near complete resolution and formation of a patent and mature neointima in wild-type mice. At only 14 days, both groups harbor comparable burdens of resolving thrombi, but wild-type mice increase production of type III collagen in actively resolving tissues, while mutant mice do not. Rather, thrombi in mutant mice contain higher burdens of macrophages and proliferative myofibroblasts, which persist through 21 days while wild-type thrombi, inflammatory cells, and proliferation all regress. At the same time that increased macrophage burdens were observed at 14 and 21 days post ligation, the medial layer of mutant arterial walls concurrently harbored a significantly higher incidence of penetrating neovessels compared with those in wild-type mice. To assess whether limited type III collagen production alters myofibroblast behavior, fibroblasts from vEDS patients with COL3A1 missense mutations were seeded into three-dimensional fibrin gel constructs and stimulated with transforming growth factor-β1 to initiate myofibroblast differentiation. Although early signaling events occur similarly in all cell lines, late extracellular matrix- and mechanically-regulated events like transcriptional upregulation of type I and type III collagen secretion are delayed in mutant cultures, while transcription of genes encoding intracellular contractile machinery is increased. Sophisticated imaging of collagen synthesized de novo by resident myofibroblasts visualizes complex matrix reorganization by control cells but only meager remodeling by COL3A1 mutant cells, concordant with their compensatory contraction to maintain tension in the matrix. Finally, administration of immunosuppressive rapamycin to mice following carotid ligation sufficiently halts the initial inflammatory phase of thrombus resolution and fully prevents both myofibroblast migration into the thrombus and the differential development of neovessels between mutant and wild-type mice, suggesting that pathological defects in mutant arteries develop secondarily to myofibroblast dysfunction and chronic inflammatory stimulation, rather than as a manifestation of tissue fragility. Together these data establish evidence that pathological defects in the vessel wall architecture develop in mutant arteries as sequelae to abnormal healing and remodeling responses activated by arterial injury. Thus, these data support the hypothesis that events threatening the integrity of type III collagen-deficient vessels develop not as a result of inherent tissue weakness and fragility at baseline but instead as an episodic byproduct of abnormally persistent granulation tissue and fibroproliferative intravascular remodeling.

The effects of long (C20/22) and short (C18) chain omega-3 fatty acids on keel bone fractures, bone biomechanics, behavior, and egg production in free-range laying hens.

Keel fractures in the laying hen are the most critical animal welfare issue facing the egg production industry, particularly with the increased use of extensive systems in response to the 2012 EU directive banning conventional battery cages. The current study is aimed at assessing the effects of 2 omega-3 (n3) enhanced diets on bone health, production endpoints, and behavior in free-range laying hens. Data was collected from 2 experiments over 2 laying cycles, each of which compared a (n3) supplemented diet with a control diet. Experiment 1 employed a diet supplemented with a 60:40 fish oil-linseed mixture (n3:n6 to 1.35) compared with a control diet (n3:n6 to 0.11), whereas the n3 diet in Experiment 2 was supplemented with a 40:60 fish oil-linseed (n3:n6 to 0.77) compared to the control diet (n3:n6 to 0.11). The n3 enhanced diet of Experiment 1 had a higher n3:n6 ratio, and a greater proportion of n3 in the long chain (C20/22) form (0.41 LC:SC) than that of Experiment 2 (0.12 LC:SC). Although dietary treatment was successful in reducing the frequency of fractures by approximately 27% in Experiment 2, data from Experiment 1 indicated the diet actually induced a greater likelihood of fracture (odds ratio: 1.2) and had substantial production detriment. Reduced keel breakage during Experiment 2 could be related to changes in bone health as n3-supplemented birds demonstrated greater load at failure of the keel, and tibiae and humeri that were more flexible. These results support previous findings that n3-supplemented diets can reduce fracture likely by increasing bone strength, and that this can be achieved without detriment to production. However, our findings suggest diets with excessive quantities of n3, or very high levels of C20/22, may experience health and production detriments. Further research is needed to optimize the quantity and type of n3 in terms of bone health and production variables and investigate the potential associated mechanisms.

