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STUDY DESIGN: Case report. PURPOSE: The purpose of this case report is to illustrate the utility of ECMO as possible treatment in the management of perioperative massive pulmonary embolism (PE) during spine surgery. We present a case report of an intra-operative massive PE managed with ECMO and review relevant literature of perioperative massive PE. Treatment poses substantial risk given the need for anticoagulation. ECMO has not previously been described in the management of this condition in spine surgery. METHODS: The patient is a 75-year-old male with hypertension, diabetes mellitus type II, chronic obstructive pulmonary disease, and prior cerebral infarction with minimal residual deficits who presented for Lumbar 2-Sacral 1 (L2-S1) revision posterior spinal decompression and fusion with L3-4 TLIF (Transforaminal Lumbar Interbody Fusion). The operation was routine until removing him from the operative table when he suffered a massive pulmonary embolism. RESULTS: The patient became extremely unstable hemodynamically requiring massive doses of three vasopressors. He was too unstable for additional imaging or to transport for mechanical thrombectomy so with the guidance of our cardiologist we initiated ECMO. The patient ultimately recovered well and was discharged from the hospital at his neurological baseline and preserved cardiac function. CONCLUSION: ECMO is a viable option for management of acute perioperative massive pulmonary embolism when less invasive treatments are not sufficient.
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Oxigenação por Membrana Extracorpórea , Embolia Pulmonar , Fusão Vertebral , Humanos , Masculino , Idoso , Oxigenação por Membrana Extracorpórea/métodos , Vértebras Lombares/cirurgia , Fusão Vertebral/efeitos adversos , Embolia Pulmonar/etiologia , Embolia Pulmonar/terapiaRESUMO
OBJECTIVE: The current Roussouly classification identifies four groups of "normal" sagittal spine morphology, which has greatly expanded the understanding of normal heterogeneity of the spine. While there has been extensive characterization of the influence of spinopelvic parameters on outcomes after degenerative spine surgery, the influence of spinopelvic parameters on thoracolumbar trauma has yet to be described. The goal of this study was to determine if spinopelvic parameters and global spine morphology influence fracture location, fracture morphology, and rate of neurological deficit in the setting of thoracolumbar trauma. METHODS: Of 2896 patients reviewed in the authors' institutional spine database between January 2014 and April 2020 with an ICD-9/10 diagnosis of thoracolumbar trauma, 514 met the inclusion criteria of acute thoracolumbar fracture on CT and visible femoral heads on sagittal CT. Pelvic incidence (PI) was calculated on sagittal CT. Demographic and clinical data including age, sex, BMI, smoking status, concomitant cervical fracture, mechanism of injury, major fracture location, neurological deficit, AO Spine thoracolumbar injury classification, and management type (operative vs nonoperative) were collected. Patients were stratified into high-PI (≥ 50°) and low-PI (< 50°) groups. RESULTS: Patients with high PI had a lower incidence of fractures in the lower lumbar spine (below L2) compared with patients with low PI (16% vs 8%, p < 0.01). The last lordotic vertebrae were observed between T10 and L4, and of fractures that occurred at these levels, 75% were at the last lordotic vertebrae. Fall from height was the most common cause of neurological deficit, accounting for 47%. Of the patients presenting with a fall from height, AO Spine type B distraction injuries were more common in the high-PI group (41% vs 18%, p = 0.01). Similarly, within the same subgroup, AO Spine type A compression injuries were more common in the low-PI group (73% vs 53%, p = 0.01). CONCLUSIONS: Spinopelvic parameters and sagittal balance influence the location and morphology of thoracolumbar fractures. Fractures of the thoracolumbar junction are strongly associated with the inflection point, which is defined by sagittal alignment. While the importance of considering sagittal balance is known for decision-making in degenerative spinal pathology, further studies are required to determine if spinopelvic parameters and sagittal balance should play a role in the decision-making for management of thoracolumbar fractures.
