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1.
Sci Adv ; 8(31): eabo5633, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35921423

RESUMO

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

2.
Plast Reconstr Surg Glob Open ; 9(3): e3448, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33747688

RESUMO

Cannabis use is increasingly prevalent. Cannabinoid receptors regulate pro-inflammatory cytokines, and compounds in marijuana exert diverse physiologic effects. As more patients use cannabis, clinicians should recognize implications of perioperative cannabis use. Although the role of cannabis use in perioperative pain control has been explored, little is known about its effect on perioperative wound healing or on hematologic, pulmonary, and cardiovascular physiology. METHODS: We searched PubMed for English-language articles related to cannabis (ie, marijuana, cannabidiol oil, and tetrahydrocannabinol) and wound healing, cardiovascular, pulmonary, or hematologic outcomes, and surgery. Titles and abstracts were reviewed, and relevant articles were analyzed. Human, animal, and pathology studies were included. Editorials, case reports, and review articles were excluded. RESULTS: In total, 2549 wound healing articles were identified; 5 human studies and 8 animal/pathology studies were included. Results were conflicting. An estimated 2900 articles related to cardiovascular effects were identified, of which 2 human studies were included, which showed tetrahydrocannabinol and marijuana caused tachycardia. A total of 142 studies regarding pulmonary effects were identified. Three human studies were included, which found no difference in respiratory complications. In total, 114 studies regarding hematologic effects were identified. The 3 included human studies found conflicting venous thromboembolism risks. The overall study quality was poor. Information about dose/duration, administration route, and follow-up was reported with variable completeness. CONCLUSIONS: Surgeons should consider effects of cannabis in the perioperative setting. Little is known about its perioperative effects on wound healing, or on cardiovascular, pulmonary, and hematologic physiology. Further research should elucidate the effects of administration route, dose, and timing of cannabis use among surgical patients.

3.
Arthritis Rheumatol ; 73(5): 858-865, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33258553

RESUMO

OBJECTIVE: This open-label 12-week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment-refractory active dermatomyositis (DM). METHODS: Tofacitinib in extended-release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid-sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety. RESULTS: At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin. CONCLUSION: This is the first prospective, open-label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan-JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.


Assuntos
Dermatomiosite/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Dermatomiosite/metabolismo , Dermatomiosite/fisiopatologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Projetos Piloto , Estudo de Prova de Conceito , Estudos Prospectivos , RNA-Seq , Fator de Transcrição STAT1/metabolismo , Pele/metabolismo , Resultado do Tratamento
4.
J Plast Reconstr Aesthet Surg ; 73(7): 1306-1311, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32307234

RESUMO

INTRODUCTION: Optimum timing of postoperative showering varies. Earlier showering improves patient satisfaction, but the impact of the timing of showering on postoperative infection is unclear. We conducted a systematic literature review and meta-analysis to investigate the outcomes of various postoperative showering practices. METHODS: We searched PubMed to identify relevant human clinical studies in English, and searched these for additional references. Articles were reviewed for patient demographics, surgical specialty and procedure, wound closure method, placement of drains, showering protocol, and rates of infection and complications. Only randomized controlled trials were analyzed. A random-effects meta-analysis model was used to determine overall infection and complication rates between patients allowed to shower within the first 48 h postoperatively or later. RESULTS: Out of 357 studies, seven and five were included in the infection and complications rate meta-analyses, respectively. A total of 1,881 and 958 patients were included in each analysis; 605 and 477 patients in each analysis were allowed to shower on or before postoperative day 2 ("early"), while the remainder were prohibited from showering until postoperative day 3 to beyond one week ("delayed") postoperatively. There was no difference in infection (p = 0.45, [-0.0052, 2 × 0.007 95% CI]) or complication rate (p = 0.36, [-0.0046, 2 × 0.005 95% CI]) with earlier vs. delayed showering protocols. CONCLUSION: Published literature demonstrates no increase in the overall rate of wound infections or complications when patients showered earlier in the postoperative period. Additional randomized studies are needed to determine the ideal time for postoperative showering. These data should be considered by surgeons while determining when to permit patients to shower after surgery.


Assuntos
Banhos/normas , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Banhos/efeitos adversos , Humanos , Período Pós-Operatório , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecção da Ferida Cirúrgica/etiologia , Fatores de Tempo
5.
Sci Transl Med ; 11(497)2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217334

RESUMO

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor-ß2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFß2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.