Arsenic speciation in edible alga samples by microwave-assisted extraction and high performance liquid chromatography coupled to atomic fluorescence spectrometry

Twelve commercially available edible marine algae from France, Japan and Spain and the certified reference material (CRM) NIES No. 9 Sargassum fulvellum were analyzed for total arsenic and arsenic species. Total arsenic concentrations were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) after microwave digestion and ranged from 23 to 126 μg g−1. Arsenic species in alga samples were extracted with deionized water by microwave-assisted extraction and showed extraction efficiencies from 49 to 98%, in terms of total arsenic. The presence of eleven arsenic species was studied by high performance liquid chromatography–ultraviolet photo-oxidation–hydride generation atomic–fluorescence spectrometry (HPLC–(UV)–HG–AFS) developed methods, using both anion and cation exchange chromatography. Glycerol and phosphate sugars were found in all alga samples analyzed, at concentrations between 0.11 and 22 μg g−1, whereas sulfonate and sulfate sugars were only detected in three of them (0.6-7.2 μg g−1). Regarding arsenic toxic species, low concentration levels of dimethylarsinic acid (DMA) (<0.9 μg g−1) and generally high arsenate (As(V)) concentrations (up to 77 μg g−1) were found in most of the algae studied. The results obtained are of interest to highlight the need to perform speciation analysis and to introduce appropriate legislation to limit toxic arsenic species content in these food products.

Nanoinformatics approaches for information extraction and text mining in nanomedical research texts

