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1.
Arch Orthop Trauma Surg ; 142(5): 763-768, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33389020

RESUMO

INTRODUCTION: Cementless femoral revision total hip arthroplasty (RTHA) after periprosthetic fracture, aseptic loosening or infection is a challenging surgical procedure. The aim of this study was to evaluate the incidence and reasons for failure after two-stage septic revision, periprosthetic fracture or aseptic loosening that may reveal a rationale for cementless RTHA in two-stage revisions. MATERIALS AND METHODS: A consecutive series of 105 cases using cementless femoral revision prostheses were evaluated retrospectively. Indications for revision were 39 two-stage revisions after infection, 49 aseptic loosenings, and 17 periprosthetic fractures. A Kaplan-Meier analysis was performed using infection with or without removal of the implant as an endpoint. RESULTS: Incidence of infection with or without implant removal was significantly higher in patients treated for periprosthetic fractures compared to two-stage revisions or aseptic loosening (log-rank P < 0.0001). The mean follow-up period was 6.4 (2.0-13.7) years. Using infection with or without implant removal as the endpoint, 12 patients were diagnosed after the index operation resulting in a cumulative risk after 13.7 years of 29.9% (95% CI 0-61.2). CONCLUSION: Cementless revision using a modular tapered device is reliable with respect to reinfection risk in two-stage procedures.


Assuntos
Artroplastia de Quadril , Prótese de Quadril , Fraturas Periprotéticas , Artroplastia de Quadril/métodos , Seguimentos , Prótese de Quadril/efeitos adversos , Humanos , Fraturas Periprotéticas/epidemiologia , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/cirurgia , Desenho de Prótese , Falha de Prótese , Reoperação/efeitos adversos , Estudos Retrospectivos , Fatores de Risco
2.
Nat Commun ; 11(1): 3653, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694534

RESUMO

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.


Assuntos
Mitocôndrias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/patologia , Neovascularização Fisiológica , Cicatrização/fisiologia , Trifosfato de Adenosina/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Linhagem Celular Tumoral/transplante , Respiração Celular , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/fisiologia , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Neoplasias/irrigação sanguínea , Fosforilação Oxidativa
3.
J Orthop ; 22: 33-37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280166

RESUMO

INTRODUCTION: Demographic change and demand for high quality of life lead to increasing implantation numbers. Aim of this study was to compare the Plasmafit® cup to Allofit® and Plasmacup®. METHODS: The study included 174 patients who had received 33 Plasmacup®, 68 Allofit® and 73 Plasmafit® cup implants. These were reviewed postoperatively, after 6 months control and after 12 months. RESULTS: No significant progressive migration could be discovered in any of the cup systems. At each follow-up the cups showed nearly constant values. CONCLUSIONS: All examined acetabular cups showed excellent migration behavior within the first 12 postoperative months.

4.
J Orthop ; 19: 229-232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32071519

RESUMO

BACKGROUND: Snowboarding is a very common sport especially among young adults. Common injuries are hand, wrist, shoulder and ankle injuries. PURPOSE: of this study was to analyze different injury pattern in children and young adults comparing with adults. METHODS: Patients who were admitted for ambulant or stationary treatment as a result of injury practicing snowboard received a questionnaire and were divided into three groups (children, young adults and adults) according to their age. Between october 2002 and may 2007 1929 injured snowboard sportsmen were included in the study. Data such as location, date and time of accident as well as information about the slope were carried out. In addition snowboard skills were classified and patients were questioned whether they wore special protectors. RESULTS: 32.5% of injured patients were female (n = 626) and 67.5% male (n = 1303) with a mean age of patients of 21.9 (7-66) years. 13% of all patients were in group I (children), 19.2% in group II (young adults) and 67.8% in group III (adults).Most common injuries with 60% of all accidents were injuries of the hand wrist especially in children beginning with snowboard sports. Injuries on the regular track were most common followed by jumps in the kicker park and rails in the fun-park. 20.6% in group I, 13.6% in group II and 12.8% group III did not wear any protectors. CONCLUSION: Children and adolescents presented different injury patterns than adults. Young participants of up to 14 years of age are endangered especially during the first days of learning this sport. Further development of protectors with regard to biomechanical characteristics is important to achieve an optimal protective effect. LEVEL OF EVIDENCE: 2b.