Assuntos
Epigênese Genética/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Fator de Crescimento Transformador beta2/genética , Proteínas de Ciclo Celular , Epigênese Genética/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Histona Acetiltransferases/metabolismo , Humanos , NF-kappa B/metabolismo , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Fatores de Transcrição , Fator de Crescimento Transformador beta/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
6.
Nat Commun ; 10(1): 1128, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850660

RESUMO

Scleroderma is an autoimmune rheumatic disorder accompanied by severe fibrosis in skin and other internal organs. During scleroderma progression, resident fibroblasts undergo activation and convert to α-smooth muscle actin (α-SMA) expressing myofibroblasts (MFBs) with increased capacity to synthesize collagens and fibrogenic components. Accordingly, MFBs are a major therapeutic target for fibrosis in scleroderma and treatment with blocking MFBs could produce anti-fibrotic effects. TLY012 is an engineered human TNF-related apoptosis-inducing ligand (TRAIL) which induces selective apoptosis in transformed cells expressing its cognate death receptors (DRs). Here we report that TLY012 selectively blocks activation of dermal fibroblasts and induces DR-mediated apoptosis in α-SMA+ MFBs through upregulated DR5 during its activation. In vivo, TLY012 reverses established skin fibrosis to near-normal skin architecture in mouse models of scleroderma. Thus, the TRAIL pathway plays a critical role in tissue remodeling and targeting upregulated DR5 in α-SMA+ MFBs is a viable therapy for fibrosis in scleroderma.


Assuntos
Actinas/genética , Derme/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Escleroderma Sistêmico/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Actinas/metabolismo , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Diferenciação Celular , Colágeno/genética , Colágeno/metabolismo , Derme/metabolismo , Derme/patologia , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Engenharia de Proteínas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Transdução de Sinais
7.
Plast Reconstr Surg Glob Open ; 6(1): e1560, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29464150

RESUMO

BACKGROUND: It has been proposed that negative pressure wound therapy (NPWT) applied prophylactically to a closed incision may decrease the incidence of wound complications. Patients undergoing reduction mammaplasty are at risk of wound complications such as delayed healing, infection, and dehiscence, and the bilateral nature of the surgery allows for a within-patient randomized study to evaluate incisional NPWT's effect in reducing healing complications. METHODS: In this multicenter trial, 200 patients undergoing bilateral reduction mammaplasty were treated with PICO Single-Use NPWT System or standard wound-care dressings randomized to right or left breast for up to 14 days to enable within-patient comparison. Follow-up assessments were conducted to evaluate the difference in incision healing complications up to 21 days postsurgery. Healing complications (for the primary endpoint) were defined as delayed healing (incision not 100% closed by 7 days) and occurrence of dehiscence or infection within 21 days. Individual healing complications were assessed separately as secondary endpoints. RESULTS: Significantly fewer healing complications (primary endpoint) were noted in NPWT-treated breasts [113 (56.8%)] versus standard care [123 (61.8%)]. The difference of 10 (5.0%) patients with fewer healing complications using NPWT was statistically significant (P = 0.004). NPWT also resulted in a significantly lower incidence of dehiscence (secondary endpoint) compared with standard care [32 patients (16.2%) versus 52 patients (26.4%)] by day 21, a relative reduction of 38% (P < 0.001). CONCLUSIONS: This is the first major prospective, within-patient, randomized, controlled, multicenter study to provide evidence for an incisional NPWT strategy to reduce healing complications.