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Lordose , Fraturas da Coluna Vertebral , Traumatismos da Coluna Vertebral , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Lordose/diagnóstico por imagem , Traumatismos da Coluna Vertebral/complicações , Radiografia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgiaRESUMO
We examine the use of synchronization as a mechanism for extracting parameter and state information from experimental systems. We focus on important aspects of this problem that have received little attention previously and we explore them using experiments and simulations with the chaotic Colpitts oscillator as an example system. We explore the impact of model imperfection on the ability to extract valid information from an experimental system. We compare two optimization methods: an initial value method and a constrained method. Each of these involves coupling the model equations to the experimental data in order to regularize the chaotic motions on the synchronization manifold. We explore both time-dependent and time-independent coupling and discuss the use of periodic impulse coupling. We also examine both optimized and fixed (or manually adjusted) coupling. For the case of an optimized time-dependent coupling function u(t) we find a robust structure which includes sharp peaks and intervals where it is zero. This structure shows a strong correlation with the location in phase space and appears to depend on noise, imperfections of the model, and the Lyapunov direction vectors. For time-independent coupling we find the counterintuitive result that often the optimal rms error in fitting the model to the data initially increases with coupling strength. Comparison of this result with that obtained using simulated data may provide one measure of model imperfection. The constrained method with time-dependent coupling appears to have benefits in synchronizing long data sets with minimal impact, while the initial value method with time-independent coupling tends to be substantially faster, more flexible, and easier to use. We also describe a method of coupling which is useful for sparse experimental data sets. Our use of the Colpitts oscillator allows us to explore in detail the case of a system with one positive Lyapunov exponent. The methods we explored are easily extended to driven systems such as neurons with time-dependent injected current. They are expected to be of value in nonchaotic systems as well. Software is available on request.
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BACKGROUND: Proximal junctional kyphosis (PJK) is a common problem after multilevel spine instrumentation. OBJECTIVE: To determine if junctional tethers reduce PJK after multilevel instrumented surgery for adult spinal deformity (ASD). METHODS: ASD patients who underwent posterior instrumented fusion were divided into 3 groups: no tether (NT), polyethylene tether-only (TO; tied securely through the spinous processes of the uppermost instrumented vertebra [UIV] + 1 and UIV-1), and tether with crosslink (TC; passed through the spinous process of UIV+1 and tied to a crosslink between UIV-1 and UIV-2). PJK was defined as proximal junctional angle ≥ 10° and ≥ 10° greater than the corresponding preoperative measurement. RESULTS: One hundred eighty-four (96%) of 191 consecutive patients achieved minimum 3-mo follow-up (mean = 20 mo [range:3-56 mo]; mean age = 66 yr; 67.4% female). There were no significant differences between groups based on demographic, surgical, and sagittal radiographic parameters. PJK rates were 45.3% (29/64), 34.4% (22/64), and 17.9% (10/56) for NT, TO, and TC, respectively. PJK rate for all tethered patients (TO + TC; 26.7% [32/120]) was significantly lower than NT (P = .011). PJK rate for TC was significantly lower than NT (P = .001). Kaplan-Meier analysis showed significant time-dependent PJK reduction for TC vs NT (log rank test, P = .010). Older age and greater change in lumbar lordosis were independent predictors of PJK, while junctional tethers had a significant protective effect. CONCLUSION: Junctional tethers significantly reduced occurrence of PJK. This difference was progressive from NT to TO to TC, but only reached pairwise significance for NT vs TC. This suggests potential benefit of tethers to reduce PJK, and that future prospective studies are warranted.
