RESUMO
Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment ("drug on"), the impact of drug withdrawal ("drug off") implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment ("drug on") and subsequent withdrawal ("drug off") through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.
Assuntos
Regeneração Óssea/efeitos dos fármacos , Fraturas Ósseas/genética , MAP Quinase Quinase Quinases/genética , Células-Tronco Mesenquimais/enzimologia , Osteoblastos/enzimologia , Cicatrização/genética , Animais , Regeneração Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Nucleotidiltransferases/genética , DNA Nucleotidiltransferases/metabolismo , Feminino , Efeito Fundador , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/enzimologia , Fraturas Ósseas/patologia , Regulação da Expressão Gênica , Integrases/genética , Integrases/metabolismo , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/deficiência , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Crânio/efeitos dos fármacos , Crânio/lesões , Crânio/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
Decompressive craniectomy is an increasingly implemented intervention for relief of intracranial hypertension refractory to medical therapy. Despite its therapeutic benefit, a myriad of short and long-term complications may arise when the once fixed-volume cranial vault remains decompressed. The authors present a case of recurrent Syndrome of the Trephined in a patient undergoing repeated craniectomy and cranioplasty.A 70-year old male with history significant for smoking and chronic obstructive pulmonary disease presented with frontoparietal subdural hematoma with midline shift following a ground level fall necessitating craniotomy and hematoma evacuation. Three months postoperatively, the patient developed an infection of his craniotomy bone flap necessitating craniectomy without cranioplasty. Six weeks post-craniectomy the patient began demonstrating right sided sensorimotor deficits with word finding difficulties. Alloplastic cranioplasty was performed following resolution of infection, with resolution of neurologic symptoms 6 weeks post cranioplasty. Due to recurrent cranioplasty infections, multiple alloplastic cranioplasties were performed, each with reliable re-demonstration of neurologic symptoms with craniectomy, and subsequent resolution following each cranioplasty. Final cranioplasty was successfully performed using a new alloplastic implant in combination with latissimus muscle flap, with subsequent return of neurologic function.Decompressive craniectomy is a life-saving procedure, but carries many short- and long-term complications, including the Syndrome of the Trephined. Our case is the first published report, to our knowledge, to demonstrate recurrent Syndrome of the Trephined as a complication of craniectomy, with reliable resolution of the syndrome with restoration of the cranial vault.
Assuntos
Crânio/cirurgia , Idoso , Humanos , Masculino , Complicações Pós-Operatórias , Procedimentos de Cirurgia Plástica , Crânio/diagnóstico por imagem , Retalhos Cirúrgicos/cirurgia , Resultado do TratamentoRESUMO
PURPOSE: Timing of bone grafting for maxillary alveolar clefts is not standardized. Secondary bone grafting is often performed; however, consensus does not exist regarding use of chronologic versus dental age to guide treatment. Several authors suggest an early chronologic age is associated with greater success. Available literature was systematically reviewed for evidence for optimal timing for grafting maxillary alveolar clefts. METHODS: PubMed, MEDLINE, and Cochrane Central Registrar of Controlled Trials databases were queried for manuscripts pertaining to maxillary alveolar cleft bone grafting. Inclusion criteria included manuscripts with level of evidence 4 or greater. Studies not using bone graft, lacking postoperative follow up, and clinical reports were excluded. Seventeen articles met criteria. RESULTS: Nine manuscripts recommended grafting based on dental age prior to eruption of the permanent canines, while 8 recommended grafting between ages 7 to 12. The most commonly reported complication was wound dehiscence, followed by graft-site infection. Ten studies used perioperative treatment protocols, 8 of which included preoperative and/or postoperative orthodontia for maxillary expansion. Correlation between chronologic age and success was not significant, but trended towards greater success with increasing age. CONCLUSION: Success of secondary grafting is high, but significant variability exists in the timing of grafting. Evidence is lacking to support specific chronologic age; rather, perioperative protocols, systematic surgical technique, and a multidisciplinary discussion are likely more substantial in achieving success, and may be confounders in studies where an early age at grafting appears associated with success. The timing of bone grafting for maxillary alveolar clefts would benefit from a prospective randomized study.