5.
Curr Oncol ; 26(2): e180-e187, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31043825

RESUMO

Background: Variations in treatment choice, or late stage at first diagnosis, mean that, despite guideline recommendations, not all patients with hormone receptor (hr)-positive locally advanced or metastatic breast cancer (la/mbca) will have received endocrine therapy before disease progression. In the present study, we aimed to estimate the proportion of women with postmenopausal hr-positive la/mbca in the United States who are endocrine therapy-naïve. Methods: Women in the Optum Electronic Health Record (ehr) database with a breast cancer (bca) diagnosis (January 2008-March 2015) were included. Patient and malignancy characteristics were identified using structured data fields and natural-language processing of free-text clinical notes. The proportion of women with postmenopausal hr-positive, human epidermal growth factor 2 (her2)-negative (or unknown) la/mbca who had not received prior endocrine therapy was determined. Results were extrapolated to the entire U.S. population using the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results database. Results are presented descriptively. Results: In the ehr database, 11,831 women with bca had discernible information on postmenopausal status, hr status, and disease stage. Of those women, 1923 (16.3%) had postmenopausal hr-positive, her2-negative (or unknown) la/mbca, and 70.7% of those 1923 patients (n = 1360) had not received prior endocrine therapy, accounting for 11.5% of the overall population. Extrapolating those estimates nationally suggests an annual incidence of 14,784 cases, and a 5-year limited duration prevalence of 50,638 cases. Conclusions: A substantial proportion of women with postmenopausal hr-positive la/mbca in the United States could be endocrine therapy-naïve.


Assuntos
Neoplasias da Mama/epidemiologia , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Prevalência , Receptores de Esteroides , Estados Unidos/epidemiologia
6.
Arch Orthop Trauma Surg ; 139(6): 843-849, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887123

RESUMO

INTRODUCTION: High loosening rates after distal femoral replacement may be due to implant design not adapted to specific anatomic and biomechanical conditions. MATERIALS AND METHODS: A modular tumor system (MUTARS®, Implantcast GmbH) was implanted with either a curved hexagonal or a straight tapered stems in eight Sawbones® in two consecutively generated bone defect (10 cm and 20 cm proximal to knee joint level). Implant-bone-interface micromotions were measured to analyze main fixation areas and to characterize the fixation pattern. RESULTS: Although areas of highest relative micromotions were measured distally in all groups, areas and lengths of main fixation differed with respect to stem design and bone defect size. Regardless of these changes, overall micromotions could only be reduced with extending bone defects in case of tapered stems. CONCLUSIONS: The tapered design may be favorable in larger defects whereas the hexagonal may be advantageous in defects located more distally.


Assuntos
Interface Osso-Implante/fisiologia , Fêmur , Procedimentos Ortopédicos/instrumentação , Procedimentos de Cirurgia Plástica/instrumentação , Fêmur/fisiologia , Fêmur/cirurgia , Humanos , Desenho de Prótese
7.
Neth Heart J ; 26(12): 620-627, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30443709

RESUMO

OBJECTIVE: Permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI) is the most common complication after the procedure. PPMI rates remain high with the new-generation TAVI devices despite improved outcomes concerning paravalvular aortic regurgitation and vascular access complications. However, the impact of PPMI on mortality and clinical outcome is still a matter of debate, and data with new-generation devices on this matter are scarce. Therefore, we sought to analyse the influence of PPMI in patients treated with the new-generation devices on one-year outcome. METHODS: We enrolled 612 consecutive patients without prior pacemaker undergoing transfemoral TAVI with the new-generation devices. Patients with or without PPMI were compared with respect to clinical outcome within one year. RESULTS: PPMI was performed in 168 patients (24.4% of the overall study population). There was no significant difference in one-year outcome concerning all-cause mortality (PPMI vs. no-PPMI: 12.2% vs. 12.5%, p = 0.94), rate of major adverse events including cardiac, cerebral or valve-related events and bleeding complications (22.1% vs. 24.5%, p = 0.55) or need for rehospitalisation due to cardiac symptoms (16.1% vs. 18.1%, p = 0.63). In patients with reduced ejection fraction (<45%) there was also no impact of PPMI on one-year mortality (14.3% vs. 15.7%, p = 0.86). Furthermore, multivariate analysis did not reveal PPMI to be independently associated with one-year mortality (odds ratio 0.94, 95% confidence interval 0.50-1.74, p = 0.83). CONCLUSIONS: In this large all-comers TAVI population with new-generation devices the need for postprocedural PPMI did not show a statistical significant impact on survival or combined endpoint of major adverse events within one year.