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Cifose/prevenção & controle , Polietileno , Complicações Pós-Operatórias/prevenção & controle , Curvaturas da Coluna Vertebral/cirurgia , Fusão Vertebral/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Radiografia , Estudos Retrospectivos , Fusão Vertebral/instrumentação , Técnicas de Sutura/instrumentaçãoRESUMO
Pedicle subtraction osteotomy (PSO) is an effective technique to correct fixed sagittal malalignment. A variation of this technique, the "trans-discal" or "extended" PSO (Schwab grade IV osteotomy), involves extending the posterior wedge resection of the index vertebra to include the superior adjacent disc for radical discectomy. The posterior wedge may be resected in asymmetric fashion to correct concurrent global coronal malalignment.This video illustrates the technical nuances of an extended asymmetrical lumbar PSO for adult spinal deformity. A 62-yr-old female with multiple prior lumbar fusions presented with worsening back pain and posture. Preoperative scoliosis X-rays demonstrated severe global sagittal and coronal malalignment (sagittal vertical axis [SVA, C7-plumbline] of 13.5 cm, pelvic incidence [PI] of 60°, lumbar lordosis [LL] of 14° [in kyphosis], pelvic tilt [PT] of 61°, thoracic kyphosis [TK] of 18°, and rightward coronal shift of 9.3 cm). The patient gave informed consent to surgery and for use of her imaging for medical publication. Briefly, surgery first involved transpedicular instrumentation from T10 to S1 with bilateral iliac screw fixation, and then T11-12 and T12-L1 Smith-Petersen osteotomies were performed. Next, an extended asymmetrical L4 PSO was performed and a 12° lordotic cage (9 × 14 × 40 mm) was placed at the PSO defect. Rods were placed from T10 to iliac bilaterally, and accessory supplemental rods spanning the PSO were attached. Postoperative scoliosis X-rays demonstrated improved alignment: SVA 5.5 cm, PI 60°, LL 55°, PT 36°, TK 37°, and 3.7 cm of rightward coronal shift. The patient had uneventful recovery.
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OBJECTIVE: The aims of this retrospective cohort study were to 1) identify new alignment risk factors for proximal junctional kyphosis (PJK) in adult spinal deformity (ASD) patients with lower thoracic upper instrumented vertebra (UIV) and 2) determine the effect of junctional tethers on PJK and UIV alignment. METHODS: We analyzed consecutive ASD patients who underwent posterior instrumented fusion with lower thoracic UIV (T9-T11). Posteriorly anchored junctional tethers were used more recently for ligamentous augmentation to prevent PJK. In addition to regional and global parameters, upper segmental lumbar lordosis (ULL) versus lower segmental lumbar lordosis and UIV angle (measured from UIV inferior endplate to horizontal) were assessed. Primary outcome of PJK was defined as proximal junctional angle >10° and >10° greater than the corresponding preoperative measurement. Univariable and multivariable analyses were performed. RESULTS: The study cohort comprised 120 ASD patients (mean age, 67 years) with minimum 1-year follow-up. Preoperative ULL (P = 0.034) and UIV angle (P = 0.026) were associated with PJK. No independent preoperative alignment risk factors of PJK were identified in multivariable analysis. Tether use was protective against PJK (odds ratio, 0.063 [0.016-0.247]; P < 0.001). PJK in tethered patients was more common with greater postoperative ULL (P = 0.047) and UIV angle (P = 0.026). CONCLUSIONS: Junctional tethers significantly reduced PJK in ASD patients with lower thoracic UIV. In tethered patients, PJK was more common with greater postoperative lordosis of the upper lumbar spine and greater UIV angle. This finding suggests potential benefit of tethers to mitigate effects of segmental lumbar and focal UIV malalignment that may occur after deformity surgery.
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Cifose/etiologia , Fusão Vertebral/efeitos adversos , Coluna Vertebral/anormalidades , Idoso , Feminino , Humanos , Lordose/etiologia , Vértebras Lombares/cirurgia , Masculino , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Coluna Vertebral/cirurgia , Vértebras Torácicas/cirurgiaRESUMO
Cervical spine sagittal malalignment correlates with worse symptoms and outcomes in patients with degenerative cervical myelopathy (DCM), and should influence surgical management. An anterior versus posterior surgical approach may not significantly change outcomes in patients with preoperative lordosis; however, most studies suggest improved neurologic recovery among kyphotic patients after adequate correction of local sagittal alignment through an anterior or combined anterior-posterior approach. There are no comprehensive guidelines for DCM management in the setting of cervical malalignment; therefore, surgical management should be tailored to individual patients and decisions made at the discretion of treating surgeons with attention to basic principles.