La nanotecnología es un área de investigación de reciente creación que trata con la manipulación y el control de la materia con dimensiones comprendidas entre 1 y 100 nanómetros. A escala nanométrica, los materiales exhiben fenómenos físicos, químicos y biológicos singulares, muy distintos a los que manifiestan a escala convencional. En medicina, los compuestos miniaturizados a nanoescala y los materiales nanoestructurados ofrecen una mayor eficacia con respecto a las formulaciones químicas tradicionales, así como una mejora en la focalización del medicamento hacia la diana terapéutica, revelando así nuevas propiedades diagnósticas y terapéuticas. A su vez, la complejidad de la información a nivel nano es mucho mayor que en los niveles biológicos convencionales (desde el nivel de población hasta el nivel de célula) y, por tanto, cualquier flujo de trabajo en nanomedicina requiere, de forma inherente, estrategias de gestión de información avanzadas. Desafortunadamente, la informática biomédica todavía no ha proporcionado el marco de trabajo que permita lidiar con estos retos de la información a nivel nano, ni ha adaptado sus métodos y herramientas a este nuevo campo de investigación. En este contexto, la nueva área de la nanoinformática pretende detectar y establecer los vínculos existentes entre la medicina, la nanotecnología y la informática, fomentando así la aplicación de métodos computacionales para resolver las cuestiones y problemas que surgen con la información en la amplia intersección entre la biomedicina y la nanotecnología. Las observaciones expuestas previamente determinan el contexto de esta tesis doctoral, la cual se centra en analizar el dominio de la nanomedicina en profundidad, así como en el desarrollo de estrategias y herramientas para establecer correspondencias entre las distintas disciplinas, fuentes de datos, recursos computacionales y técnicas orientadas a la extracción de información y la minería de textos, con el objetivo final de hacer uso de los datos nanomédicos disponibles. El autor analiza, a través de casos reales, alguna de las tareas de investigación en nanomedicina que requieren o que pueden beneficiarse del uso de métodos y herramientas nanoinformáticas, ilustrando de esta forma los inconvenientes y limitaciones actuales de los enfoques de informática biomédica a la hora de tratar con datos pertenecientes al dominio nanomédico. Se discuten tres escenarios diferentes como ejemplos de actividades que los investigadores realizan mientras llevan a cabo su investigación, comparando los contextos biomédico y nanomédico: i) búsqueda en la Web de fuentes de datos y recursos computacionales que den soporte a su investigación; ii) búsqueda en la literatura científica de resultados experimentales y publicaciones relacionadas con su investigación; iii) búsqueda en registros de ensayos clínicos de resultados clínicos relacionados con su investigación. El desarrollo de estas actividades requiere el uso de herramientas y servicios informáticos, como exploradores Web, bases de datos de referencias bibliográficas indexando la literatura biomédica y registros online de ensayos clínicos, respectivamente. Para cada escenario, este documento proporciona un análisis detallado de los posibles obstáculos que pueden dificultar el desarrollo y el resultado de las diferentes tareas de investigación en cada uno de los dos campos citados (biomedicina y nanomedicina), poniendo especial énfasis en los retos existentes en la investigación nanomédica, campo en el que se han detectado las mayores dificultades. El autor ilustra cómo la aplicación de metodologías provenientes de la informática biomédica a estos escenarios resulta efectiva en el dominio biomédico, mientras que dichas metodologías presentan serias limitaciones cuando son aplicadas al contexto nanomédico. Para abordar dichas limitaciones, el autor propone un enfoque nanoinformático, original, diseñado específicamente para tratar con las características especiales que la información presenta a nivel nano. El enfoque consiste en un análisis en profundidad de la literatura científica y de los registros de ensayos clínicos disponibles para extraer información relevante sobre experimentos y resultados en nanomedicina —patrones textuales, vocabulario en común, descriptores de experimentos, parámetros de caracterización, etc.—, seguido del desarrollo de mecanismos para estructurar y analizar dicha información automáticamente. Este análisis concluye con la generación de un modelo de datos de referencia (gold standard) —un conjunto de datos de entrenamiento y de test anotados manualmente—, el cual ha sido aplicado a la clasificación de registros de ensayos clínicos, permitiendo distinguir automáticamente los estudios centrados en nanodrogas y nanodispositivos de aquellos enfocados a testear productos farmacéuticos tradicionales. El presente trabajo pretende proporcionar los métodos necesarios para organizar, depurar, filtrar y validar parte de los datos nanomédicos existentes en la actualidad a una escala adecuada para la toma de decisiones. Análisis similares para otras tareas de investigación en nanomedicina ayudarían a detectar qué recursos nanoinformáticos se requieren para cumplir los objetivos actuales en el área, así como a generar conjunto de datos de referencia, estructurados y densos en información, a partir de literatura y otros fuentes no estructuradas para poder aplicar nuevos algoritmos e inferir nueva información de valor para la investigación en nanomedicina. ABSTRACT Nanotechnology is a research area of recent development that deals with the manipulation and control of matter with dimensions ranging from 1 to 100 nanometers. At the nanoscale, materials exhibit singular physical, chemical and biological phenomena, very different from those manifested at the conventional scale. In medicine, nanosized compounds and nanostructured materials offer improved drug targeting and efficacy with respect to traditional formulations, and reveal novel diagnostic and therapeutic properties. Nevertheless, the complexity of information at the nano level is much higher than the complexity at the conventional biological levels (from populations to the cell). Thus, any nanomedical research workflow inherently demands advanced information management. Unfortunately, Biomedical Informatics (BMI) has not yet provided the necessary framework to deal with such information challenges, nor adapted its methods and tools to the new research field. In this context, the novel area of nanoinformatics aims to build new bridges between medicine, nanotechnology and informatics, allowing the application of computational methods to solve informational issues at the wide intersection between biomedicine and nanotechnology. The above observations determine the context of this doctoral dissertation, which is focused on analyzing the nanomedical domain in-depth, and developing nanoinformatics strategies and tools to map across disciplines, data sources, computational resources, and information extraction and text mining techniques, for leveraging available nanomedical data. The author analyzes, through real-life case studies, some research tasks in nanomedicine that would require or could benefit from the use of nanoinformatics methods and tools, illustrating present drawbacks and limitations of BMI approaches to deal with data belonging to the nanomedical domain. Three different scenarios, comparing both the biomedical and nanomedical contexts, are discussed as examples of activities that researchers would perform while conducting their research: i) searching over the Web for data sources and computational resources supporting their research; ii) searching the literature for experimental results and publications related to their research, and iii) searching clinical trial registries for clinical results related to their research. The development of these activities will depend on the use of informatics tools and services, such as web browsers, databases of citations and abstracts indexing the biomedical literature, and web-based clinical trial registries, respectively. For each scenario, this document provides a detailed analysis of the potential information barriers that could hamper the successful development of the different research tasks in both fields (biomedicine and nanomedicine), emphasizing the existing challenges for nanomedical research —where the major barriers have been found. The author illustrates how the application of BMI methodologies to these scenarios can be proven successful in the biomedical domain, whilst these methodologies present severe limitations when applied to the nanomedical context. To address such limitations, the author proposes an original nanoinformatics approach specifically designed to deal with the special characteristics of information at the nano level. This approach consists of an in-depth analysis of the scientific literature and available clinical trial registries to extract relevant information about experiments and results in nanomedicine —textual patterns, common vocabulary, experiment descriptors, characterization parameters, etc.—, followed by the development of mechanisms to automatically structure and analyze this information. This analysis resulted in the generation of a gold standard —a manually annotated training or reference set—, which was applied to the automatic classification of clinical trial summaries, distinguishing studies focused on nanodrugs and nanodevices from those aimed at testing traditional pharmaceuticals. The present work aims to provide the necessary methods for organizing, curating and validating existing nanomedical data on a scale suitable for decision-making. Similar analysis for different nanomedical research tasks would help to detect which nanoinformatics resources are required to meet current goals in the field, as well as to generate densely populated and machine-interpretable reference datasets from the literature and other unstructured sources for further testing novel algorithms and inferring new valuable information for nanomedicine.

