Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 37
Filtrar
1.
Cell ; 184(18): 4784-4818.e17, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450027

RESUMO

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.


Assuntos
Predisposição Genética para Doença , Genética Populacional , Osteoartrite/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Osteoartrite/tratamento farmacológico , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Caracteres Sexuais , Transdução de Sinais/genética
3.
Semin Cell Dev Biol ; 62: 67-77, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27422331

RESUMO

Articular cartilage is a highly specialized tissue whose remarkable properties of deformability, resistance to mechanical loading, and low-friction gliding are essential to joint function. Due to its role as a cushion in bone articulation, articular cartilage is subject to many types of damaging insults, including decades of wear and tear, and acute joint injuries. However, this built-for-life tissue has a very poor intrinsic ability in adulthood to durably heal defects created by damaging insults. Consequently, articular cartilage progressively deteriorates and is eventually eroded, exposing the subchondral bone to the joint space, triggering inflammation and osteophyte development, and generating severe pain and joint incapacitation. The disease is called osteoarthritis (OA) and is today the leading cause of pain and disability in the human population. Researchers and clinicians have worked for decades to develop strategies to treat OA and restore joint function, but they are still far from being able to offer patients effective preventive or restorative treatments. Novel ideas, knowledge and technologies that nurture hope for major new breakthroughs are therefore sought. In this review, we first outline the composition, structure, and functional properties of normal human adult articular cartilage, as a reference for tissue conservation and regenerative strategies. We then describe current options that have been used clinically and in pre-clinical trials to treat osteoarthritic patients, and we discuss the benefits and inadequacies of these treatment options. Next, we review research efforts that are currently ongoing to try and achieve durable repair of functional cartilage tissue. Methods include engineering of tissue implants and we discuss the needs and options for tissue scaffolds, cell sources, and growth and differentiation factors to generate de novo or repair bona fide articular cartilage.


Assuntos
Cartilagem Articular/fisiologia , Regeneração , Medicina Regenerativa/métodos , Animais , Humanos , Próteses e Implantes , Engenharia Tecidual , Alicerces Teciduais/química
4.
Pediatr Endocrinol Rev ; 10 Suppl 2: 389-96, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23858622

RESUMO

Fibrous dysplasia is a developmental abnormality of bone that is characterized by a highly disorganized mixture of immature fibrous tissue and fragments of immature trabecular bone. Fibrous dysplasia may arise as a single, discrete (monostotic) lesion or can occur with a more widespread distribution with multiple lesions that affect many bones (oligo- or polyostotic). Fibrous dysplasia is usually an isolated skeletal finding but can sometimes occur as a component of a multisystem developmental disorder known as McCune-Albright syndrome (MAS) that is also associated with endocrine hyperfunction (e.g. precocious puberty) and caf au lait cutaneous macules. The identification of activating mutations in GNAS in a subset of human GH-secreting pituitary tumors and autonomously functioning human thyroid tumors provided the initial basis for understanding the molecular pathophysiology of McCune-Albright syndrome and fibrous dysplasia. These observations led to the concept that activating mutations of the GNAS gene convert it into a putative oncogene referred to as gsp (Gsa or Gas). The classic radiographic feature of fibrous dysplasia is a hazy, radiolucent, or ground-glass, pattern resulting from the defective mineralization of immature dysplastic bone; it is usually strikingly different from the radiographic appearance of normal bone, calcified cartilage, or soft tissue. The surgical approach to fibrous dysplasia should in general be conservative. Recent research suggests that the WntlB-catenin pathway may play a role in fibrous dysplasia as patients with activating GNAS mutations specifically showed that Gas mutations activated Wnt/B-catenin signaling. Thus inhibition of 8-catenin signaling or silencing GNAS alleles that encode constitutively active Gsa molecules in fibrous dysplasia and McCune-Albright syndrome offer potential therapeutic promise and deserve further study. In summary fibrous dysplasia is a developmental abnormality of bone with a known molecular etiology; Further knowledge about the molecular pathology of fibrous dysplasia may lead to improved conservative therapies in the near future.


Assuntos
Displasia Fibrosa Monostótica/diagnóstico , Displasia Fibrosa Poliostótica/diagnóstico , Displasia Fibrosa Monostótica/genética , Displasia Fibrosa Monostótica/terapia , Displasia Fibrosa Poliostótica/genética , Displasia Fibrosa Poliostótica/terapia , Humanos
5.
Biochem Biophys Res Commun ; 425(1): 25-32, 2012 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-22820184

RESUMO

SH3BP2 activating mutations lead to an unique clinical condition in which patients develop symmetrical bone resorptive lesions of the jaw, a condition termed cherubism. Due to this specific temporal sequence and location of bone resorption, we investigated the transcriptional regulation of SH3BP2 expression. Analyses of 5'- and 3'-serial promoter deletions defined the core promoter/regulatory elements, including two repressor sites (from -1,200 to -1,000 and from +86 to +115, respectively) and two activator sites (a PARP1 binding site from -44 to -21 and a second activator site from +57 to +86). We identified that PARP1 binds to DNA from -44 to -21 by Streptavidin-biotin purification and confirmed this binding by electrophoretic mobility shift assay (EMSA). Mutagenesis of the PARP1 binding site on the SH3BP2 promoter showed that this binding site is essential for SH3BP2 expression. EMSA and chromatin immunoprecipitation (ChIP) assays confirmed that PARP1 was able to bind to the SH3BP2 promoter in vitro and in vivo. Indeed, knockout of Parp1 in mice BMMs reduced expression of SH3BP2. These results demonstrate that PARP1 regulates expression of SH3BP2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Regiões Promotoras Genéticas , Ativação Transcricional , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Imunoprecipitação da Cromatina , Clonagem Molecular , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Camundongos , Dados de Sequência Molecular , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , Sítio de Iniciação de Transcrição , Transcrição Gênica
6.
J Surg Oncol ; 103(1): 85-91, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21165983