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Vértebras Cervicais/cirurgia , Doenças da Medula Espinal/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Descompressão Cirúrgica , Progressão da Doença , Humanos , Radiografia , Doenças da Medula Espinal/diagnóstico por imagem , Resultado do TratamentoRESUMO
We present a novel salvage technique for pediatric subaxial cervical spine fusion in which lateral mass screw fixation was not possible due to anatomic constraints. The case presentation details a 4-year-old patient with C5-C6 flexion/distraction injury with bilateral jumped facets. Posterior cervical fixation was attempted; however, lateral mass fracture occurred during placement of screws. Using a wire-screw construct, an attempt was made to provide stable fixation. The patient was followed post-operatively for assessment of outcomes. After the patient had progressive kyphosis following initial closed reduction and external orthosis, internal reduction with fusion/fixation was performed. Lateral mass fracture occurred during placement of lateral mass screws. After placement of a sub-laminar wire-lateral mass screw construct, intra-operative evaluation determined stability. Post-operatively, the procedure resulted in stable fixation with evidence of bony fusion on follow-up. Pediatric subaxial cervical spine instrumentation provides rigid fixation however is technically difficult due to anatomic and instrumentation related constraints. In the presented patient, the wire-screw construct resulted in stable fixation and bony fusion on follow-up. A modified sublaminar wire-lateral mass screw construct is an example of a salvage technique that provides immediate stability in the event of instrumentation related lateral mass fracture.
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Fraturas Ósseas/etiologia , Fraturas Ósseas/cirurgia , Fusão Vertebral/instrumentação , Fusão Vertebral/métodos , Parafusos Ósseos , Vértebras Cervicais/cirurgia , Criança , Feminino , Humanos , Cifose/etiologia , Cifose/cirurgia , Masculino , Reoperação/instrumentação , Reoperação/métodos , Terapia de Salvação , Fusão Vertebral/efeitos adversosRESUMO
BACKGROUND: Cervical spondylotic myelopathy (CSM) is a common indication for cervical spine surgery. Surgical options include anterior, posterior, or combined procedures each with specific advantages and disadvantages. QUESTIONS/PURPOSES: This article will provide a description of the various anterior alternatives and discuss the available evidence used in guiding the surgical decision making process with the aim of answering the following questions: (1) What anatomical/disease related factors favor anterior over posterior surgeries? (2) What are the common anterior procedures and how safe and effective are they? (3) What are the most effective options for multilevel CSM? (4) Is there a role for motion preservation? An additional objective is to discuss technical advances that have improved success rates for anterior procedures. METHODS: The PubMed database was searched. Keywords were CSM and anterior surgery. Three hundred eighty two articles were found one hundred three were reviewed. Articles describing anterior cervical techniques were selected along with studies describing the various anterior techniques or comparisons of anterior to posterior techniques. RESULTS: Anterior decompression and fusion procedures are more effective than posterior procedures for patients with primarily ventrally located compression especially in the presence of cervical kyphosis. ACDF, ACCF, and hybrid combinations are safe and effective treatment options for multilevel CSM. Anterior procedures may be more cost effective and result in significantly improved postoperative quality of life and health-related quality of life measures compared to posterior procedures. CONCLUSION: Anterior cervical decompression techniques are safe and effective in the treatment of CSM. Anterior surgeries may be preferable to posterior approaches, when considering health-related quality of life measures and cost effectiveness.
