RESUMO
We identified a human mutation that causes dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (SNHL). Unlike previously described mutations causing dilated cardiomyopathy that affect structural proteins, this mutation deletes 4,846 bp of the human transcriptional coactivator gene EYA4. To elucidate the roles of eya4 in heart function, we studied zebrafish embryos injected with antisense morpholino oligonucleotides. Attenuated eya4 transcript levels produced morphologic and hemodynamic features of heart failure. To determine why previously described mutated EYA4 alleles cause SNHL without heart disease, we examined biochemical interactions of mutant Eya4 peptides. Eya4 peptides associated with SNHL, but not the shortened 193-amino acid peptide associated with dilated cardiomyopathy and SNHL, bound wild-type Eya4 and associated with Six proteins. These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function.
Assuntos
Cardiomiopatia Dilatada/genética , Perda Auditiva Neurossensorial/genética , Mutação/genética , Transativadores/genética , Peixe-Zebra/metabolismo , Animais , Northern Blotting , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Éxons/genética , Proteínas do Olho/genética , Coração/fisiopatologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imunoprecipitação , Hibridização In Situ , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/embriologia , Proteína Homeobox SIX3RESUMO
BACKGROUND: Several available compositional MRIs seem to detect early osteoarthritis before radiographic appearance. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) has been most frequently used in clinical studies and reportedly predicts premature joint failure in patients undergoing Bernese periacetabular osteotomies (PAOs). QUESTIONS/PURPOSES: We asked, given regional variations in biochemical composition in dysplastic hips, whether the dGEMRIC index of the anterior joint would better predict premature joint failure after PAOs than the coronal dGEMRIC index as previously reported. METHODS: We retrospectively reviewed 43 hips in 41 patients who underwent Bernese PAO for hip dysplasia. Thirty-seven hips had preserved joints after PAOs and six were deemed premature failures based on pain, joint space narrowing, or subsequent THA. We used dGEMRIC to determine regional variations in biochemical composition. Preoperative demographic and clinical outcome score, radiographic measures of osteoarthritis and severity of dysplasia, and dGEMRIC indexes from different hip regions were analyzed in a multivariable regression analysis to determine the best predictor of premature joint failure. Minimum followup was 24 months (mean, 32 months; range, 24-46 months). RESULTS: The two cohorts were similar in age and sex distribution. Severity of dysplasia was similar as measured by lateral center-edge, anterior center-edge, and Tönnis angles. Preoperative pain, joint space width, Tönnis grade, and coronal and sagittal dGEMRIC indexes differed between groups. The dGEMRIC index in the anterior weightbearing region of the hip was lower in the prematurely failed group and was the best predictor. CONCLUSIONS: Success of PAO depends on the amount of preoperative osteoarthritis. These degenerative changes are seen most commonly in the anterior joint. The dGEMRIC index of the anterior joint may better predict premature joint failure than radiographic measures of hip osteoarthritis and coronal dGEMRIC index. LEVEL OF EVIDENCE: Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence.
Assuntos
Cartilagem Articular/cirurgia , Meios de Contraste , Gadolínio DTPA , Luxação Congênita de Quadril/cirurgia , Articulação do Quadril/cirurgia , Imageamento por Ressonância Magnética , Osteoartrite do Quadril/cirurgia , Osteotomia/efeitos adversos , Adolescente , Adulto , Artroplastia de Quadril , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Distribuição de Qui-Quadrado , Feminino , Luxação Congênita de Quadril/diagnóstico por imagem , Luxação Congênita de Quadril/patologia , Articulação do Quadril/anormalidades , Articulação do Quadril/diagnóstico por imagem , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Análise Multivariada , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/patologia , Valor Preditivo dos Testes , Radiografia , Reoperação , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Adulto JovemRESUMO
BACKGROUND CONTEXT: Spinal epidural abscess (SEA) is a serious condition that can lead to significant morbidity and mortality if not expeditiously diagnosed and appropriately treated. However, the nonspecific findings that accompany SEAs often make its diagnosis difficult. Concurrent noncontiguous SEAs are even more challenging to diagnose because whole-spine imaging is not routinely performed unless the patient demonstrates neurologic findings that are inconsistent with the identified lesion. Failure to recognize a separate SEA can subject patients to a second operation, continued sepsis, paralysis, or even death. PURPOSE: To formulate a set of clinical and laboratory predictors for identifying patients with concurrent noncontiguous SEAs. STUDY DESIGN: A retrospective, case-control study. PATIENT SAMPLE: Patients aged 18 years or older admitted to our institution during the study period who underwent entire spinal imaging and were diagnosed with one or more SEAs. OUTCOME MEASURES: The presence or absence of concurrent noncontiguous SEAs on magnetic resonance imaging or computed tomography (CT)-myelogram. METHODS: A retrospective review was performed on 233 adults with SEAs who presented to our health-care system from 1993 to 2011 and underwent entire spinal imaging. The clinical and radiographic features of patients with concurrent noncontiguous SEAs, defined as at least two lesions in different anatomical regions of the spine (ie, cervical, thoracic, or lumbar), were compared with those with a single SEA. Multivariate logistic regression identified independent predictors for the presence of a skip SEA, and a prediction algorithm based on these independent predictors was constructed. Institutional review board committee approval was obtained before initiating the study. RESULTS: Univariate and multivariate analyses comparing patients with skip SEA lesions (n=22) with those with single lesions (n=211) demonstrated significant differences in three factors: delay in presentation (defined as symptoms for ≥7 days), a concomitant area of infection outside the spine and paraspinal region, and an erythrocyte sedimentation rate of >95 mm/h at presentation. The predicted probability for the presence of a skip lesion was 73% for patients possessing all three predictors, 13% for two, 2% for one, and 0% for zero predictors. Receiver operating characteristic curve analysis, used to evaluate the predictive accuracy of the model, revealed a steep shoulder with an area under the curve of 0.936 (p<.001). CONCLUSIONS: The proposed set of three predictors may be a useful tool in predicting the risk of a skip SEA lesion and, consequently, which patients would benefit from entire spinal imaging.