8.
Acta Chir Orthop Traumatol Cech ; 85(1): 54-56, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30257770

RESUMO

PURPOSE OF THE STUDY With the concept of the lateral compression plate (LLCP) a technique has been available designed to combine the advantages of a fixed-angle fixation with a complete sinking of the implant into the proximal bone. The objective of the present study was to investigate the results of the LLCP compared with classical screw osteosynthesis (SO). MATERIAL AND METHODS 31 patients with pes planovalgus who received calcaneal displacement osteotomy and osteosyntheses with screws (n = 17) or LLCP (n = 14) between 2010 and 2015 were investigated retrospectively.The ankle-hindfoot scale, Kaikkonen score, VAS, and the SF-36 were determined preoperatively as well as at the last clinical follow-up. In addition, a radiological control of osseous integration was performed in all patients 12 weeks after surgery. RESULTS With regard to clinical scores both methods depicted significant improvement. In the overall cohort there were no pseudarthroses. In the SO group 5 cases (29%) showed hardware irritation, in the LLCP group there were none. Results in the LLCP group were significantly superior in the area of the physical section of the SF 36. CONCLUSIONS Based on the results of our study, surgical treatment of stage II pes planovalgus by means of calcaneal displacement osteotomy using the LLCP is equivalent to SO with a lower incidence of hardware irritation. Key words:pes planovalgus, lateral compression plate, osteosynthesis, screw, hardware irritation. LEVEL OF EVIDENCE: Level IV, retrospective case serie.


Assuntos
Pé Chato/cirurgia , Fixação Interna de Fraturas , Osteotomia , Complicações Pós-Operatórias , Lesões dos Tecidos Moles , Placas Ósseas , Parafusos Ósseos , Calo Ósseo/diagnóstico por imagem , Calcâneo/cirurgia , Pesquisa Comparativa da Efetividade , Feminino , Pé Chato/diagnóstico , Fixação Interna de Fraturas/efeitos adversos , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/métodos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Osteotomia/efeitos adversos , Osteotomia/instrumentação , Osteotomia/métodos , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Lesões dos Tecidos Moles/diagnóstico , Lesões dos Tecidos Moles/etiologia , Lesões dos Tecidos Moles/prevenção & controle
9.
Knee ; 25(3): 392-397, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29551277

RESUMO

BACKGROUND: Unicompartmental knee arthroplasty (UKA) is an effective treatment for patients with medial osteoarthritis of the knee joint. Instrumented gait analysis provides an objective measure to quantify and qualify postoperative changes of gait. The purpose of this study was to evaluate standardized instrumented gait analysis for functional recovery and gait as an outcome of mobile-bearing UKA in patients with medial osteoarthritis of the knee. METHODS: Twenty-one patients with isolated medial osteoarthritis of the knee joint received mobile-bearing UKA. They were examined by a gait analysis before surgery and after an average follow-up time of seven months. Gait analysis was performed on a treadmill with six infrared-cameras to identify changes of gait characteristics (e.g., velocity, stride time, stride length, knee adduction and hip abduction). RESULTS: Mean velocity (chosen by individuals) increased from 0.61 to 0.76m/s and further significant advancements, particularly in the knee adduction and the hip abduction were detected. Time and length of strides improved significantly as well as the clinical scores American Knee Society Score (AKSS), Oxford-12, Hannover Functional Ability Questionnaire for Osteoarthritis (FFbH-OA) Score and Devane Score. CONCLUSION: Mobile-bearing UKA can restore physiological axis of the leg and improve gait and function of the knee joint. The combination of instrumented gait analysis with clinical scores constitutes an eligible measuring instrument to quantify and qualify changes in patients' gait patterns.


