Fraturas de tornozelo: mecanismo e anatomia.

Trabalho de Conclusão de Curso - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Departamento de Clínica Médica, Curso de Medicina, Florianópolis, 198

Novel Functions of Adrenomedullin, Receptor Activity-Modifying Protein 2, and Gpr182 in Cardiovascular Disease and Cancer

The multifunctional circulating peptide, adrenomedullin (AM) signaling through its G protein-coupled receptor (GPCR) complex, comprised of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (Ramp2), is required for lymphatic development and embryonic survival, as well as numerous functions in adult cardiovascular physiology. However these functions, especially during adulthood, have not been fully elucidated. Using both gain- and loss-of-function mouse models these studies aimed to further elucidate the roles of AM signaling during cardiovascular homeostasis and tumor progression. Endothelial restoration of Ramp2 is sufficient to rescue the embryonic lethality-associated with global loss of Ramp2. However, the developmental loss of Ramp2 in non-endothelial cells led to spontaneous hypotension, dilated cardiomyopathy, and multi-organ inflammation in adult survivors. Smooth muscle cell- or global-deletion of CLR did not recapitulate these phenotypes, indicating that Ramp2 is likely interacting with other GPCRs, including parathyroid hormone and glucagon receptors, to maintain cardiovascular homeostasis. While AM signaling is essential for lymphatic development and maintenance, it is unclear how AM influences tumor lymphatics. Tumor cells engineered to overexpress or knockdown AM did not alter tumor growth or angiogenesis. High tumor-derived AM caused tumor and lymph node lymphangiogenesis and increased metastasis. While AM is typically considered protective, these data suggest that AM signaling could enhance tumor progression. While CLR/Ramp2 is the canonical AM receptor, it was previously thought that the AM receptor was the orphan GPCR, Gpr182, of which almost nothing is known. Using a knock-in reporter mouse model to map Gpr182 expression in vivo, Gpr182 was enriched in the active stem cells in the small intestine. Gpr182 was dispensable during development and homeostasis, but when challenged with irradiation injury or adenoma model, reduced Gpr182 led to intestinal hyperproliferation during regeneration and enhanced adenoma formation, respectively. Together, these studies demonstrated the importance of endothelial AM signaling during development, the complexity of GPCR/RAMP interactions in vivo, the underappreciated functions of AM signaling in tumor lymphatic metastasis, and the role of Gpr182 as a negative regulator of intestinal proliferation; all of which could represent pharmacological-tractable targets to treat a number of cardiovascular and neoplastic diseases.Doctor of Philosoph

Ba2AlSi5N9

Ba2AlSi5N9 was synthesized starting from Si3N4, AlN, and Ba in a radio-frequency furnace at temperatures of about 1725°C. The new nitridoalumosilicate crystallizes in the triclinic space group P1 (no. 1), a=9.860(1) Å, b=10.320(1) Å, c=10.346(1) Å, α=90.37(2)°, β=118.43(2)°; γ=103.69(2)°, Z=4, R1=0.0314. All synthesized crystals were characteristically twinned by reticular pseudomerohedry with twin law (1 0 0, −0.5 −1 0, −1 0 −1). The crystal structure of Ba2AlSi5N9 was determined from single-crystal X-ray diffraction data of a twinned crystal and confirmed by Rietveld refinement both on X-ray and on neutron powder diffraction data. Statistical distribution Si/Al is corroborated by lattice energy calculations (MAPLE). 29Si and 27Al solid-state NMR are in accordance with the crystallographic results. Ba2AlSi5N9 represents a new type of network structure made up of TN4 tetrahedra (T = Si, Al). Highly condensed layers of dreier rings with nitrogen connecting three neighboring tetrahedral centers occur which are further crosslinked by dreier rings and vierer rings. The dreier rings consist of corner-sharing tetrahedra, whereas some of the vierer rings exhibit two pairs of edge-sharing tetrahedra. In the resulting voids of the network there are eight different Ba2+ sites with coordination numbers between 6 and 10. Thermogravimetric investigations confirmed a thermal stability of Ba2AlSi5N9 up to about 1515°C (He atmosphere). Luminescence measurements on Ba2AlSi5N9:Eu2+ (2 mol % Eu2+) with an excitation wavelength of 450 nm revealed a broadband emission peaking at 584 nm (FWHM=100 nm) originating from dipole-allowed 4f6(7F)5d1 → 4f7(8S7/2) transitions

