RESUMO
OBJECTIVE: To characterize and compare the incidence of basketball-related, soccer-related, and hockey-related injuries over a 10-year period. DESIGN: Cohort analysis of sport-related injuries using multiple Ontario healthcare databases. SETTING: Emergency department visits in Ontario, Canada. PATIENTS: Any patient who sustained musculoskeletal injuries sustained while playing basketball, soccer, or hockey between 2006 and 2017 were identified. ASSESSMENT OF RISK FACTORS: Sport of injury, age, sex, rurality index, marginalization status, and comorbidity score. MAIN OUTCOME MEASURES: Annual Incidence Density Rates of injury were calculated for each sport, and significance of trends was analyzed by assessing overlap of 95% confidence intervals. RESULTS: One lakhs eighty five thousand eighty hundred sixty-eight patients (median age: 16 years, interquartile range 13-26) received treatment for sport-related injuries (basketball = 55 468; soccer = 67 021; and hockey = 63 379). The incidence of basketball-related and soccer-related injuries increased from 3.4 (3.3-3.5) to 5.6 (5.5-5.7) and 4.4 (4.3-4.5) to 4.9 (4.8-5) per 10 000 person years, respectively, whereas the incidence of hockey-related injuries decreased from 4.7 (4.6-4.8) to 3.7 (3.6-3.8). Patients with basketball injuries were more marginalized (3.01 ± 0.74) compared with patients with soccer and hockey injuries (2.90 ± 0.75 and 2.72 ± 0.69, respectively). CONCLUSIONS: Accurate regional epidemiologic information regarding sports injuries can be used to guide policy development for municipal planning and sport program development. The trends and demographic patterns described highlight general and sport-specific injury patterns in Ontario. Populations with the highest incidence of injury, most notably adolescents and men older than 50, may represent an appropriate population for injury risk prevention.
Assuntos
Traumatismos em Atletas , Basquetebol , Hóquei , Futebol , Adolescente , Traumatismos em Atletas/epidemiologia , Traumatismos em Atletas/prevenção & controle , Basquetebol/lesões , Canadá , Hóquei/lesões , Humanos , Masculino , Futebol/lesõesRESUMO
PURPOSE: International uniformity of definition and classification are crucial for diagnosis and management of cauda equina syndrome (CES). They are also useful for clinicians when discussing CES with patients and relatives, and for medicolegal purposes. METHODS: We reviewed published literature using PubMed on definition and classification of cauda equina syndrome since 2000 (21 years). Using the search terms 'cauda equina' and 'definition' or 'classification', we found and reviewed 212 papers. RESULTS: There were 17 different definitions of CES used in the literature. There were three well-defined methods of classification of CES. The two-stage system of incomplete CES (CESI) versus CES with retention (CESR) is the most commonly used classification, and has prognostic value although the details of this continue to be debated. CONCLUSION: We used the existing literature to propose a clear definition of CES. We also drew on peer-reviewed published literature that has helped to amplify and expand the CESI/CESR dichotomy, adding categories that are both less severe than CESI, and more severe than CESR, and we propose clear definitions in a table form to assist current and future discussion and management of CES.
Assuntos
Síndrome da Cauda Equina , Polirradiculopatia , Síndrome da Cauda Equina/diagnóstico , Humanos , Polirradiculopatia/diagnóstico , PrognósticoRESUMO
PURPOSE: Knee dislocations (KDs) are potentially devastating injuries, leading to loss of function or limb in often young patients. This retrospective database review aims to determine the relative incidence and risk factors for KDs presenting to North American Level I and II trauma centers. METHODS: The National Trauma Data Bank (NTDB) was retrospectively interrogated using ICD-9-CM codes to identify KDs between 2010 and 2014 to derive KD incidence. KDs were stratified by age, sex, Injury Severity Score (ISS), Glasgow Coma Scale (GCS), drug and alcohol use, injury mechanism, open vs. closed KD, vascular injury and fracture. Each co-variate was tested against different mechanisms of injury, using Chi-squared tests and risk adjusted analyses to derive risk factors for KD. The same calculations were done for secondary outcomes (vascular and neurological injuries, compartment syndrome, amputation, and mortality). RESULTS: A total of 6454 KDs met the inclusion criteria (18/10,000 admissions). KDs occurred most commonly amongst men, aged 20-39, with an ISS score 1-14 and following motor vehicle collision (MVC). A vascular investigation was performed in 29%, with injury documented in 15% of KDs and 10.8% receiving a vascular procedure. Associated fractures were observed in 41.4% of KDs. Open injuries in 13.6%. Neurological injury documented in 6.2%, compartment syndrome in 2.7%, amputation in 3.8% (> 50% had vascular injury) and 2.8% died. MVC was the most common mechanism of injury (p < 0.001), significantly more common in young, male patients, associated with higher ISS and lower GCS, especially when drugs or alcohol were involved (p < 0.0001). Being male, having a vascular injury or open KD were all risk factors for compartment syndrome, amputation and neurological injuries. CONCLUSIONS: KDs are rare injuries, but their relative incidence may be increasing. Young, male patients involved in MVCs are risk factors for KDs and their associated injuries, such as neurological injuries, amputations and compartment syndrome. Vascular injury occurs at a frequency of around 15%. The findings of the current study may guide future research and help to inform clinicians on the expected rates of associated injuries in patients identified to have KD in a trauma center population. It informs regarding risk factors for KD, which may improve diagnosis rates of spontaneously reduced knee dislocations by increasing index of suspicion in high-risk patients and identifies specific links with impaired driving. LEVEL OF EVIDENCE: IV.