Assuntos
Enxerto de Osso Alveolar , Fissura Palatina/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Enxerto de Osso Alveolar/efeitos adversos , Enxerto de Osso Alveolar/métodos , Humanos , Tempo para o TratamentoRESUMO
BACKGROUND: Existing data suggest decreased willingness of plastic surgeons to participate in Medicare and Medicaid. Significant disparities exist in Medicare and Medicaid reimbursement for various general surgical procedures. The aims of this study were to investigate variations in Medicare and Medicaid reimbursement across the nation for common plastic surgery procedures. METHODS: Medicare and Medicaid reimbursement data for 2017 were obtained by means of the Centers for Medicare & Medicaid Services and publicly available fee schedules from each state, respectively, for eight common plastic surgery procedures. The difference in Medicare and Medicaid reimbursement was calculated across all states. The difference in value ascribed to each procedure was determined by comparing the payment from each payer to the work relative value units. RESULTS: Medicaid reimbursement rates were significantly lower for the selected procedures, with a median national discount of -25 percent ($16.09 per work relative value unit) compared to Medicare. There were higher median rates of reimbursement per work relative value unit by Medicaid in only five states when compared to Medicare. Significant variations of more than 15 percent in the Medicaid-to-Medicare reimbursement ratios between our selected procedures were identified in 28 states. CONCLUSIONS: Variations exist between Medicare and Medicaid reimbursement for common plastic surgery procedures. The within-state variations in Medicaid reimbursement are likely reflective of important yet nontransparent differences in determining Medicaid reimbursement. These variations likely affect access to care for underserved populations. Professional societies should continue to convey the value of these important procedures and raise awareness regarding disparities in access to care.
Assuntos
Medicaid/economia , Medicare/economia , Procedimentos de Cirurgia Plástica/economia , Mecanismo de Reembolso/estatística & dados numéricos , Disparidades em Assistência à Saúde/economia , Humanos , Planos Governamentais de Saúde/economia , Estados UnidosRESUMO
PURPOSE: Early treatment of heterotopic ossification (HO) is currently limited by delayed diagnosis due to limited visualization at early time points. In this study, we validate the use of spectral ultrasound imaging (SUSI) in an animal model to detect HO as early as one week after burn tenotomy. METHODS: Concurrent SUSI, micro CT, and histology at 1, 2, 4, and 9weeks post-injury were used to follow the progression of HO after an Achilles tenotomy and 30% total body surface area burn (n=3-5 limbs per time point). To compare the use of SUSI in different types of injury models, mice (n=5 per group) underwent either burn/tenotomy or skin incision injury and were imaged using a 55MHz probe on VisualSonics VEVO 770 system at one week post injury to evaluate the ability of SUSI to distinguish between edema and HO. Average acoustic concentration (AAC) and average scatterer diameter (ASD) were calculated for each ultrasound image frame. Micro CT was used to calculate the total volume of HO. Histology was used to confirm bone formation. RESULTS: Using SUSI, HO was visualized as early as 1week after injury. HO was visualized earliest by 4weeks after injury by micro CT. The average acoustic concentration of HO was 33% more than that of the control limb (n=5). Spectroscopic foci of HO present at 1week that persisted throughout all time points correlated with the HO present at 9weeks on micro CT imaging. CONCLUSION: SUSI visualizes HO as early as one week after injury in an animal model. SUSI represents a new imaging modality with promise for early diagnosis of HO.
Assuntos
Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/diagnóstico , Ultrassonografia/métodos , Animais , Modelos Animais de Doenças , Diagnóstico Precoce , Camundongos , Ossificação Heterotópica/patologia , Ossificação Heterotópica/cirurgia , Osteogênese/fisiologia , TenotomiaRESUMO
Thermal ring injuries are rarely reported in the literature. For this reason, treatment is varied without a standard approach. We describe a case of a thermal wedding ring injury sustained during a welding accident. It is critical to understand the 3 zones of burn injuries when managing these infrequent cases. Furthermore, the dynamic progression that ensues a thermal burn will directly affect outcome. A case is presented along with a graduated approach to the management of such injuries.