Assuntos
Artroplastia do Joelho/métodos , Marcha/fisiologia , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/cirurgia , Idoso , Artroplastia do Joelho/instrumentação , Feminino , Humanos , Joelho/fisiopatologia , Articulação do Joelho/cirurgia , Prótese do Joelho , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica
10.
Clin Res Cardiol ; 107(6): 507-516, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29453592

RESUMO

OBJECTIVES: The aim of this study was to adapt patient-specifically a co-registration procedure for image fusion (IF) of a pre-interventional CT dataset with real-time X-ray (XR) fluoroscopy during transfemoral transcatheter aortic valve implantation (TAVI), enabling improved performance of the procedure. BACKGROUND: The ability to use 3D models of the respective anatomies to complement the anatomic information obtained by XR fluoroscopy and provide a greater degree of real-time anatomical guidance holds great potential for complex cardiac interventions, especially for TAVI procedures with cerebral protection. METHODS: Initial registration of two datasets was performed during the femoral puncture and sheath introduction using routinely acquired arteriographies. On-time refinement of the co-registration was then performed during the on-going procedure avoiding additional angiograms for the co-registration. Performance of the method was evaluated quantitatively in terms of procedural characteristics and clinical events. RESULTS: Significant reduction of the radiation dose [51 (42-55) vs. 64 (49-81) Gy cm2, p = 0.032] and contrast agent (CA) volume [80 (50-95) vs. 100 (80-110) ml, p = 0.010] was achieved with the optimized approach as compared to the control group without IF, with simultaneous decrease of procedural [48 (41-58) vs. 61 (53-67) min, p = 0.002] and fluoroscopy times [14.8 (12.7-18.5) vs. 17.8 (14.3-19.4), p = 0.108]. CONCLUSIONS: In this proof-of-concept study we have demonstrated a novel co-registration approach for IF during TAVI not requiring any additional CA or XR scan. We have evaluated its potential benefit with the strong focus on guiding the femoral puncture, placement of the double-filter cerebral embolic protection device, and deployment of the valve prosthesis. We achieved improved performance and safety of the procedure with the introduced approach.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/diagnóstico por imagem , Angiografia por Tomografia Computadorizada/métodos , Fluoroscopia/métodos , Próteses Valvulares Cardíacas , Imageamento Tridimensional , Cirurgia Assistida por Computador/métodos , Idoso , Idoso de 80 Anos ou mais , Aorta Torácica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico , Feminino , Artéria Femoral/diagnóstico por imagem , Seguimentos , Humanos , Artéria Ilíaca/diagnóstico por imagem , Período Intraoperatório , Masculino , Estudos Prospectivos , Reprodutibilidade dos Testes , Substituição da Valva Aórtica Transcateter/métodos
11.
Int J Cardiol ; 249: 90-95, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28935463

RESUMO

The study was aimed at evaluation of the feasibility and potential benefit of image fusion (IF) of pre-procedural CT angiography (CTA) and x-ray (XR) fluoroscopy for image-guided navigation in transfemoral transcatheter aortic valve implantation (TAVI) with the strong focus on guiding the double-filter cerebral embolic protection device and valve prosthesis placement. METHODS: In 31 patients undergoing TAVI, image registration of CTA-derived 3D anatomical models of the relevant cardiac anatomy and vasculature, and live XR was performed applying a commercially available navigation tool. The approach was evaluated in terms of the accuracy of the overlay. In 27 TAVI patients with IF receiving double-filter cerebral embolic protection device overall procedure time, fluoroscopy time, radiation dose, and total volume of intra-procedural iodinated contrast agent (CA) were registered and compared to those of a control group of prospectively enrolled during the same period of time N=27 patients receiving the same protection system but without IF. RESULTS AND CONCLUSIONS: Image co-registration and model-based guidance is feasible in TAVI procedures. The overlay facilitates placement of the embolic protection device, placement of the guide wire in the left ventricle and initial alignment of the valve prosthesis prior to final deployment, thus improving the confidence level of the operators during the procedure without compromising CA or XR dose.


Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Tomografia Computadorizada de Feixe Cônico/métodos , Ecocardiografia/métodos , Embolia Intracraniana/diagnóstico por imagem , Monitorização Neurofisiológica Intraoperatória/métodos , Substituição da Valva Aórtica Transcateter/métodos , Estenose da Valva Aórtica/cirurgia , Estudos de Viabilidade , Feminino , Humanos , Embolia Intracraniana/prevenção & controle , Masculino , Estudos Prospectivos
12.
Anat Histol Embryol ; 46(4): 397-404, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28677231