Assuntos
Luxação do Joelho/epidemiologia , Centros de Traumatologia/estatística & dados numéricos , Acidentes de Trânsito/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Luxação do Joelho/complicações , Luxação do Joelho/diagnóstico , Luxação do Joelho/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Adulto JovemRESUMO
We report the development of a potent, selective histone deacetylase 6 (HDAC6) inhibitor. This HDAC6 inhibitor blocks growth of normal and transformed cells but does not induce death of normal cells. The HDAC6 inhibitor alone is as effective as paclitaxel in anticancer activity in tumor-bearing mice.
Assuntos
Antineoplásicos/síntese química , Benzenoacetamidas/química , Benzenoacetamidas/farmacologia , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/genética , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/química , Camundongos , Estrutura Molecular , Paclitaxel , Tubulina (Proteína)/metabolismoRESUMO
Exercise-induced rhabdomyolysis is an unusual clinical entity for physicians and one that is frequently misdiagnosed. With the ever-increasing use of sonography by radiologists, sonographers, and sports physicians in the diagnosis of acute muscle injury, recognition of the typical sonographic appearance of rhabdomyolysis is paramount. Current literature using high-resolution ultrasound equipment is limited, with much of the literature offering dated or incongruent descriptions. We describe the sonographic findings of hyperechoic muscle and a hypoechoic halo of edema in 2 proven cases of rectus abdominis rhabdomyolysis after exercise.
Assuntos
Exercício Físico , Reto do Abdome/diagnóstico por imagem , Reto do Abdome/lesões , Rabdomiólise/complicações , Rabdomiólise/diagnóstico por imagem , Ultrassonografia/métodos , Adulto , Feminino , HumanosRESUMO
BACKGROUND: We report a prospective randomized study comparing early clinical results between the direct anterior approach (DAA) and posterior approach (PA) in primary hip arthroplasty. METHODS: Surgeries were performed by 2 senior hip arthroplasty surgeons. Seventy-two patients with complete data were assessed preoperatively 2, 6, and 12 weeks postoperatively. The primary outcomes were the Western Ontario McMasters Arthritis Index and Oxford Hip Scores. Secondary outcome measures included the EuroQoL, 10-meter walk test, and clinical and radiographic parameters. RESULTS: Data analyses showed no difference between DAA (n = 35) and PA (n = 37) groups when comparing total scores for primary outcomes. No significant differences were observed for 10-meter walk test, EuroQoL, and radiographic analyses. Subgroup analysis for surgeon 1 identified that the DAA group had shorter acute hospital stay, less postoperative opiate requirements, and smaller wounds. However, this was offset by increased operative time, higher intraoperative blood loss, and weaker hip flexion at 2 and 6 weeks. Subgroup analysis of items on the Western Ontario McMasters Arthritis Index and Oxford Hip Score identified that hip flexion activity favored the DAA group up to 6 weeks postoperatively. There was an 83% incidence of lateral cutaneous nerve of thigh neuropraxia at the 12-week mark in the DAA group. No neuropraxias occurred in the PA group. One dislocation occurred in each group. A single patient from the DAA group required reoperation for leg-length discrepancy. CONCLUSION: DAA total hip arthroplasty (THA) has comparable results with PA THA. Choice of surgical approach for THA should be based on patient factors, surgeon preference, and experience.