Assuntos
Abscesso Epidural/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Estudos de Casos e Controles , Abscesso Epidural/diagnóstico por imagem , Abscesso Epidural/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Estudos Retrospectivos , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Adulto JovemRESUMO
STUDY DESIGN: A retrospective radiological study. OBJECTIVE: To analyze the course of intra-axial vertebral artery (IAVA) and evaluate the relationship between the 3-dimensional (3D) courses for IAVA with respect to safe trajectory for C2 pedicle screw (C2PS). SUMMARY OF BACKGROUND DATA: The VA at the level of C2 has a distinct 3D course. The traditional concept of "high riding (HR)" VA was based on sagittal plane but does not provide all the 3D course of IAVA for safe C2PS placement. However, 3D course of IAVA has not been previously analyzed. METHODS: Three-dimensional, vascular-enhanced computed tomographic scans on the cervical spine of 100 patients, 200 IAVA (male to female ratio = 50:50; mean age, 58.4 yr) were analyzed. (1) The arterial parameters including (1) "medial-shifting (MS)" (A: lateral, B: neutral, C: medial to C3 transverse foramen [TF]) and (2) "HR" (0: below C2TF, 1 within C2TF, 2: above C2TF) of IAVA was measured. (2) The bony parameters including pedicle diameter, medial convergence angle, and sagittal angle of C2PS were measured. Correlation between the arterial and bony parameters, differences between sex, laterality, dominance of VA, and age were analyzed. RESULTS: MS (grade A, 37.5%; B, 37%; and C, 25.5%) and HR (grade 0 in 34%, 1 in 42%, and 2 in 24%) showed significant correlation with each other (P < 0.001). The main patterns of IAVA were A-0 (26%), B-1 (26.5%), and C-2 (18.5%). Higher grade of MS and HR showed significantly smaller pedicle diameter, larger medial convergence angle, and smaller sagittal angle (P < 0.001). Female sex and older age are factors that showed significantly higher grade of MS and HR (P < 0.001). CONCLUSION: Tortuosity of IAVA was greater in the female sex and it also increased with aging. The different IAVA courses significantly influenced the pedicle diameter and the safe trajectory for C2PS; therefore, these factors should be considered before planning C2 pedicle screw placement. LEVEL OF EVIDENCE: 3.
Assuntos
Vértebras Cervicais/cirurgia , Procedimentos Ortopédicos , Parafusos Pediculares , Artéria Vertebral/cirurgia , Adulto , Idoso , Feminino , Humanos , Imageamento Tridimensional/métodos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND CONTEXT: The notion that all patients with spinal epidural abscess (SEA) require surgical decompression has been recently challenged by reports of successful medical management of select patients with SEA. PURPOSE: The purpose of this study was to identify the independent variables that determine success or failure of medical management of SEA. STUDY DESIGN/SETTING: This was a retrospective, case-control study. PATIENT SAMPLE: Patients 18 years or older with diagnosis of SEA admitted to our institution during the study period were included in the sample. OUTCOME MEASURES: The outcome measure was successful management of SEA by eradication of the infection without worsening of neurologic deficits. METHODS: All patients admitted to our health-care system with a diagnosis of SEA from 1993 to 2011 were identified and the data were retrospectively collected. Patients 18 years or older diagnosed with SEA were included. Excluded were those with postsurgical SEA or phlegmon without an abscess and those with a complete spinal cord injury from SEA for longer than 48 hours. RESULTS: A total of 355 patients with average age of 60 years met our inclusion criteria. Of the patients who initially underwent nonoperative treatment, 54 patients failed medical management and 73 patients were successfully treated without surgery. Univariate and multivariate analysis identified incomplete or complete spinal cord deficits as the most significant risk factor for failure of medical management. Age older than 65 years, diabetes, and methicillin-resistant Staphylococcus aureus (MRSA) were also independent risk factors for failure. An algorithm for probability of failed antibiotic management of spinal epidural abscess predicted 99% probability of failure for patients with all four of these risk factors. CONCLUSIONS: SEA treated with medical management alone has a very high risk for failure if the patient is older than 65 years with diabetes, MRSA infection, or neurologic compromise. In the absence of these risk factors, nonoperative management of spinal epidural abscess may be considered as the initial line of treatment with close monitoring.
Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas do Sistema Nervoso Central/tratamento farmacológico , Descompressão Cirúrgica , Abscesso Epidural/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Infecções Bacterianas do Sistema Nervoso Central/cirurgia , Abscesso Epidural/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Retratamento , Estudos Retrospectivos , Fatores de Risco , Infecções Estafilocócicas/cirurgia , Falha de Tratamento , Adulto JovemRESUMO
STUDY DESIGN: Retrospective and radiological analysis of spinopelvic sagittal alignment in Chinese patients with thoracic and thoracolumbar kyphosis. OBJECTIVE: To determine the impact of thoracic and thoracolumbar kyphosis on pelvic sagittal morphology and the mechanisms of adjusting trunk sagittal balance. SUMMARY OF BACKGROUND DATA: Previous studies have reported the normative values of pelvic sagittal parameters and classification of normal patterns of sagittal curvature, but no study has analyzed the impact of thoracic and thoracolumbar kyphosis on pelvic sagittal morphology and the mechanisms of maintaining the sagittal balance. METHODS: Whole spine and standing lateral radiographs of 49 Chinese patients with thoracic and thoracolumbar kyphosis were obtained before surgery, immediately after surgery, and in the final follow-up. The pelvic and spinal parameters were measured and the correlations of all parameters were analyzed. A descriptive analysis characterizing these parameters and a multivariate analysis were performed. RESULTS: The patients had a mean age of 30.3 years, whereas the mean age at which the patients who developed kyphosis was 7.1 years. Preoperative pelvic incidence was significantly less than that of normal subjects, and there was no difference in the preoperative, in the immediate postoperative, and in the final follow-up radiographs. The magnitude of kyphosis and the levels involved were independent factors of pelvic incidence. Pelvis anteversion and lumbar hyperlordosis were the mechanisms of adjusting the trunk sagittal balance. Although kyphosis and sagittal imbalance was corrected by surgery, pelvic sagittal morphology remained unchanged. CONCLUSION: Thoracic and thoracolumbar angular kyphosis occurring during the growth period will lead to abnormal pelvic morphology. The greater the kyphotic angle and lower the kyphotic levels, the greater the impact on the pelvic morphology during skeletal maturation. The mechanisms of adjusting the trunk sagittal balance not only include pelvis anteverting, but also lumbar hyperlordosis. The latter serves as the main mechanism once skeletal maturation has been established. After skeletal maturation, surgery can re-establish the spinal sagittal balance but not the pelvis morphology. LEVEL OF EVIDENCE: 3.
Assuntos
Cifose/cirurgia , Vértebras Lombares/cirurgia , Pelve/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Cifose/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Período Pós-Operatório , Período Pré-Operatório , Radiografia/métodos , Estudos Retrospectivos , Vértebras Torácicas/diagnóstico por imagem , Adulto JovemRESUMO
The cardiac conduction system (CCS)-lacZ insertional mouse mutant strain genetically labels the developing and mature CCS. This pattern of expression is presumed to reflect the site of transgene integration rather than regulatory elements within the transgene proper. We sought to characterize the genomic structure of the integration locus and identify nearby gene(s) that might potentially confer the observed CCS-specific transcription. We found rearrangement of chromosome 7 between regions D1 and E1 with altered transcription of multiple genes in the D1 region. Several lines of evidence suggested that regulatory elements from at least one gene, Slco3A1, influenced CCS-restricted reporter gene expression. In embryonic hearts, Slco3A1 was expressed in a spatial pattern similar to the CCS-lacZ transgene and was similarly neuregulin-responsive. At later stages, however, expression patterns of the transgene and Slco3A1 diverged, suggesting that the Slco3A1 locus may be necessary, but not sufficient to confer CCS-specific transgene expression in the CCS-lacZ line.
Assuntos
Sistema de Condução Cardíaco/metabolismo , Óperon Lac/genética , Transgenes , Animais , Hibridização in Situ Fluorescente , Óperon Lac/fisiologia , Camundongos , Camundongos TransgênicosRESUMO
The La protein protects the 3' ends of many nascent small RNAs from exonucleases. Here we report that La is required for efficient folding of certain pre-tRNAs. A mutation in pre-tRNA(Arg)(CCG) causes yeast cells to be cold-sensitive and to require the La protein Lhp1p for efficient growth. When the mutant cells are grown at low temperature, or when Lhp1p is depleted, mature tRNA(Arg)(CCG) is not efficiently aminoacylated. The mutation causes the anticodon stem of pre-tRNA(Arg)(CCG) to misfold into an alternative helix in vitro. Intragenic suppressor mutations that disrupt the misfolded helix or strengthen the correct helix alleviate the requirement for Lhp1p, providing evidence that the anticodon stem misfolds in vivo. Chemical and enzymatic footprinting experiments suggest a model in which Lhp1p stabilizes the correctly folded stem. Lhp1p is also required for efficient aminoacylation of two wild-type tRNAs when yeast are grown at low temperature. These experiments reveal that pre-tRNAs can require protein assistance for efficient folding in vivo.