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BACKGROUND: Cervical spondylosis is now recognised as the leading cause of myelopathy and spinal cord dysfunction worldwide. Chronic spinal cord compression results in chronic inflammation, cellular apoptosis, and microvacular insufficiency, which are thought to the biologic basis for cervical spondylotic myelopathy (CSM). QUESTIONS/PURPOSES: Our purpose was to address the key principles of CSM, including natural history and presentation, pathogenesis, optimal surgical approach, results and complication rates of posterior surgical approaches for CSM so that the rationale for addressing CSM by a posterior approach can be fully understood. METHODS: We conducted a systematic search of PubMed/MEDLINE and the Cochrane Collaboration Library for literature published through February 2014 to identify articles that evaluated CSM and its management. Reasons for exclusion included patients with ossification of the posterior longitudinal ligament (OPLL), patients with degenerative disc disease without CSM, and patients with spine tumor, trauma and infection. Meeting abstracts/proceedings, white articles and editorials were additionally excluded. RESULTS: The search strategy yielded 1,292 articles, which was reduced to 52 articles, after our exclusion criteria were introduced. CSM is considered to be a surgical disorder due to its progressive nature. There is currently no consensus in the literature whether multilevel spondylotic compression is best treated via an anterior or posterior surgical approach. CONCLUSION: Multilevel CSM may be safely and effectively treated using a posterior approach, either by laminoplasty or with a laminectomy and fusion technique.
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STUDY DESIGN: Observational study. OBJECTIVE: To demonstrate use of magnetic resonance (MR) neurography to visualize the course of the lumbar plexus at the L4-L5 disc space. SUMMARY OF BACKGROUND DATA: Risk of injury to the lumbar plexus during lateral transpsoas approach for lumbar interbody fusion (LLIF) is significant. We describe a new technique for preoperative mapping using magnetic resonance neurography to directly visualize the course of the plexus relative to the L4-L5 disc space. METHODS: Consecutive lumbar plexus MR neurograms (n=35 patients, 70 sides) were studied. Scans were obtained on a Siemens 3-Tesla Skyra magnetic resonance imaging scanner. T1- and T2-color-coded fusion maps were generated along with 3-dimensional models of the lumbosacral plexus with attention to the L4-L5 interspace. The position of the plexus and the shape of the psoas muscle at the L4-L5 interspace were evaluated and recorded. RESULTS: Direct imaging of the lumbar plexus using MR neurography revealed a substantial variability in the position of the lumbar plexus relative to the L4-L5 disc space. The left-side plexus was identified in zone 2 (5.7%), zone 3 (54.3%), and zone 4 (40%) (P = 0.0014); on the right, zone 2 (8.6%), zone 3 (42.9%) or zone 4 (45.7%), and zone 5 (2.9%) (P = 0.01). Right-left symmetry was found in 18 of 35 subjects (51.4%) (P = 0.865). There was no association between the position of the plexus and the shape of the overlying psoas muscle identified. In patients with an elevated psoas (n = 12), the lumbar plexus was identified in zone 3 in 75% and 66% (left and right) compared with patients without psoas elevation (n = 23), 30.4% and 43.5% (left and right). CONCLUSION: The course of the lumbosacral plexus traversing the L4-L5 disc space may be more variable than has been suggested by previous studies. Magnetic resonance neurography may provide a more reliable means of preoperatively identifying the plexus when compared with current methods. LEVEL OF EVIDENCE: 3.