Análise funcional da coaptação do nervo mediano: estudo em ratos wistar

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-graduação em Ciências MédicasIntrodução: As lesões de nervos periféricos constituem um grande desafio para uma quantidade significativa de pacientes e médicos. Não foi encontrada ainda a forma perfeita de reparo destas lesões. O padrão preconizado de tratamento, a sutura término- terminal nem sempre é possível de ser realizada. Necessita-se deste modo de algum material interpondo os cotos seccionados, necessitando-se sacrificar nervos doadores. Assim, a entubulização de nervos surgiu como provável alternativa para o uso de enxertos nervosos. Objetivo: Avaliar a força de preensão máxima do membro torácico do rato Wistar utilizando-se a reconstrução do nervo mediano via sutura monofilamentar de nylon 10-0 e a entubulização de nervos mantendo-se a distância entre os cotos em 5 e 10 milímetros. Métodos: 60 ratos Wistar machos, foram divididos em 4 grupos, escolhidos aleatoriamente, grupo sham, 15 animais, nervo mediano normal, grupo T5, 15 animais, entubulização do nervo mediano com distância entre os cotos de 5 milímetros,grupo T10 ,15 animais, entubulização do nervo mediano com distância entre os cotos de 10 milímetros, e grupo S, 15 animais com sutura dos cotos com fio de nylon monofilamentar 10-0. Resultados: Grupo sham- O grau de preensão máxima deste grupo foi estatísticamente superior aos demais.Grupo T5 - Os animais deste grupo apresentaram recuperação funcional muito inferior ao grupo sham. Grupo T10 - Somente 2 dos 15 animais obtiveram alguma força de preensão mensurável após o período de recuperação esperado. Grupo S- Todos os animais recuperaram a força de preensão ,mas a níveis inferiores ao grupo sham. Conclusões: De acordo com esta pesquisa, a entubulização de nervos não é uma alternativa viável à sutura término-terminal na recuperação funcional de nervos medianos em ratos Wistar. Unitermos : Nervo mediano, regeneração nervosa, entubulização, teste funcional, rato wistar

O Reparo de tela de polipropileno: alternativa para correção de perdas nervosas segmentares