Assuntos
Artroplastia de Quadril/métodos , Artroplastia de Quadril/estatística & dados numéricos , Idoso , Artrite , Artroplastia de Quadril/efeitos adversos , Perda Sanguínea Cirúrgica , Feminino , Humanos , Luxações Articulares , Articulações , Desigualdade de Membros Inferiores , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Período Pós-Operatório , Estudos Prospectivos , Radiografia , Amplitude de Movimento Articular , Reoperação , Cirurgiões , Coxa da Perna , Resultado do TratamentoRESUMO
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.
Assuntos
Histona Desacetilases/genética , Doença de Huntington/enzimologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Epigênese Genética , Feminino , Técnicas de Silenciamento de Genes , Histona Desacetilases/metabolismo , Proteína Huntingtina , Doença de Huntington/fisiopatologia , Doença de Huntington/terapia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Neurônios/fisiologia , Fenótipo , Teste de Desempenho do Rota-Rod , Transmissão Sináptica , Transcrição GênicaRESUMO
Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.
Assuntos
Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Transformada/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Doxorrubicina/farmacologia , Etoposídeo/farmacologia , Inibidores de Histona Desacetilases/química , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Trealose/farmacologia , Tubulina (Proteína)/metabolismo , Vorinostat , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Plantar fasciosis is a common complaint of athletes, particularly for runners. The medial calcaneal nerve (MCN) may play a role in the pain syndrome, and radiofrequency (RF) denervation has been previously reported. The hypothesis is that ultrasound-guided denervation of the MCN results in symptomatic improvement. DESIGN: Retrospective cohort. SETTING: Private practice. PATIENTS: Twenty-nine patients previously receiving ultrasound-guided RF denervation of the MCN, having failed conservative therapy, were assessed in 2 groups, those more than (group 1, n = 16) or less than (group 2, n = 13) 6 months since the procedure. INTERVENTIONS: Ultrasound-guided RF denervation of the MCN. MAIN OUTCOME MEASURES: Pain scores before denervation, as well as at maximal pain relief and the time of the interview. Levels of satisfaction and attitudes toward surgery were also assessed. RESULTS: Pain scores decreased significantly in both groups, for both best and residual pain scores. Group 1 mean pain scores were 8.56 before procedure, 2.81 (P < 0.001 compared to baseline) at best pain score, and 3.75 (P < 0.01) residual pain score. Group 2 mean pain scores were 7.23 before procedure, 3.77 (P < 0.01) at best pain score and 4.92 (P < 0.01) residual pain score. Levels of satisfaction were predominantly positive (69% of group 1% and 54% of group 2 were either somewhat or very satisfied), with attitudes toward surgery unchanged. CONCLUSIONS: For patients with refractory plantar heel pain, ultrasound-guided denervation of the MCN can potentially improve symptoms, although efficacy needs assessing in comparative studies. CLINICAL RELEVANCE: Ultrasound-guided denervation of the MCN provides a further management option for patients with refractory plantar fasciosis.
Assuntos
Denervação/métodos , Calcanhar/inervação , Ultrassonografia de Intervenção , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to assess the variability of the microfracture technique when performed by experienced knee arthroscopy surgeons. METHOD: Four surgeons were each asked to perform microfracture on six preformed cartilage defects in fresh human cadaveric knees. Surgeons were instructed on penetration depth, inter-hole distance, and to place the holes perpendicular to the subchondral surface. Micro-computed tomography was used to calculate depth error, inter-hole distance error, and deviation of penetration angles from the perpendicular. RESULTS: All surgeons misjudged depth and inter-hole distance, tending to make microfracture holes too deep (depth error 1.1 mm ± 1.9) and too close together (inter-hole distance error: -0.8 mm ± 0.4). Fifty-one per cent of holes were angled more than 10° from the perpendicular (range 2.6°-19.8°). Both depth and distance errors were significantly lower in the trochlear groove than on the femoral condyle (p < 0.05). Surface shearing was associated with both penetration depth >4 mm and angles >20°. Inter-hole infraction occurred in holes closer than 2.5 mm to each other. CONCLUSION: Even experienced knee arthroscopy surgeons demonstrate inconsistency in surgical technique when performing microfracture. While further research will be required to demonstrate that these variations in surgical technique are associated with poorer clinical outcomes after microfracture, surgeons should attempt to minimizing such variations in order to prevent surface shearing and inter-hole infraction.