8.
Plast Reconstr Surg ; 138(6): 1211-1220, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27879589

RESUMO

BACKGROUND: The purpose of this study was to determine whether the American Society of Anesthesiologists classification system could be used preoperatively to identify patients at high risk for complications after abdominal contouring. METHODS: Using the National Surgical Quality Improvement Program database from 2007 to 2012, patients undergoing abdominal contouring procedures were identified and stratified by American Society of Anesthesiologists class. The primary outcome was any complication within 30 days. Secondary outcomes included minor wound, major surgical, and medical complication. Adjusted odds ratios were calculated using logistic regression. RESULTS: A total of 3637 patients were analyzed; 14.6 percent of patients were class I, 59.1 percent were class II, 23.4 percent were class III, and 2.9 percent were class IV. Overall complication and mortality rates were 12 percent and 0.2 percent, respectively. There was a significant trend of increasing odds of any complication with increasing class (class I, OR, 1.0; class II, OR, 1.5; class III, OR, 2.5; class IV, OR, 5.6; p-trend < 0.001). This trend was seen consistently for minor wound complications, medical complications, and major surgical complications (p = 0.007, p = 0.005, and p = 0.001, respectively). CONCLUSIONS: The American Society of Anesthesiologists classification system, which is simple and universally applicable, appears to predict significant complications and can be used to rapidly screen patients before abdominal contouring. Furthermore, the authors' results can be used to inform patient-physician discussion about the risks incurred when undergoing these procedures based on their individual class. Together with optimization of high-risk patients, patient selection using American Society of Anesthesiologists classification may prevent complications and improve outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.


Assuntos
Abdominoplastia , Tomada de Decisão Clínica/métodos , Técnicas de Apoio para a Decisão , Indicadores Básicos de Saúde , Seleção de Pacientes , Complicações Pós-Operatórias/etiologia , Adulto , Idoso , Anestesiologia , Bases de Dados Factuais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Medição de Risco , Fatores de Risco , Sociedades Médicas , Estados Unidos
9.
Pediatr Dermatol ; 33(5): e267-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27339319

RESUMO

We present the case of a male infant with violaceous bullae on the scalp that were initially thought to be bullous aplasia cutis but at 3 months of age were diagnosed as a kaposiform hemangioendothelioma. This diagnosis should be considered when evaluating newborns with bullous plaques on the scalp that do not heal in the first 2-3 weeks of life. Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor that typically presents as a violaceous to purpuric plaque at birth or early infancy. It may be associated with Kasabach-Merritt phenomenon (KMP), a potentially life-threatening consumptive coagulopathy.


Assuntos
Displasia Ectodérmica/diagnóstico , Hemangioendotelioma/diagnóstico , Síndrome de Kasabach-Merritt/diagnóstico , Sarcoma de Kaposi/diagnóstico , Couro Cabeludo , Diagnóstico Diferencial , Humanos , Lactente , Masculino
10.
J Craniofac Surg ; 26(3): 663-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25974770

RESUMO

Reconstruction of bony craniofacial defects requires precise understanding of the anatomic relationships. The ideal reconstructive technique should be fast as well as economical, with minimal donor-site morbidity, and provide a lasting and aesthetically pleasing result. There are some circumstances in which a patient's own tissue is not sufficient to reconstruct defects. The development of sophisticated software has facilitated the manufacturing of patient-specific implants (PSIs). The aim of this study was to analyze the utility of polyether ether ketone (PEEK) PSIs for craniofacial reconstruction. We performed a retrospective chart review from July 2009 to July 2013 in patients who underwent craniofacial reconstruction using PEEK-PSIs using a virtual process based on computer-aided design and computer-aided manufacturing. A total of 6 patients were identified. The mean age was 46 years (16-68 y). Operative indications included cancer (n = 4), congenital deformities (n = 1), and infection (n = 1). The mean surgical time was 3.7 hours and the mean hospital stay was 1.5 days. The mean surface area of the defect was 93.4 ± 43.26 cm(2), the mean implant cost was $8493 ± $837.95, and the mean time required to manufacture the implants was 2 weeks. No major or minor complications were seen during the 4-year follow-up. We found PEEK implants to be useful in the reconstruction of complex calvarial defects, demonstrating a low complication rate, good outcomes, and high patient satisfaction in this small series of patients. Polyether ether ketone implants show promising potential and warrant further study to better establish the role of this technology in cranial reconstruction.


Assuntos
Desenho Assistido por Computador , Anormalidades Craniofaciais/cirurgia , Cetonas , Procedimentos de Cirurgia Plástica/métodos , Polietilenoglicóis , Próteses e Implantes , Adolescente , Adulto , Idoso , Benzofenonas , Éter , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polímeros , Desenho de Prótese , Estudos Retrospectivos , Adulto Jovem
12.
J Magn Reson Imaging ; 41(2): 431-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24391057