RESUMO

The neocortex plays a key role in cognition, volitional motor control and sensory perception and has undergone tremendous expansion during evolution. The mature neocortex consists of radially aligned neurons that are arranged in six layers. Layers II-VI are often split into two groups: deep and upper layers, both building up the so-called cortical plate during embryonic and foetal development. So far cortical neurogenesis, including the generation of deep and upper layers, has mostly been studied in laboratory rodents and primates. However, precise data for most companion animals are lacking. This study determined the main period of neurogenesis, specifically the timing of deep and upper layer generation, in the developing domestic cat, pig and sheep neocortex using immunohistochemistry for specific neuronal markers, that is Tbr1 and Brn2. We found that the general sequence of neural events is preserved among cat, pig, sheep and other mammalian species. However, we observed differences in the timing of the overall cortical neurogenic period and occurrence of distinct neural events when these three species were compared. Moreover, our data provide further evidence that the cortical neurogenic period and gestation length might be tightly related. Together, these data expand our current understanding of neocortex development and are important for future studies investigating neocortex development and expansion especially in companion animals.


Assuntos
Gatos/embriologia , Neocórtex/embriologia , Ovinos/embriologia , Suínos/embriologia , Animais , Gatos/crescimento & desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imuno-Histoquímica/veterinária , Modelos Lineares , Microscopia Confocal/veterinária , Neocórtex/química , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Ovinos/crescimento & desenvolvimento , Estatística como Assunto , Suínos/crescimento & desenvolvimento , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Telencéfalo/química
13.
Anat Histol Embryol ; 46(1): 43-50, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26990890

RESUMO

The extracellular matrix (ECM) of hyaline cartilage is perfectly suited to transmit articular pressure load to the subchondral bone. Pressure is transferred by a high amount of aggrecan-based proteoglycans and collagen type II fibres in particular. After any injury, the hyaline cartilage is replaced by fibrocartilage, which is low in proteoglycans and contains collagen type I predominantly. Until now, long-term results of therapeutic procedures including cell-based therapies like autologous chondrocyte transplantation (ACT) lead to a replacement tissue meeting the composition of fibrocartilage. Therefore, it is of particular interest to discover how and to what extent isolation and in vitro cultivation of chondrocytes affect the cells and their expression of ECM components. Hyaline cartilage-derived chondrocytes were cultivated in vitro and observed microscopically over a time period of 35 days. The expression of collagen type I, collagen type II and aggrecan was analysed using RT-qPCR and Western blot at several days of cultivation. Chondrocytes presented a longitudinal shape for the entire cultivation period. While expression of collagen type I prevailed within the first days, only prolonged cultivation led to an increase in collagen type II and aggrecan expression. The results indicate that chondrocyte isolation and in vitro cultivation lead to a dedifferentiation at least to the stage of chondroprogenitor cells.


Assuntos
Agrecanas/biossíntese , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Colágeno Tipo II/biossíntese , Colágeno Tipo I/biossíntese , Matriz Extracelular/metabolismo , Cartilagem Articular/citologia , Células Cultivadas , Condrócitos/citologia , Colágeno Tipo I/genética , Colágeno Tipo II/genética , Humanos , Proteoglicanas/metabolismo , RNA Mensageiro/genética
14.
Allergy ; 70(7): 764-74, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25833810

RESUMO

BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. MATERIAL AND METHODS: We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. RESULTS: MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. CONCLUSIONS: Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.


Assuntos
Mastócitos/imunologia , Mastócitos/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Mastocitose/genética , Mastocitose/imunologia , Mastocitose/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Fator de Células-Tronco/metabolismo , Fator de Células-Tronco/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
15.
Neuroscience ; 295: 175-86, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-25813711