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Pontos de Referência Anatômicos , Disco Intervertebral/inervação , Vértebras Lombares/inervação , Plexo Lombossacral/anatomia & histologia , Imageamento por Ressonância Magnética , Músculos Psoas/anatomia & histologia , Fusão Vertebral/métodos , Cirurgia Assistida por Computador , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Disco Intervertebral/patologia , Disco Intervertebral/cirurgia , Vértebras Lombares/patologia , Vértebras Lombares/cirurgia , Variações Dependentes do Observador , Traumatismos dos Nervos Periféricos/prevenção & controle , Valor Preditivo dos Testes , Músculos Psoas/cirurgia , Reprodutibilidade dos Testes , Fusão Vertebral/efeitos adversos , Cirurgia Assistida por Computador/efeitos adversosRESUMO
In statistical data assimilation one evaluates the conditional expected values, conditioned on measurements, of interesting quantities on the path of a model through observation and prediction windows. This often requires working with very high dimensional integrals in the discrete time descriptions of the observations and model dynamics, which become functional integrals in the continuous-time limit. Two familiar methods for performing these integrals include (1) Monte Carlo calculations and (2) variational approximations using the method of Laplace plus perturbative corrections to the dominant contributions. We attend here to aspects of the Laplace approximation and develop an annealing method for locating the variational path satisfying the Euler-Lagrange equations that comprises the major contribution to the integrals. This begins with the identification of the minimum action path starting with a situation where the model dynamics is totally unresolved in state space, and the consistent minimum of the variational problem is known. We then proceed to slowly increase the model resolution, seeking to remain in the basin of the minimum action path, until a path that gives the dominant contribution to the integral is identified. After a discussion of some general issues, we give examples of the assimilation process for some simple, instructive models from the geophysical literature. Then we explore a slightly richer model of the same type with two distinct time scales. This is followed by a model characterizing the biophysics of individual neurons.
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OBJECT: The Internet has become a widespread source for disseminating health information to large numbers of people. Such is the case for spine surgery as well. Given the complexity of spinal surgeries, an important point to consider is whether these resources are easily read and understood by most Americans. The average national reading grade level has been estimated to be at about the 7th grade. In the present study the authors strove to assess the readability of open spine surgery resources and minimally invasive spine surgery resources to offer suggestions to help improve the readability of patient resources. METHODS: Online patient education resources were downloaded in 2013 from 50 resources representing either traditional open back surgery or minimally invasive spine surgery. Each resource was assessed using 10 scales from Readability Studio Professional Edition version 2012.1. RESULTS: Patient education resources representing traditional open back surgery or minimally invasive spine surgery were all found to be written at a level well above the recommended 6th grade level. In general, minimally invasive spine surgery materials were written at a higher grade level. CONCLUSIONS: The readability of patient education resources from spine surgery websites exceeds the average reading ability of an American adult. Revisions may be warranted to increase quality and patient comprehension of these resources to effectively reach a greater patient population.
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Internet , Procedimentos Cirúrgicos Minimamente Invasivos , Procedimentos Neurocirúrgicos , Educação de Pacientes como Assunto , Leitura , Doenças da Coluna Vertebral/cirurgia , Adulto , Compreensão , HumanosRESUMO
OBJECTIVE AND IMPORTANCE: Currently, n-butyl cyanoacrylate (n-BCA) is one of the most widely used liquid embolic agents in the treatment of intracranial arteriovenous malformations (AVMs). The cases of three patients are reported who underwent endovascular embolization with n-BCA, followed by resection in two and post-embolization hemorrhage with emergent evacuation in one, with histologic demonstration of an eosinophilic vasculitis found in resected AVM specimens. This is probably the first report of this tissue reaction, which may have theoretically serious clinical implications. CLINICAL PRESENTATION: In this series, three patients (2 women, 1 man) presented with intracranial AVMs (Spetzler-Martin I-III) with the lesions located in the frontal lobe in two of the patients and in the parietal lobe in one. All patients presented with headache, and one also had new-onset seizures. INTERVENTION: All patients underwent embolization with n-BCA before a planned, staged surgical resection of the embolized AVMs. One patient had four embolizations over a 5-month period, one had three embolizations over 3 months complicated by hemorrhage after embolization requiring emergent evacuation of the hematoma, and the third patient had a single embolization. In all three patients, surgical and autopsy specimens showed an inflammatory response within the embolized vasculature with a prominent eosinophilic infiltrate. CONCLUSION: The eosinophilic vasculitis seen in the pathology specimens may represent a previously undocumented hypersensitivity reaction following exposure to n-BCA, with the potential for adverse sequelae, including increased risk of hemorrhage as was seen in one of our patients.