RESUMO

PURPOSE: To determine the relation between glucose metabolic changes of the primary visual cortex, structural abnormalities of the corresponding visual tracts, and visual symptoms in children with Sturge-Weber syndrome (SWS). MATERIALS AND METHODS: In 10 children with unilateral SWS (ages 1.5-5.5 years), a region-of-interest analysis was applied in the bilateral medial occipital cortex on positron emission tomography (PET) and used to track diffusion-weighted imaging (DWI) streamlines corresponding to the central visual pathway. Normalized streamline volumes of individual SWS patients were compared with values from age-matched control groups as well as correlated with normalized glucose uptakes and visual field deficit. RESULTS: Lower glucose uptake and lower corresponding streamline volumes were detected in the affected occipital lobe in 9/10 patients, as compared to the contralateral side. Seven of these 9 patients had visual field deficit and normal or decreased streamline volumes on the unaffected side. The two other children had no visual symptoms and showed high contralateral visual streamline volumes. There was a positive correlation between the normalized ratios on DWI and PET, indicating that lower glucose metabolism was associated with lower streamline volume in the affected hemisphere (R = 0.70, P = 0.024). CONCLUSION: We demonstrated that 18F-flurodeoxyglucose (FDG)-PET combined with DWI tractography can detect both brain damage on the side of the lesion and contralateral plasticity in children with early occipital lesions.


Assuntos
Imagem de Tensor de Difusão/métodos , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Síndrome de Sturge-Weber/patologia , Córtex Visual/patologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18 , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos , Compostos Radiofarmacêuticos
13.
Pediatr Neurol ; 50(4): 337-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24507695

RESUMO

BACKGROUND: Reorganization of the corticospinal tract after early damage can limit motor deficit. In this study, we explored patterns of structural corticospinal tract reorganization in children with Sturge-Weber syndrome. METHODS: Five children (age 1.5-7 years) with motor deficit resulting from unilateral Sturge-Weber syndrome were studied prospectively and longitudinally (1-2 years follow-up). Corticospinal tract segments belonging to hand and leg movements were separated and their volume was measured by diffusion tensor imaging tractography using a recently validated method. Corticospinal tract segmental volumes were normalized and compared between the Sturge-Weber syndrome children and age-matched healthy controls. Volume changes during follow-up were also compared with clinical motor symptoms. RESULTS: In the Sturge-Weber syndrome children, hand-related (but not leg-related) corticospinal tract volumes were consistently decreased in the affected cerebral hemisphere at baseline. At follow-up, two distinct patterns of hand corticospinal tract volume changes emerged. (1) Two children with extensive frontal lobe damage showed a corticospinal tract volume decrease in the lesional hemisphere and a concomitant increase in the nonlesional (contralateral) hemisphere. These children developed good hand grasp but no fine motor skills. (2) The three other children, with relative sparing of the frontal lobe, showed an interval increase of the normalized hand corticospinal tract volume in the affected hemisphere; these children showed no gross motor deficit at follow-up. CONCLUSIONS: Diffusion tensor imaging tractography can detect differential abnormalities in the hand corticospinal tract segment both ipsi- and contralateral to the lesion. Interval increase in the corticospinal tract hand segment suggests structural reorganization, whose pattern may determine clinical motor outcome and could guide strategies for early motor intervention.


Assuntos
Lobo Frontal/patologia , Tratos Piramidais/patologia , Síndrome de Sturge-Weber/patologia , Criança , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Feminino , Seguimentos , Lobo Frontal/fisiopatologia , Mãos/patologia , Mãos/fisiopatologia , Força da Mão/fisiologia , Humanos , Lactente , Perna (Membro)/patologia , Perna (Membro)/fisiopatologia , Estudos Longitudinais , Masculino , Atividade Motora/fisiologia , Destreza Motora/fisiologia , Plasticidade Neuronal , Tamanho do Órgão , Estudos Prospectivos , Tratos Piramidais/fisiopatologia , Síndrome de Sturge-Weber/fisiopatologia
14.
J Exp Med ; 211(2): 217-31, 2014 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-24446491

