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J Craniomaxillofac Surg ; 45(12): 1962-1970, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29066041


The benefit of computer-assisted planning in orthognathic surgery has been extensively documented over the last decade. This study aims to evaluate the accuracy of a virtual orthognathic surgical plan by a novel three dimensional (3D) analysis method. Ten patients who required orthognathic surgery were included in this study. A virtual surgical plan was achieved by the combination of a 3D skull model acquired from computed tomography (CT) and surface scanning of the upper and lower dental arch respectively and final occlusal position. Osteotomies and movement of maxilla and mandible were simulated by Dolphin Imaging 11.8 Premium® (Dolphin Imaging and Management Solutions, Chatsworth, CA). The surgical plan was transferred to surgical splints fabricated by means of Computer Aided Design/Computer Aided Manufacturing (CAD/CAM). Differences of three dimensional measurements between the virtual surgical plan and postoperative results were evaluated. The results from all parameters showed that the virtual surgical plans were successfully transferred by the assistance of CAD/CAM fabricated surgical splint. Wilcoxon's signed rank test showed that no statistically significant deviation between surgical plan and post-operational result could be detected. However, deviation of angle U1 axis-HP and distance of A-CP could not fulfill the clinical success criteria. Virtual surgical planning and CAD/CAM fabricated surgical splint are proven to facilitate treatment planning and offer an accurate surgical result in orthognathic surgery.

Algoritmos , Projeto Auxiliado por Computador , Imagem Tridimensional , Procedimentos Cirúrgicos Ortognáticos/métodos , Planejamento de Assistência ao Paciente , Cirurgia Assistida por Computador , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
Aging Cell ; 13(6): 1038-48, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25273919


Methionine restriction (MetR) extends lifespan in animal models including rodents. Using human diploid fibroblasts (HDF), we report here that MetR significantly extends their replicative lifespan, thereby postponing cellular senescence. MetR significantly decreased activity of mitochondrial complex IV and diminished the accumulation of reactive oxygen species. Lifespan extension was accompanied by a significant decrease in the levels of subunits of mitochondrial complex IV, but also complex I, which was due to a decreased translation rate of several mtDNA-encoded subunits. Together, these findings indicate that MetR slows down aging in human cells by modulating mitochondrial protein synthesis and respiratory chain assembly.

Fibroblastos/citologia , Fibroblastos/metabolismo , Metionina/deficiência , Fatores Etários , Animais , Diploide , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Humanos , Metionina/administração & dosagem , Metionina/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia
Eur J Heart Fail ; 15(8): 910-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23666681


AIMS: NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed. METHODS AND RESULTS: A total of 495 chronic HF patients, aged ≥60, with an LVEF ≤45%, NYHA class ≥II, randomized to NT-proBNP-guided or symptom-guided therapy and ≥1 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs/patient-year 4.7 (2.8-9.4) vs. 5.4 (2.7-11.4), P = 0.69; number of severe AEs/patient-year 0.7 (0-2.7) vs. 1.3 (0-3.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects-although small and related to non-severe AEs only-were only seen in the older and more co-morbid patients. CONCLUSIONS: NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients. Trial registration ISRCTN43596477.

Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Espironolactona/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Diuréticos/uso terapêutico , Relação Dose-Resposta a Droga , Tratamento Farmacológico/métodos , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Resultado do Tratamento
BMC Genomics ; 14: 224, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23557329