RESUMO

Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Intravitreal administration of neurotrophins such as brain-derived neurotrophic factor (BDNF) is known to promote survival of retinal neurons. Here, we show that exogenous BDNF inhibits the osmotic swelling of Müller cell somata induced by superfusion of rat retinal slices or freshly isolated cells with a hypoosmotic solution containing barium ions. BDNF also inhibited the osmotic swelling of bipolar cell somata in retinal slices, but failed to inhibit the osmotic soma swelling of freshly isolated bipolar cells. The inhibitory effect of BDNF on Müller cell swelling was mediated by activation of tropomyosin-related kinase B (TrkB) and transactivation of fibroblast growth factor receptors. Exogenous basic fibroblast growth factor (bFGF) fully inhibited the osmotic swelling of Müller cell somata while it partially inhibited the osmotic swelling of bipolar cell somata. Isolated Müller cells displayed immunoreactivity of truncated TrkB, but not full-length TrkB. Isolated rod bipolar cells displayed immunoreactivities of both TrkB isoforms. Data suggest that the neuroprotective effect of exogenous BDNF in the retina is in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. While BDNF directly acts on Müller cells by activation of TrkB, BDNF indirectly acts on bipolar cells by inducing glial release of factors like bFGF that inhibit bipolar cell swelling.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Edema/tratamento farmacológico , Células Ependimogliais/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Células Bipolares da Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Análise de Variância , Animais , Bário/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Edema/etiologia , Feminino , Técnicas In Vitro , Masculino , Pressão Osmótica , Proteína Quinase C/metabolismo , Ratos , Ratos Long-Evans , Receptor trkB/metabolismo , Retina/citologia , Estatísticas não Paramétricas , Fatores de Tempo
16.
Cell Death Dis ; 6: e1691, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25766330

RESUMO

Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the specific alteration of the cytochrome c oxidase (COX), representing a common defect found in mitochondrial diseases, facilitates mitochondrial apoptosis in response to oxidative stress. Our data identified an increased ceramide synthase 6 (CerS6) activity as an important pro-apoptotic response to COX dysfunction induced either by chemical or genetic approaches. The elevated CerS6 activity resulted in accumulation of the pro-apoptotic C16 : 0 ceramide, which facilitates the mitochondrial apoptosis in response to oxidative stress. Accordingly, inhibition of CerS6 or its specific knockdown diminished the increased susceptibility of COX-deficient cells to oxidative stress. Our results provide new insights into how mitochondrial RC dysfunction mechanistically interferes with the apoptotic machinery. On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction.


Assuntos
Apoptose/genética , Deficiência de Citocromo-c Oxidase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/biossíntese , Proteínas de Membrana/biossíntese , Esfingosina N-Aciltransferase/biossíntese , Animais , Deficiência de Citocromo-c Oxidase/genética , Deficiência de Citocromo-c Oxidase/patologia , Complexo IV da Cadeia de Transporte de Elétrons/genética , Células HeLa , Humanos , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo , Consumo de Oxigênio , Esfingosina N-Aciltransferase/antagonistas & inibidores
17.
Clin Pharmacol Ther ; 97(2): 186-93, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25670524

RESUMO

Using data from a large commercial health insurer, we studied prescribing of romiplostim (Nplate) and eltrombopag (Promacta), two drugs for primary immune thrombocytopenia (ITP) for which risk evaluation and mitigation strategies (REMS) with elements to assure safe use were initially imposed and then removed. We identified 103 and 117 new users of romiplostim and eltrombopag, respectively. Use was almost exclusively for FDA-approved indications ("on-label") while the REMS with elements to assure safe use were in place. After these elements were lifted, off-label use of eltrombopag among patients with hepatitis C virus (HCV), a subsequently approved indication, increased. The ratio of incidence rate ratios of off-label/HCV to on-label initiation of eltrombopag between the two time periods was significant (13.41; P < 0.001). Our finding of an association with reduced off-label prescribing suggests that REMS with elements to assure safe use can help promote patient safety but may also prevent promising off-label drug uses.


Assuntos
Benzoatos/uso terapêutico , Hepatite C/tratamento farmacológico , Hidrazinas/uso terapêutico , Uso Off-Label/estatística & dados numéricos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Medição de Risco , Comportamento de Redução do Risco , Trombopoetina/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
18.
Bone Joint J ; 97-B(1): 89-93, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25568419

RESUMO

Hypovitaminosis D has been identified as a common risk factor for fragility fractures and poor fracture healing. Epidemiological data on vitamin D deficiency have been gathered in various populations, but the association between vertebral fragility fractures and hypovitaminosis D, especially in males, remains unclear. The purpose of this study was to evaluate serum levels of 25-hydroxyvitamin D (25-OH D) in patients presenting with vertebral fragility fractures and to determine whether patients with a vertebral fracture were at greater risk of hypovitaminosis D than a control population. Furthermore, we studied the seasonal variations in the serum vitamin D levels of tested patients in order to clarify the relationship between other known risk factors for osteoporosis and vitamin D levels. We measured the serum 25-OH D levels of 246 patients admitted with vertebral fractures (105 men, 141 female, mean age 69 years, sd 8.5), and in 392 orthopaedic patients with back pain and no fractures (219 men, 173 female, mean age 63 years, sd 11) to evaluate the prevalence of vitamin D insufficiency. Statistical analysis found a significant difference in vitamin D levels between patients with vertebral fragility fracture and the control group (p = 0.036). In addition, there was a significant main effect of the tested variables: obesity (p < 0.001), nicotine abuse (p = 0.002) and diabetes mellitus (p < 0.001). No statistical difference was found between vitamin D levels and gender (p = 0.34). Vitamin D insufficiency was shown to be a risk factor for vertebral fragility fractures in both men and women.