Assuntos
Artroplastia Subcondral/métodos , Cartilagem Articular/cirurgia , Articulação do Joelho/cirurgia , Artroscopia , Cadáver , Doenças das Cartilagens/diagnóstico por imagem , Doenças das Cartilagens/cirurgia , Cartilagem Articular/diagnóstico por imagem , Fêmur/cirurgia , Humanos , Imageamento Tridimensional , Articulação do Joelho/diagnóstico por imagem , Microtomografia por Raio-XRESUMO
Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient-sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced nonapoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Morte Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Linhagem Celular , Camundongos , Proteínas Serina-Treonina Quinases , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais Cultivadas , VorinostatRESUMO
Histone deacetylase inhibitors (HDACi) are a new group of anticancer drugs with tumor selective toxicity. Normal cells are relatively resistant to HDACi-induced cell death compared with cancer cells. Previously, we found that vorinostat induces DNA breaks in normal and transformed cells, which normal but not cancer cells can repair. In this study, we found that checkpoint kinase 1 (Chk1), a component of the G2 DNA damage checkpoint, is important in the resistance of normal cells to HDACi in vitro and in vivo. Inhibition of Chk1 activity with Chk1 inhibitor (UCN-01, AZD7762, or CHIR-124) in normal cells increases their sensitivity to HDACi (vorinostat, romidepsin, or entinostat) induced cell death, associated with extensive mitotic disruption. Mitotic abnormalities included loss of sister chromatid cohesion and chromosomal disruption. Inhibition of Chk1 did increase HDACi-induced cell death of transformed cells. Thus, Chk1 is an important factor in the resistance of normal cells, and some transformed cells, to HDACi-induced cell death. Use of Chk1 inhibitors in combination with anticancer agents to treat cancers may be associated with substantial toxicity.
Assuntos
Resistência a Medicamentos , Inibidores de Histona Desacetilases/farmacologia , Proteínas Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quinase 1 do Ponto de Checagem , Dano ao DNA , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Prepúcio do Pênis/citologia , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Immunoblotting , Masculino , Camundongos , Proteínas Quinases/genética , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Interferência de RNA/fisiologia , Baço/efeitos dos fármacos , Baço/metabolismo , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , VorinostatRESUMO
OBJECTIVE: There are few agreed quantifiable outcome measures in pituitary surgery. The goal of this study is to present the measurement of resection volume after surgery for pituitary tumours as a surgeon-specific outcome measure that may have use in illustrating the performance of individual surgeons internally and externally, and contribute to quality improvement in pituitary surgery. METHOD: The authors used an existing validated method to measure the volume of pituitary tumours. This method was used to retrospectively assess the extent of resection (EOR) in all patients undergoing pituitary surgery for tumour volume reduction over a 3-year period in Leeds, UK. Three surgeons and two techniques (endonasal transsphenoidal surgery and conventional microscopic surgery) were compared. The results are summarised using Funnel plot methodology. RESULTS: The overall mean EOR for the 3 years of study was 54%. There was no difference between endoscopic and microscopic techniques in terms of EOR. Significant differences were found between surgeons' case mix (as estimated by preoperative tumour size) and EOR. One surgeon had smaller tumour cases at operation than the other two surgeons (p = 0.004). One surgeon achieved larger resections than the two other surgeons (p = 0.038 and 0.005). CONCLUSIONS: Measuring pituitary volumes manually using segmentation methods and existing software is possible for surgeons and provides valuable information on individual surgeon performance and departmental practice. A simple retrospective review of 3 years of practice has demonstrated that surgeons have different case-mix and their EOR can vary within safe limits. During a period of transition when we changed personnel and technique, the EOR was little affected and this was reassuring from a governance perspective. Performance assessment for low-volume conditions is possible .
Assuntos
Revelação , Neurocirurgia/estatística & dados numéricos , Hipófise/cirurgia , Neoplasias Hipofisárias/cirurgia , Feminino , Humanos , Masculino , Microcirurgia/métodos , Microcirurgia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Procedimentos Neurocirúrgicos/métodos , Hipófise/patologia , Neoplasias Hipofisárias/patologia , Estudos Retrospectivos , Cirurgiões , Resultado do TratamentoRESUMO
Histone deacetylase 6 (HDAC6) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases. Here we show that chemical inhibition with the HDAC6-selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan-HDAC inhibitor SAHA (vorinostat) in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (human foreskin fibroblast cells). The inactive analogue of tubacin, nil-tubacin, does not sensitize transformed cells to these anticancer agents. Further, we show that down-regulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by etoposide, doxorubicin, and SAHA. Tubacin in combination with SAHA or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells, as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk. HDAC6 inhibition with tubacin induces the accumulation of γH2AX, an early marker of DNA double-strand breaks. Tubacin enhances DNA damage induced by etoposide or SAHA as indicated by increased accumulation of γH2AX and activation of the checkpoint kinase Chk2. Tubacin induces the expression of DDIT3 (CHOP/GADD153), a transcription factor up-regulated in response to cellular stress. DDIT3 induction is further increased when tubacin is combined with SAHA. These findings point to mechanisms by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells.
Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Dano ao DNA , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Quinase do Ponto de Checagem 2 , Replicação do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Etoposídeo/farmacologia , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Inibidores da Topoisomerase II/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (gammaH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, gammaH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death.
Assuntos
Dano ao DNA , Reparo do DNA , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Acetilação/efeitos dos fármacos , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Citometria de Fluxo , Prepúcio do Pênis/citologia , Histonas/metabolismo , Humanos , Immunoblotting , Masculino , Microscopia de Fluorescência , VorinostatRESUMO
PURPOSE: The objective of our study was to summarize the available clinical evidence pertaining to the combined arthroscopic Bankart repair and remplissage procedure (BRR) for the management of recurrent anterior glenohumeral instability. METHODS: We searched Medline (1946 to the third week of November, 2012), the Cochrane Central Register of Controlled Trials, Embase (1947 to the 50th week of 2012), and PubMed for studies that reported clinical outcome data at a minimum of 1 year after BRR. Two independent reviewers selected studies for inclusion, assessed methodological quality, and extracted relevant data. Clinical outcome data were pooled and summarized. RESULTS: Seven clinical studies with a total of 220 patients met the inclusion criteria. Mean patient age was 29 years and mean follow-up was 26 months. Among all studies, the pooled rate of recurrent dislocation after BRR was 3.4%. Compared with preoperative range of motion (ROM) and ROM after Bankart repair (BR) for similar pathologic conditions, there were no clinically significant losses in glenohumeral motion after BRR. Moreover, BRR resulted in favorable functional outcome scores and high patient satisfaction. Four studies reported on postoperative imaging and found high rates of healing and tissue fill-in at the site of infraspinatus tenodesis. CONCLUSIONS: After BRR, the rate of recurrent dislocation is low and there are no clinically significant losses in glenohumeral ROM. Moreover, functional outcome scores are good and there is a high rate of patient satisfaction. Going forward, there is a need for high-level clinical studies to support the findings of this systematic review and to develop an evidence-based approach to the management of patients with recurrent glenohumeral instability in the setting of a Hill-Sachs defect (HSD).
Assuntos
Artroscopia/métodos , Instabilidade Articular/cirurgia , Adulto , Animais , Feminino , Humanos , Masculino , Satisfação do Paciente , Amplitude de Movimento Articular/fisiologia , Recuperação de Função Fisiológica/fisiologia , Recidiva , Escápula/cirurgia , Luxação do Ombro/cirurgia , Técnicas de Sutura , Resultado do TratamentoRESUMO
PURPOSE: The purpose of this systematic review was to synthesize the available Level I and Level II literature on platelet-rich plasma (PRP) as a therapeutic intervention in the management of symptomatic knee osteoarthritis (OA). METHODS: A systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, PubMed, and www.clinicaltrials.gov was performed to identify all randomized controlled trials and prospective cohort studies that evaluated the clinical efficacy of PRP versus a control injection for knee OA. A random-effects model was used to evaluate the therapeutic effect of PRP at 24 weeks by use of validated outcome measures (Western Ontario and McMaster Universities Arthritis Index, visual analog scale for pain, International Knee Documentation Committee Subjective Knee Evaluation Form, and overall patient satisfaction). RESULTS: Six Level I and II studies satisfied our inclusion criteria (4 randomized controlled trials and 2 prospective nonrandomized studies). A total of 577 patients were included, with 264 patients (45.8%) in the treatment group (PRP) and 313 patients (54.2%) in the control group (hyaluronic acid [HA] or normal saline solution [NS]). The mean age of patients receiving PRP was 56.1 years (51.5% male patients) compared with 57.1 years (49.5% male patients) for the group receiving HA or NS. Pooled results using the Western Ontario and McMaster Universities Arthritis Index scale (4 studies) showed that PRP was significantly better than HA or NS injections (mean difference, -18.0 [95% confidence interval, -28.8 to -8.3]; P < .001). Similarly, the International Knee Documentation Committee scores (3 studies) favored PRP as a treatment modality (mean difference, 7.9 [95% confidence interval, 3.7 to 12.1]; P < .001). There was no difference in the pooled results for visual analog scale score or overall patient satisfaction. Adverse events occurred more frequently in patients treated with PRP than in those treated with HA/placebo (8.4% v 3.8%, P = .002). CONCLUSIONS: As compared with HA or NS injection, multiple sequential intra-articular PRP injections may have beneficial effects in the treatment of adult patients with mild to moderate knee OA at approximately 6 months. There appears to be an increased incidence of nonspecific adverse events among patients treated with PRP. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.