BACKGROUND: Cellular senescence can be induced by a variety of extrinsic stimuli, and sustained exposure to sunlight is a key factor in photoaging of the skin. Accordingly, irradiation of skin fibroblasts by UVB light triggers cellular senescence, which is thought to contribute to extrinsic skin aging, although molecular mechanisms are incompletely understood. Here, we addressed molecular mechanisms underlying UVB induced senescence of human diploid fibroblasts. RESULTS: We observed a parallel activation of the p53/p21(WAF1) and p16(INK4a)/pRb pathways. Using genome-wide transcriptome analysis, we identified a transcriptional signature of UVB-induced senescence that was conserved in three independent strains of human diploid fibroblasts (HDF) from skin. In parallel, a comprehensive screen for microRNAs regulated during UVB-induced senescence was performed which identified five microRNAs that are significantly regulated during the process. Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. Already known targets of these miRNAs were identified in each case, validating the approach. Several new targets were identified for all of these miRNAs, with the potential to provide new insight in the process of UVB-induced senescence at a genome-wide level. Subsequent analysis was focused on miR-101 and its putative target gene Ezh2. We confirmed that Ezh2 is regulated by miR-101 in human fibroblasts, and found that both overexpression of miR-101 and downregulation of Ezh2 independently induce senescence in the absence of UVB irradiation. However, the downregulation of miR-101 was not sufficient to block the phenotype of UVB-induced senescence, suggesting that other UVB-induced processes induce the senescence response in a pathway redundant with upregulation of miR-101. CONCLUSION: We performed a comprehensive screen for UVB-regulated microRNAs in human diploid fibroblasts, and identified a network of miRNA-mRNA interactions mediating UVB-induced senescence. In addition, miR-101 and Ezh2 were identified as key players in UVB-induced senescence of HDF.

Senescência Celular/genética , Fibroblastos/metabolismo , MicroRNAs/fisiologia , Complexo Repressor Polycomb 2/genética , RNA Mensageiro/genética , Linhagem Celular Tumoral , Senescência Celular/efeitos da radiação , Diploide , Proteína Potenciadora do Homólogo 2 de Zeste , Fibroblastos/efeitos da radiação , Redes Reguladoras de Genes/efeitos da radiação , Humanos , Complexo Repressor Polycomb 2/metabolismo , Interferência de RNA/efeitos da radiação , Transcriptoma/efeitos da radiação , Raios Ultravioleta
Aging (Albany NY) ; 4(10): 664-73, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23117410


Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescencein vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease.

Senescência Celular , Cistationina beta-Sintase/metabolismo , Células Endoteliais/enzimologia , Envelhecimento/metabolismo , Cistationina beta-Sintase/genética , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos
Exp Gerontol ; 45(7-8): 638-44, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20211237


Mitotic cells in culture show a limited replicative potential and after extended subculturing undergo a terminal growth arrest termed cellular senescence. When cells reach the senescent phenotype, this is accompanied by a significant change in the cellular phenotype and massive changes in gene expression, including the upregulation of secreted factors. In human fibroblasts, senescent cells also acquire resistance to apoptosis. In contrary, in human endothelial cells, both replicative and stress-induced premature senescence is accompanied by increased cell death; however mechanisms of cell death are poorly explored. In this communication, we addressed the role of endonuclease G (EndoG), a mitochondrial mediator of caspase-independent cell death, in senescence-associated cell death of human endothelial cells. Using immunofluorescence microscopy, we found, that EndoG is localized in the mitochondria in young cells, but relocalizes to the nucleus upon senescence. When EndoG gene expression was downregulated by lentiviral shRNA vectors, we found a significant reduction in the replicative life span and a corresponding increase in cell death. We also observed a slight shift in the cell death phenotype from necrosis to apoptosis. Together these observations suggest an important role of EndoG in the senescence program of human endothelial cells.

Apoptose/genética , Apoptose/fisiologia , Senescência Celular/genética , Senescência Celular/fisiologia , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Células Endoteliais/citologia , Células Endoteliais/enzimologia , Transporte Ativo do Núcleo Celular , Envelhecimento/genética , Envelhecimento/metabolismo , Células Cultivadas , Endodesoxirribonucleases/antagonistas & inibidores , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Lentivirus/genética , Potencial da Membrana Mitocondrial , Necrose/enzimologia , Necrose/genética , Necrose/patologia , RNA Interferente Pequeno/genética