RESUMO

Hematopoietic stem cells (HSCs) are heterogeneous with respect to their self-renewal, lineage, and reconstitution potentials. Although c-Kit is required for HSC function, gain and loss-of-function c-Kit mutants suggest that even small changes in c-Kit signaling profoundly affect HSC function. Herein, we demonstrate that even the most rigorously defined HSCs can be separated into functionally distinct subsets based on c-Kit activity. Functional and transcriptome studies show HSCs with low levels of surface c-Kit expression (c-Kit(lo)) and signaling exhibit enhanced self-renewal and long-term reconstitution potential compared with c-Kit(hi) HSCs. Furthermore, c-Kit(lo) and c-Kit(hi) HSCs are hierarchically organized, with c-Kit(hi) HSCs arising from c-Kit(lo) HSCs. In addition, whereas c-Kit(hi) HSCs give rise to long-term lymphomyeloid grafts, they exhibit an intrinsic megakaryocytic lineage bias. These functional differences between c-Kit(lo) and c-Kit(hi) HSCs persist even under conditions of stress hematopoiesis induced by 5-fluorouracil. Finally, our studies show that the transition from c-Kit(lo) to c-Kit(hi) HSC is negatively regulated by c-Cbl. Overall, these studies demonstrate that HSCs exhibiting enhanced self-renewal potential can be isolated based on c-Kit expression during both steady state and stress hematopoiesis. Moreover, they provide further evidence that the intrinsic functional heterogeneity previously described for HSCs extends to the megakaryocytic lineage.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Megacariócitos/citologia , Megacariócitos/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Animais , Linhagem da Célula , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Fluoruracila/farmacologia , Perfilação da Expressão Gênica , Hematopoese/genética , Hematopoese/fisiologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/classificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-kit/genética , Trombopoese/genética , Trombopoese/fisiologia
15.
J Exp Med ; 210(12): 2641-59, 2013 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-24218140

RESUMO

Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10-30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.


Assuntos
Anormalidades Múltiplas/etiologia , Síndromes Mielodisplásicas/etiologia , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Anormalidades Múltiplas/genética , Animais , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Dioxigenases , Modelos Animais de Doenças , Epigênese Genética , Feminino , Deleção de Genes , Mutação em Linhagem Germinativa , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fenótipo , Gravidez , Ligação Proteica , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/metabolismo
16.
Int J Oral Maxillofac Surg ; 42(4): 453-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23290086

RESUMO

Despite the emergence of free tissue transfer, the pectoralis major myocutaneous flap (PMMF) still has a role in anterior base skull reconstruction (when free tissue transfer is not feasible). The aim of this study is to evaluate the results of external PMMF in anterior skull base reconstruction. A retrospective study from 1977 to 2006 was conducted at Yale New Haven Hospital. 16 patients (mean age 64 years), presenting with a malignant tumour of the anterior base skull, were included. The primary pathology was recurrent squamous carcinoma. Tumour resection resulted in orbital exenteration in 60%, and bone resection of the anterior skull base in 81% of patients. The initial skin defect was 49 cm(2) (range 16-100 cm(2)). The PMMF was the primary reconstructive choice in 87%, and utilized after free flap failure in two cases. Three minor complications were noted. Orbital exenteration and anterior base skull resection is a surgical procedure that leads to significant reconstructive challenges. The PMMF remains a safe and versatile reconstructive tool in anterior skull base tumour resection. The externalized pedicle allows this flap to reach periorbital and anterior skull base.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Retalhos de Tecido Biológico/transplante , Neoplasias de Cabeça e Pescoço/cirurgia , Músculos Peitorais/transplante , Procedimentos de Cirurgia Plástica/métodos , Neoplasias da Base do Crânio/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orbitárias/cirurgia , Estudos Retrospectivos
17.
Plast Surg Int ; 2012: 731029, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23304488

RESUMO

In 1955, Millard developed the concept of rotation-advancement flap to treat cleft lip. Almost 6 decades later, it remains the most popular technique worldwide. Since the technique evolved and Millard published many technical variations, we decided to ask 10 experienced cleft surgeons how they would mark Millard's 7 points in two unilateral cleft lip patient photos and compared the results. In both pictures, points 1 and 2 were marked identically among surgeons. Points 3 were located adjacent to each other, but not coincident, and the largest distances between points 3 were 4.95 mm and 4.03 mm on pictures 1 and 2, respectively. Similar patterns were obtained for points 4, eight of them were adjacent, and the greatest distance between the points was 4.39 mm. Points 5 had the most divergence between the points among evaluators, which were responsible for the different shapes of the C-flap. Points 6 also had dissimilar markings, and such difference accounts for varying resection areas among evaluators. The largest distances observed were 11.66 mm and 7 mm on pictures 1 and 2, respectively. In summary, much has changed since Millard's initial procedure, but his basic principles have survived the inexorable test of time, proving that his idea has found place among the greatest concepts of modern plastic surgery.