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em Ciências Médicas.Introdução: As lesões de nervos periféricos envolvem uma série de eventos complexos referentes ao tecido lesado, incluindo comprometimento da sinalização axonal, alteração funcional no corpo celular neuronal, ativação de células da glia, e inflamação sistêmica. O que se deseja é a total regeneração de nervos periféricos e completa recuperação da função motora e proprioceptiva. Objetivos: 1) Avaliar em ratos Wistar regeneração do nervo mediano submetido a diferentes procedimentos de reconstrução (sutura epiperineural término-terminal (SS), sutura epiperineural imediata sob tensão aliviada (STA) e sutura epiperineural imediata sob tensão (SST), por meio de testes funcionais e dosagem de fatores de crescimento neural. 2) Avaliar os resultados do reparo do nervo mediano em seres humanos com enxertia nervosa e comparar ao reparo que utiliza o suporte com tela externa aplicada aos cotos nervosos, utilizando-se o método de sutura nervosa sob tensão aliviada (STA). Métodos e Resultados: 1) Estudo experimental: Quatro grupos experimentais (10 animais/grupo) foram avaliados, baseados no modelo de regeneração nervosa do nervo mediano do rato Wistar (SS, SST e STA). A análise da função do nervo mediano foi aferida pelo retorno da mobilidade das articulações interfalangeanas e metacarpofalangeanas diariamente. O Grasping Test foi avaliado de 30 a 180 dias após o procedimento cirúrgico. A recuperação da atrofia do grupamento muscular flexo-pronador do membro torácico do rato Wistar foi aferido 180 dias após. A expressão do RNAm para as neurotrofinas NT-3 e NGF, foram avaliadas pela técnica PCR-RT após 180 dias. Nos grupos SS e STA a média e o erro padrão da média (e.p.m.) do dia de retorno da função de flexão dos dedos do membro torácico foi de 13,8 ± 0,38 e 13,7 ± 0,30, respectivamente. Para o grupo SST não se observou nenhum sinal de regeneração. A regeneração do nervo mediano observada indiretamente pelo Grasping Test ocorreu ao longo do período de 180 dias de observação nos grupos SS e STA, sem a menor evidência de regeneração no grupo SST. Neste protocolo experimental observou-se recuperação significativa da atrofia muscular da musculatura flexo-pronadora nos grupos SS e STA quando comparados ao grupo controle (P < 0,01). Os resultados demonstraram que houve nos grupos SS e STA, houve aumento significativo da expressão do RNAm para NGF e NT-3 no período de 180 dias pós cirurgia (P < 0,01). Não houve recuperação da expressão de neurotrofinas no grupo experimental SST. 2) Estudo clínico: Neste estudo foi comparado um grupo de pacientes (n = 4) utilizando a técnica da STA com a tela de polipropileno e um grupo de pacientes submetido à enxertia nervosa (n = 6). O nervo mediano foi objeto destas reconstruções, e a evolução da regeneração foi acompanhada pelo retorno do tato epicrítico e a funcionalidade do músculo abductor curto do polegar. Os resultados obtidos no estudo clínico demonstraram a superioridade do retorno da sensibilidade bem como da força de apreensão do abductor curto do polegar nos pacientes submetidos à reconstrução cirúrgica com a técnica da sutura sob tensão aliviada após 12 meses de acompanhamento pós-cirúrgico. Conclusão: os resultados apresentados demonstraram tanto em nível experimental como em pacientes que as vantagens obtidas com a reconstrução nervosa utilizando-se o método de sutura sob tensão aliviada por meio de um suporte externo,comparando-se funções motoras e sensitivas, em perdas nervosas segmentares é comparável à sutura direta imediata, evitando-se a utilização de enxertia nervosa e as comorbidades inerentes a área doadora de nervos

Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models

Adrenomedullin is a highly conserved peptide implicated in a variety of physiological processes ranging from pregnancy and embryonic development to tumor progression. This review highlights past and present studies that have contributed to our current appreciation of the important roles adrenomedullin plays in both normal and disease conditions. We provide a particular emphasis on the functions of adrenomedullin in vascular endothelial cells and how experimental approaches in genetic mouse models have helped to drive the field forward

Endothelial Restoration of Receptor Activity-Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy.