Assuntos
Osteoartrite do Joelho/terapia , Plasma Rico em Plaquetas , Adulto , Medicina Baseada em Evidências , Humanos , Ácido Hialurônico/administração & dosagem , Injeções Intra-Articulares , Medição da Dor , Satisfação do Paciente , Estudos Prospectivos , Resultado do TratamentoRESUMO
PURPOSE: To determine the accuracy of secondary magnetic resonance (MR) imaging signs of anterior cruciate ligament (ACL) insufficiency in predicting clinical anterior translational knee laxity, in the presence of an intact graft, after ACL reconstruction. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirement to obtain informed consent was waived. Fifty-two patients with ACL reconstruction and no injury to the contralateral knee were included. Three patients with visible ACL graft tears at MR imaging were excluded. All patients underwent MR imaging of the affected knee, functional assessment with use of the International Knee Documentation Committee (IKDC) score, and arthrometric testing of both the affected and uninjured knee. A side-to-side difference of more than 3 mm at 133 N was considered to be indicative of knee laxity. Two radiologists independently evaluated all MR images for seven signs of anterior knee laxity. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated for each MR imaging sign. RESULTS: Ten patients demonstrated knee laxity at arthrometric testing. Patients with knee laxity at arthrometric testing had significantly lower IKDC scores (P < .03). Sensitivities for all signs were low (0%-50%). Anterior translation of the tibia of more than 7 mm, a posterior cruciate ligament (PCL) angle of less than 100°, and a PCL curvature ratio of more than 0.39 demonstrated high specificity (range, 82%-90%). Uncovering of the posterior horn of the lateral meniscus and the posterior femoral line had a specificity of 97%-100% and a sensitivity of 0%. All signs had a low PPV and high NPV for laxity. All MR imaging signs demonstrated near-perfect interobserver agreement. CONCLUSION: Although MR imaging signs of knee laxity in the presence of an intact ACL graft have a high specificity, the low PPV means that MR imaging is of little value in predicting anterior knee laxity as demonstrated with mechanical testing.
Assuntos
Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/fisiopatologia , Instabilidade Articular/diagnóstico , Instabilidade Articular/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
PURPOSE: The objective of this systematic review was to determine the efficacy of anatomic Bankart repair in patients with a first-time shoulder dislocation compared with either arthroscopic lavage or traditional sling immobilization. METHODS: We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, Web of Science, LILACS, and a clinical trials registry for ongoing and completed randomized or quasi-randomized controlled trials comparing anatomic Bankart repair with either rehabilitation or arthroscopic lavage. Two reviewers selected studies for inclusion, assessed methodologic quality, and extracted data. Pooled analyses were performed by use of a random-effects model, and risk ratio (RR) and 95% confidence intervals (CIs) were computed. RESULTS: We included 3 randomized trials and 1 quasi-randomized trial comprising 228 patients. Of the included trials, 2 compared anatomic Bankart repair with sling immobilization whereas 2 compared Bankart repair with arthroscopic lavage. A meta-analysis of all 4 trials showed that the rate of recurrent instability was significantly lower among participants undergoing anatomic Bankart repair compared with those undergoing either immobilization or arthroscopic lavage (RR, 0.18; 95% CI, 0.10 to 0.33). Subgroup analysis showed that this effect persisted when Bankart repair was compared with arthroscopic lavage alone (2 studies) (RR, 0.14; 95% CI, 0.06 to 0.31) or sling immobilization alone (2 studies) (RR, 0.26; 95% CI, 0.10 to 0.67). Western Ontario Shoulder Instability scores were better with anatomic Bankart repair compared with either arthroscopic lavage or immobilization (2 studies) (mean difference, -232; 95% CI, -317 to -146). CONCLUSIONS: There is evidence to suggest treatment of young patients with a first-time shoulder dislocation with anatomic Bankart repair with the goal of lowering the rate of recurrent instability over the long-term and improving short-term quality of life. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.