19.
Ann Plast Surg ; 66(5): 476-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21451367

RESUMO

The American Society of Plastic Surgery recently recorded a decline in numbers of breast reductions, one of the most common procedures performed by plastic surgeons. The purpose of this study is to characterize the reduction mammoplasty patient population which would further assist in planning the future workforce needs. Using the Nationwide Inpatient Sample database for 2007, a χ analysis of female in-patients treated with reduction mammoplasty for breast hypertrophy was performed to identify significant differences in race and payer mix. Of 8394 female in-patients with breast hypertrophy, 61% were treated with reduction mammoplasty. Black and Hispanic patients (P < 0.0001) and patients with private insurance (P < 0.0001) were more likely to undergo reduction mammoplasty. This study demonstrates racial and socioeconomic disparities in breast reduction in the United States in 2007. With the pending institution of universal healthcare, it is predicted that disparities revealed may worsen due to cost containment pressures.


Assuntos
Mama/patologia , Etnicidade/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Mamoplastia/estatística & dados numéricos , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Mama/cirurgia , Estudos de Coortes , Bases de Dados Factuais , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Hipertrofia/patologia , Hipertrofia/cirurgia , Incidência , Cobertura do Seguro/economia , Cobertura do Seguro/tendências , Mamoplastia/métodos , Estudos Retrospectivos , Medição de Risco , Fatores Socioeconômicos , Estados Unidos , População Branca/estatística & dados numéricos
20.
J Craniofac Surg ; 21(2): 411-3, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20186071

RESUMO

INTRODUCTION: Craniosynostosis is the premature fusion of 1 or more of the cranial sutures, which causes an abnormal skull shape. The treatment is complex and requires surgical intervention for correction, between 3 and 12 months of age. The current standard for diagnosing craniosynostosis is to obtain a computed tomographic (CT) scan. However, recent studies have emphasized potential problems associated with ionizing radiation. The aim of this study was to evaluate the use of the preoperative CT scan, and its findings, and to define the value of these data. MATERIALS AND METHODS: This study is a retrospective analysis of 89 patients with craniosynostosis during the period between 1998 and 2007, who had CT using the Yale-New Haven Hospital computer system. Clinical findings such as age, sex, and diagnosis were recorded. All intraoperative abnormalities were noted. Preoperative CT scans were reevaluated for accuracy and completeness of diagnosis, cerebral anomalies, and other head and neck pathologic conditions. RESULTS: Initially, 131 cases of nonsyndromic craniosynostosis were identified. Of these, we had access to CT evaluations in 89 patients. The mean age at the time of the surgery was 13 months, varying from 2 months to 18 years old. Most patients were males. The most common diagnoses were sagittal synostosis in 47 cases; unilateral coronal, 16; and metopic, 15. In most patients, the CT scan demonstrated the same diagnosis as the clinical examination-derived diagnosis. However, 6 patients had an incomplete diagnosis or misdiagnosis. In addition, 3 cases of prominence of the subarachnoid space, 2 cases of cerebral atrophy, 1 case of subarachnoid tumor, and 1 deformational dysplasia of encephalon were identified. Other minor additional diagnoses were 5 cases of fluid in the middle ear and antrum of mastoid, 2 cases of cysts in the maxilla, and 1 case of an associated cervical lymphatic tumor. CONCLUSIONS: The advantage of CT use is greater accuracy in diagnosis, less potential for inappropriate surgery, and, as an ancillary effect, a more complete and timely assessment of congenital anomalies so that more appropriate referrals can be made. Low-dose (pediatric) radiation CT still seems to have a place in the examination of a patient with skull deformity and potential craniosynostosis.


Assuntos
Craniossinostoses/diagnóstico por imagem , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adolescente , Fatores Etários , Atrofia , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Suturas Cranianas/anormalidades , Feminino , Seguimentos , Osso Frontal/anormalidades , Humanos , Lactente , Cuidados Intraoperatórios , Cistos Maxilomandibulares/diagnóstico por imagem , Masculino , Doenças Maxilares/diagnóstico por imagem , Otite Média/diagnóstico por imagem , Osso Parietal/anormalidades , Estudos Retrospectivos , Fatores Sexuais , Espaço Subaracnóideo/diagnóstico por imagem
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