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Embolização Terapêutica/efeitos adversos , Embucrilato/efeitos adversos , Eosinófilos/citologia , Malformações Arteriovenosas Intracranianas/terapia , Vasculite/etiologia , Angiografia Cerebral , Embucrilato/uso terapêutico , Feminino , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Humanos , Malformações Arteriovenosas Intracranianas/cirurgia , Masculino , Lobo Parietal/patologia , Lobo Parietal/cirurgia , Resultado do TratamentoRESUMO
The mechanisms by which homeoproteins bind selectively to target genes in vivo have long remained unresolved. Here we report that PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein by regulating its subnuclear localization and proximity to target genes. We demonstrate that the interaction of Msx1 with PIAS1, but not its sumoylation, is required for Msx1 to function as an inhibitor of myoblast differentiation through repression of myogenic regulatory genes, such as MyoD. We find that PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells and to distinguish the CER from other nonregulatory TAAT-containing sequences. We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. Furthermore, we demonstrate that myogenic regulatory genes that are repressed by Msx1, namely MyoD and Myf5, are located at the nuclear periphery in myoblast cells. We propose that a key regulatory event for DNA-binding specificity by homeoproteins in vivo is their appropriate targeting to subnuclear compartments where their target genes are located, which can be achieved by cofactors such as PIAS1.
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DNA/metabolismo , Fator de Transcrição MSX1/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Animais , Sítios de Ligação/genética , Linhagem Celular , Núcleo Celular/metabolismo , DNA/genética , Humanos , Fator de Transcrição MSX1/genética , Camundongos , Modelos Biológicos , Desenvolvimento Muscular , Mioblastos/metabolismo , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Técnicas do Sistema de Duplo-Híbrido , Ubiquitina-Proteína Ligases/metabolismoRESUMO
5-Hydroxytryptamine (5-HT)(2A) receptors have been implicated to play a role in both the treatment and pathophysiology of a number of psychiatric disorders. Therefore, the coupling of this receptor to signals, such as extracellular signal-regulated kinase (ERK), that elicit long-term neuronal changes may be relevant. In the present study we examined the coupling of the G(q)-coupled receptor to ERK in PC12 cells, a cell line commonly used as a neuronal model system. Activation of ERK occurred through a pathway different than the protein kinase C-dependent pathways described previously in studies of non-neuronal cells. Activation of ERK, in PC12 cells, was inhibited by both chelation of extracellular Ca(2+) and by depletion of intracellular Ca(2+) stores. Surprisingly, activation was not inhibited, but actually potentiated, by a variety of protein kinase C inhibitors covering all known protein kinase C isoforms. In contrast, the coupling of receptor to activation of ERK was found to be sensitive to N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7) and N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide (W13), inhibitors of calmodulin, but not to 1-(N,O-bis[5-isoquinolinesulfonyl]-N-methyl-L-tyrosyl)-4-phenylpiperazine (KN62) and 2-[N-(2-hydroxyethyl)]-N-4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) (KN93), inhibitors of calmodulin-dependent protein kinase. Additionally, the general tyrosine kinase inhibitor genistein, as well as the Src inhibitor PP1 and the epidermal growth factor receptor kinase inhibitor 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG 1478), inhibited receptor-mediated activation of ERK, suggesting a role for tyrosine kinases. In fact, 5-HT was found to stimulate tyrosine phosphorylation of a number of proteins, and this phosphorylation was inhibited by W7. 5-HT(2A) receptor-activation of ERK through a protein kinase C-independent pathway requiring Ca(2+)/calmodulin/tyrosine kinases represents a pathway distinct from those described in studies of non-neuronal cells.