Determination of selected pharmaceutical compounds in biosolids bysupported liquid extraction and gas chromatography?tandem massspectrometry

In this work, an analytical method was developed for the determination of pharmaceutical drugs inbiosolids. Samples were extracted with an acidic mixture of water and acetone (1:2, v/v) and supportedliquid extraction was used for the clean-up of extracts, eluting with ethyl acetate:methanol (90:10, v/v).The compounds were determined by gas chromatography?tandem mass spectrometry using matrix-match calibration after silylation to form their t-butyldimethylsilyl derivatives. This method presentsvarious advantages, such as a fairly simple operation for the analysis of complex matrices, the use ofinexpensive glassware and low solvent volumes. Satisfactory mean recoveries were obtained with thedeveloped method ranging from 70 to 120% with relative standard deviations (RSDs) ? 13%, and limitsof detection between 0.5 and 3.6 ng g?1. The method was then successfully applied to biosolids samplescollected in Madrid and Catalonia (Spain). Eleven of the sixteen target compounds were detected in thestudied samples, at levels up to 1.1 ?g g?1(salicylic acid). Ibuprofen, caffeine, paracetamol and fenofibratewere detected in all of the samples analyzed.

IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis

The origin and role of IL-17, a T-cell derived cytokine, in cartilage and bone destruction during rheumatoid arthritis (RA) remain to be clarified. In human ex vivo models, addition of IL-17 enhanced IL-6 production and collagen destruction, and inhibited collagen synthesis by RA synovium explants. On mouse cartilage, IL-17 enhanced cartilage proteoglycan loss and inhibited its synthesis. On human RA bone explants, IL-17 also increased bone resorption and decreased formation. Addition of IL-1 in these conditions increased the effect of IL-17. Blocking of bone-derived endogenous IL-17 with specific inhibitors resulted in a protective inhibition of bone destruction. Conversely, intra-articular administration of IL-17 into a normal mouse joint induced cartilage degradation. In conclusion, the contribution of IL-17 derived from synovium and bone marrow T cells to joint destruction suggests the control of IL-17 for the treatment of RA.

Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release

Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcer-associated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.

Improved retroviral gene transfer into murine and Rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granulocyte colony-stimulating factor.

In previous studies we showed that 5 days of treatment with granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) mobilized murine repopulating cells to the peripheral blood (PB) and that these cells could be efficiently transduced with retroviral vectors. We also found that, 7-14 days after cytokine treatment, the repopulating ability of murine bone marrow (BM) increased 10-fold. In this study we examined the efficiency of gene transfer into cytokine-primed murine BM cells and extended our observations to a nonhuman primate autologous transplantation model. G-CSF/SCF-primed murine BM cells collected 7-14 days after cytokine treatment were equivalent to post-5-fluorouracil BM or G-CSF/SCF-mobilized PB cells as targets for retroviral gene transfer. In nonhuman primates, CD34-enriched PB cells collected after 5 days of G-CSF/SCF treatment and CD34-enriched BM cells collected 14 days later were superior targets for retroviral gene transfer. When a clinically approved supernatant infection protocol with low-titer vector preparations was used, monkeys had up to 5% of circulating cells containing the vector for up to a year after transplantation. This relatively high level of gene transfer was confirmed by Southern blot analysis. Engraftment after transplantation using primed BM cells was more rapid than that using steady-state bone marrow, and the fraction of BM cells saving the most primitive CD34+/CD38- or CD34+/CD38dim phenotype increased 3-fold. We conclude that cytokine priming with G-CSF/SCF may allow collection of increased numbers of primitive cells from both the PB and BM that have improved susceptibility to retroviral transduction, with many potential applications in hematopoietic stem cell-directed gene therapy.

Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

von Willebrand factor (vWF) is essential for the induction of occlusive thrombosis in stenosed and injured pig arteries and for normal hemostasis. To separate the relative contribution of plasma and platelet vWF to arterial thrombosis, we produced chimeric normal and von Willebrand disease pigs by crossed bone marrow transplantation; von Willebrand disease (vWD) pigs were engrafted with normal pig bone marrow and normal pigs were engrafted with vWD bone marrow. Thrombosis developed in the chimeric normal pigs that showed normal levels of plasma vWF and an absence of platelet vWF; but no thrombosis occurred in the chimeric vWD pigs that demonstrated normal platelet vWF and an absence of plasma vWF. The ear bleeding times of the chimeric pigs were partially corrected by endogenous plasma vWF but not by platelet vWF. Our animal model demonstrated that vWF in the plasma compartment is essential for the development of arterial thrombosis and that it also contributes to the maintenance of bleeding time and hemostasis.

Efeitos do ramipril sobre a doença periodontal induzida experimentalmente em ratos

A doença periodontal (DP) corresponde a um grupo de doenças inflamatórias que acomete as estruturas periodontais de proteção e de suporte e pode levar à perda dentária. A etiologia está relacionada à placa dentobacteriana que leva à produção de grande quantidade de citocinas pró-inflamatórias importantes na destruição tecidual. A angiotensina (Ang) II também pode contribuir para a inflamação e destruição tecidual no periodonto agindo como mediador chave. A utilização de drogas que atuem na cascata do sistema renina-angiotensina (SRA) poderia interferir no estado de saúde ou inflamação do tecido mole, na perda óssea alveolar e na expressão gênica dos componentes do SRA e mediadores inflamatórios. Portanto, o objetivo do presente trabalho foi investigar se o ramipril, um inibidor da enzima conversora de angiotensina (ECA), altera a progressão da DP induzida experimentalmente em ratos. Foi utilizado o modelo de indução da DP por colocação de ligadura ao redor do primeiro molar inferior direito de ratos. Os grupos com 10 animais cada, foram divididos em tratados com ramipril (via gavagem 10 mg/kg/dia) ou água (veículo) durante 14 e 21 dias e o grupo Sham submetido à indução fictícia da DP. Outros quatro grupos foram submetidos ao pré-tratamento com ramipril durante os períodos de 7 e 14 dias e após a indução da DP e tratados por 14 ou 21 dias. As metodologias de avaliação foram: extração de RNA total, transcrição reversa seguida de reação em cadeia da polimerase quantitativa (RTqPCR), análises histológica e da perda óssea alveolar. Os dados foram analisados por meio de gráficos e os resultados foram submetidos à análise unidirecional de variância (ANOVA) e representaram médias e respectivos desvios-padrão. Diferenças entre os grupos foram consideradas estatisticamente significativas quando p < 0,05. Com base nos resultados obtidos pode-se concluir que o ramipril foi capaz de reduzir a progressão da perda óssea no grupo tratado por 21 dias (DP-21d-Rami), entretanto houve aumento do processo inflamatório, além de alteração da expressão de RNAm de ECA-2 e do receptor Mas, alguns mediadores do processo inflamatório, como COX2 e VEGF, e os receptores VEGF-R1 e VEGF-R2.

Postcolonial healing landscapes and mental health in a remote Indigenous community in subarctic Ontario, Canada

The concept of therapeutic landscape is concerned with a holistic, socio-ecological model of health, but most studies have attempted to explore land-health links from a Western perspective. On an Indigenous reserve in Northern Ontario, part of the Canadian subarctic, we explore the importance of spaces and places in creating postcolonial therapeutic landscapes to treat the wounds inflicted by colonialism. The aim of this research is to gain insight from views and experiences of First Nations residents living on reservations that are undergoing a process of regaining traditional spiritual beliefs and teachings to construct therapeutic spaces to face mental health problems caused by legal opioid analgesic abuse. This qualitative study used semi-structured interviews with Cree and Ojibwe participants to understand how they are reconnecting with earth, spirituality and traditional animist beliefs on their way to recovery. We find that practices such as taking part in ceremonies and ritual spaces, and seeking knowledge and advice from Elders assist with personal healing and enable Indigenous people to be physically and mentally healthy. Our research findings provide important insights into the relationship between space, healing and culture as determinants of health and well-being and document some key factors that contribute to substance abuse recovery.

Body composition and bone mineral density in male adults with hyperthyroidism. Which association?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Vitamin D in patients with atherosclerosis : a link between atherosclerosis and bone mass ?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Influence of clinicians’ experience and gender on extraction decision in orthodontics

Thesis (Master's)--University of Washington, 2016-06