RESUMO
BACKGROUND: Tracking world cases of breast implant-associated anaplastic large cell lymphoma (ALCL) is currently limited to patient registries at a few academic centers, dependent upon patient referral and case reports in the literature. The purpose of this study was to review and compare federal database adverse event reports of breast implant-associated ALCL encompassing the major breast implant markets worldwide. METHODS: Federal implantable device regulatory bodies were contacted and database queries were performed for 40 countries. Demographics, device characteristics, pathology, treatment modalities, and outcomes were assessed when available. RESULTS: For the countries queried, 363 unique cases were reported for breast implant-associated ALCL. Search terms "anaplastic" and "ALCL" were queried of the U.S. Manufacturer and User Facility Device Experience (MAUDE) database and yielded 258 unique cases as of September 2015, of which only 130 had pathologic markers performed. Implant surface was textured significantly more than smooth (50 percent versus 4.2 percent; p = 0.0001). Treatment, when reported (n = 136), included explantation [n = 125 (91.9 percent)], chemotherapy [n = 42 (30.8 percent)], radiation therapy [n = 25 (18.4 percent)], and/or stem cell transplant [n = 9 (6.6 percent)], and five deaths were reported. CONCLUSIONS: Federal reporting of breast implant-associated ALCL has limitations in providing clinical history, treatment, and oncologic follow-up. Worldwide and country-specific total and textured implant sales data are needed to determine critical incidence and prevalence analysis. International multi-institutional collaborations and centralized tissue consortiums working in concert with federal authorities are necessary to acquire accurate complete data on breast implant-associated ALCL.
Assuntos
Implantes de Mama/efeitos adversos , Bases de Dados Factuais , Linfoma Anaplásico de Células Grandes/etiologia , Complicações Pós-Operatórias/etiologia , Vigilância de Produtos Comercializados , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , Saúde Global , Humanos , Cooperação Internacional , Linfoma Anaplásico de Células Grandes/epidemiologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologiaRESUMO
PURPOSE: Heterotopic ossification (HO) occurs in the setting of persistent systemic inflammation. The identification of reliable biomarkers can serve as an early diagnostic tool for HO, especially given the current lack of effective treatment strategies. Although serum biomarkers have great utility, they can be inappropriate or ineffective in traumatic acute injuries and in patients with fibrodysplasia ossificans progressiva (FOP). Therefore, the goal of this study is to profile the cytokines associated with HO using a different non-invasive source of biomarkers. METHODS: Serum and saliva were collected from a model of trauma-induced HO (tHO) with hind limb Achilles' tenotomy and dorsal burn injury at indicated time points (pre-injury, 48 h, 1 week, and 3 weeks post-injury) and a genetic non-trauma HO model (Nfatc1-Cre/caAcvr1fl/wt ). Samples were analyzed for 27 cytokines using the Bio-Plex assay. Histologic evaluation was performed in Nfatc1-Cre/caAcvr1fl/wt mice and at 48 h and 1 week post-injury in burn tenotomy mice. The mRNA expression levels of these cytokines at the tenotomy site were also quantified with quantitative real-time PCR. Pearson correlation coefficient was assessed between saliva and serum. RESULTS: Levels of TNF-α and IL-1ß peaked at 48 h and 1 week post-injury in the burn/tenotomy cohort, and these values were significantly higher when compared with both uninjured (p < 0.01, p < 0.03) and burn-only mice (p < 0.01, p < 0.01). Immunofluorescence staining confirmed enhanced expression of IL-1ß, TNF-α, and MCP-1 at the tenotomy site 48 h after injury. Monocyte chemoattractant protein-1 (MCP-1) and VEGF was detected in saliva showing elevated levels at 1 week post-injury in our tHO model when compared with both uninjured (p < 0.001, p < 0.01) and burn-only mice (p < 0.005, p < 0.01). The Pearson correlation between serum MCP-1 and salivary MCP-1 was statistically significant (r = 0.9686, p < 0.001) Similarly, the Pearson correlation between serum VEGF and salivary VEGF was statistically significant (r = 0.9709, p < 0.05). CONCLUSION: In this preliminary study, we characterized the diagnostic potential of specific salivary cytokines that may serve as biomarkers for an early-stage diagnosis of HO. This study identified two candidate biomarkers for further study and suggests a novel method for diagnosis in the context of current difficult diagnosis and risks of current diagnostic methods in certain patients.