Assuntos
Fraturas Espontâneas/epidemiologia , Fraturas por Osteoporose/epidemiologia , Fraturas da Coluna Vertebral/epidemiologia , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Estudos de Coortes , Comorbidade , Feminino , Seguimentos , Fixação de Fratura/métodos , Fraturas Espontâneas/diagnóstico por imagem , Fraturas Espontâneas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/terapia , Prevalência , Estudos Prospectivos , Radiografia , Medição de Risco , Distribuição por Sexo , Fraturas da Coluna Vertebral/diagnóstico por imagem , Resultado do Tratamento , Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico
19.
Knee Surg Sports Traumatol Arthrosc ; 23(7): 2049-54, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24671384

RESUMO

PURPOSE: Patients with lateral osteoarthritis of the knee suffer not only from pain but also impaired gait and limited mobility. Common treatment options are total knee replacement and lateral unicompartmental knee arthroplasty (UKA). The domed lateral mobile-bearing Oxford Uni is a new treatment option for patients with isolated osteoarthritis of the lateral compartment of the knee joint. We used instrumented gait analysis and clinical scores to study patients before and after lateral UKA. METHODS: Nineteen patients suffering from lateral osteoarthritis underwent implantation of a mobile-bearing lateral UKA. They were examined in a gait analysis before the operation and after an average follow-up time of 7 months. Gait analysis was performed on a treadmill with six infrared cameras to identify gait characteristics (e.g. velocity, stride time, stride length, knee abduction or hip adduction). RESULTS: Mean velocity changed from 0.58 to 0.73 m/s. Significant advancements were also found in knee abduction and hip adduction. Time and length of strides improved significantly as well as the clinical scores American Knee Society Score, Oxford-12, FFb-H-OA and Devane Score. CONCLUSION: Patients with lateral osteoarthritis of the knee showed an impaired gait with an increased knee abduction and hip adduction angle. Implantation of a lateral mobile UKA can restore normal axis of the leg and improve gait and function of the knee. Instrumented gait analysis is a suitable measuring instrument to quantify and qualify the post-operative change of gait. LEVEL OF EVIDENCE: II.


Assuntos
Artroplastia do Joelho , Marcha , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/cirurgia , Artroplastia do Joelho/instrumentação , Humanos , Articulação do Joelho/cirurgia , Amplitude de Movimento Articular , Resultado do Tratamento
20.
Anat Histol Embryol ; 44(6): 401-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25283481

RESUMO

Clinical, anatomical and histological aspects of the equine acoustic organ have been poorly investigated and illustrated in literature so far. It is understood that an intact acoustic organ and hearing function are of vital importance for the well-being of flight animals like horses. The knowledge of the acoustic organ is usually transferred analogously from other mammals to horses. The purpose of this study was to provide a detailed and complete histological description of the healthy equine auditory organ, and to determine its congruity to other mammalians. Anatomical dissections and histological preparations were carried out on ten cadaver heads. Specimens of various parts of the equine acoustic organ were taken and evaluated histologically. The histological composition of external, middle and inner ear structures are predominantly congruent to those of other mammals, especially to human beings. Unique inwardly directed rete pegs within the osseous ear canal and the prominent tensor tympani muscle are described for the first time. Results obtained in this study can be employed as references for further research on the equine acoustic organ and improve the understanding of the clinical development of hearing loss, otitis externa/media/interna or tympanosclerosis.


Assuntos
Pavilhão Auricular/anatomia & histologia , Meato Acústico Externo/anatomia & histologia , Orelha Interna/anatomia & histologia , Orelha Média/anatomia & histologia , Cavalos/anatomia & histologia , Microscopia/veterinária , Membrana Timpânica/anatomia & histologia , Animais
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