RAMPs (receptor activity-modifying proteins) serve as oligomeric modulators for numerous G-protein-coupled receptors, yet elucidating the physiological relevance of these interactions remains complex. Ramp2 null mice are embryonic lethal, with cardiovascular developmental defects similar to those observed in mice null for canonical adrenomedullin/calcitonin receptor-like receptor signaling. We aimed to genetically rescue the Ramp2(-/-) lethality in order to further delineate the spatiotemporal requirements for RAMP2 function during development and thereby enable the elucidation of an expanded repertoire of RAMP2 functions with family B G-protein-coupled receptors in adult homeostasis. Endothelial-specific expression of Ramp2 under the VE-cadherin promoter resulted in the partial rescue of Ramp2(-/-) mice, demonstrating that endothelial expression of Ramp2 is necessary and sufficient for survival. The surviving Ramp2(-/-) Tg animals lived to adulthood and developed spontaneous hypotension and dilated cardiomyopathy, which was not observed in adult mice lacking calcitonin receptor-like receptor. Yet, the hearts of Ramp2(-/-) Tg animals displayed dysregulation of family B G-protein-coupled receptors, including parathyroid hormone and glucagon receptors, as well as their downstream signaling pathways. These data suggest a functional requirement for RAMP2 in the modulation of additional G-protein-coupled receptor pathways in vivo, which is critical for sustained cardiovascular homeostasis. The cardiovascular importance of RAMP2 extends beyond the endothelium and canonical adrenomedullin/calcitonin receptor-like receptor signaling, in which future studies could elucidate novel and pharmacologically tractable pathways for treating cardiovascular diseases

Comparative toxicity of selenium from seleno-DL-methionine, sodium selenate, and Astragalus bisulcatus in pigs

Selenium is an essential micronutrient, although ingestion in excess in pigs can cause disease conditions including neurological dysfunction and chronic skin and hoof lesions. Controlled feeding trials in growing swine, using the same Se content in feed sources, resulted in higher concentrations (p 0.05) of Se in blood and organs of pigs fed seleno-DL-methionine compared with those receiving Astragalus bisulcatus or sodium selenate. Clinical signs of Se toxicity including neurological signs of paralysis were more severe and occurred sooner in the A. bisulcatus group than in the sodium selenate or seleno-DL-methionine groups. All five pigs fed A. bisulcatus developed neurological signs of paralysis, and in four the signs occurred within 5 days of the start of treatment. Four of five pigs fed sodium selenate also developed paralysis, but this occurred 4 to 21 days after treatment began. The fifth pig in the group developed signs of chronic selenosis. Two of five pigs fed seleno-DL-methionine developed paralysis on 9 and 24 days, respectively, and the remaining three developed chronic selenosis. Selenium fed to pigs in three forms [plant (A. bisulcatus), sodium selenate, or seleno-DL-methionine] resulted in neurological dysfunction and lesions of symmetrical poliomyelomalacia. These were most severe in the A. bisulcatus group, which also had polioencephalomalacia. Although seleno-m-methionine caused the greater increase in tissue and blood Se concentrations, this did not correlate with severity of pathological changes, since animals fed A. bisulcatus developed more severe and disseminated lesions

Ba3Ga3N5 - A Novel Host Lattice for Eu2+ - Doped Luminescent Materials with Unexpected Nitridogallate Substructure

The alkaline earth nitridogallate Ba3Ga3N5 was synthesized from the elements in a sodium flux at 760°C utilizing weld shut tantalum ampules. The crystal structure was solved and refined on the basis of single-crystal X-ray diffraction data. Ba3Ga3N5 (space group C2/c (No. 15), a = 16.801(3), b = 8.3301(2), c = 11.623(2) Å, β = 109.92 (3)°, Z = 8) contains a hitherto unknown structural motif in nitridogallates, namely, infinite strands made up of GaN4 tetrahedra, each sharing two edges and at least one corner with neighboring GaN4 units. There are three Ba2+ sites with coordination numbers six or eight, respectively, and one Ba2+ position exhibiting a low coordination number 4 corresponding to a distorted tetrahedron. Eu2+ - doped samples show red luminescence when excited by UV irradiation at room temperature. Luminescence investigations revealed a maximum emission intensity at 638 nm (FWHM =2123 cm−1). Ba3Ga3N5 is the first nitridogallate for which parity allowed broadband emission due to Eu2+ - doping has been found. The electronic structure of both Ba3Ga3N5 as well as isoelectronic but not isostructural Sr3Ga3N5 was investigated by DFT methods. The calculations revealed a band gap of 1.53 eV for Sr3Ga3N5 and 1.46 eV for Ba3Ga3N5