RESUMO

BACKGROUND: In sarcoma patients the roles of smoking history, family cancer history, and leukoreduced blood transfusions have not been studied and the effect of preoperative radiation on blood loss has not been examined. METHODS: Seventy-seven patients with non-metastatic and non-recurrent thigh sarcomas surgically treated at the Cleveland Clinic were identified. Among patient variables studied were: close family history of cancer, perioperative transfusion history, smoking history, and radiation history. Median follow-up for the survivors was 3.2 years. RESULTS: We found that tumor grade, transfusion >3 U (P = 0.022), and pre- or post-operative radiation therapy (P = 0.041) were risk factors for distant metastasis. Tumor grade (P = 0.008), positive smoking history (P = 0.039), and >3 U of non-leukoreduced blood transfused (P = 0.037) were risk factors for death of any-cause. Close family history of cancer correlated with having a grade 3 sarcoma (P = 0.044). Neoadjuvant radiotherapy correlated with >3 U of blood transfused (P = 0.001) and biopsy performed at the treating institution led to a significant decrease in rate of recurrence (P = 0.016). CONCLUSIONS: We present novel findings in terms of transfusions, family history of cancer and site of initial biopsy in sarcoma patients.


Assuntos
Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Saúde da Família , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Radioterapia Adjuvante/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Sarcoma/mortalidade , Sarcoma/terapia , Fumar/efeitos adversos , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/terapia , Coxa da Perna , Reação Transfusional , Resultado do Tratamento
7.
Curr Opin Pediatr ; 22(4): 508-15, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20601885

RESUMO

PURPOSE OF REVIEW: In this review, we define hypercalcemia levels, common causes for hypercalcemia in children, and treatment in order to aid the practicing pediatrician. RECENT FINDINGS: One rare cause of hypercalcemia in the child is familial hypocalciuric hypercalcemia (also termed familial benign hypercalcemia). Mutations that inactivate the Ca-sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous. SUMMARY: Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However, the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due to osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are, therefore, effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.


Assuntos
Predisposição Genética para Doença , Hipercalcemia , Adolescente , Conservadores da Densidade Óssea/uso terapêutico , Calcitonina/uso terapêutico , Cálcio/sangue , Cálcio/urina , Sinalização do Cálcio , Criança , Humanos , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hipercalcemia/terapia , Mutação , Paratireoidectomia , Prognóstico , Receptores de Detecção de Cálcio/genética
8.
J Bone Joint Surg Am ; 102(18): 1628-1636, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32701715

RESUMO

BACKGROUND: Previous studies have demonstrated the influence of heritable factors on the development of nontraumatic osteonecrosis of the femoral head (ONFH). We hypothesized that genetic variation is associated with an increased risk of ONFH, and that variants could be identified by a genomewide association study (GWAS). METHODS: Using data collected from the MyCode Community Health Initiative, we identified 118 adult patients with radiographically confirmed nontraumatic ONFH. Study patients were statistically compared with a control population of 56,811 unrelated individuals without a diagnosis of ONFH. A case-control GWAS was performed to identify single nucleotide variants (SNVs) associated with ONFH. Sensitivity analyses were performed to evaluate the association of the top SNVs with (cortico)steroid-associated ONFH and ONFH with femoral head collapse. Gene-based analyses were performed to identify potential causal genes. RESULTS: Of the 118 patients, 114 (96.6%) had bilateral ONFH at a median of 5 years of follow-up; 90.7% had at least one 3-week steroid prescription compared with 68.3% in controls. A GWAS identified 4 SNVs reaching genomewide significance. rs116468452 near CACNA1E was significantly associated with ONFH (p = 3.26 × 10, odds ratio [OR] = 5.6, 95% confidence interval [CI] = 3.21 to 9.76). rs10953090 in SAMD9 was significantly associated with ONFH in the steroid-exposed subset (p = 2.96 × 10, OR = 2.57, 95% CI = 1.84 to 3.58). rs112467115 in PI4K1B showed enhanced association in the collapsed subset (p = 7.82 × 10, OR = 4.5, 95% CI = 2.60 to 7.79). Gene-based analyses identified PPARGC1B as the only gene significantly associated with ONFH after Bonferroni correction (p = 1 × 10), with the lead SNV being rs78814834 (OR = 2.86, 95% CI = 1.87 to 4.38). CONCLUSIONS: We identified 4 SNVs and 1 gene, PPARGC1B, associated with ONFH. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Necrose da Cabeça do Fêmur/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
9.
J Surg Oncol ; 99(6): 379-81, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19235184

RESUMO

Current treatment of acetabular defects created by metastatic disease involve extensile approaches removing the abductors from the greater trochanter or greater trochanteric osteotomy. We have developed a technique which does not involve removal of the muscle from the greater trochanter or trochanteric osteotomy. We remove the gluteus medius muscle from its anterior origin along several inches of the anterior iliac wing and the gluteus maximus from its insertion (the conjoined tendon) along the posterior proximal femur. The entire hip joint capsule is removed from anterior and posterior to the gluteus medius and minimus taking care to leave the insertion of these muscles intact. We have performed this approach in 13 patients with known metastatic disease and our preliminary results indicate that their limp and immediate weight bearing are improvements from the current standard of care involving removal of either the insertion of the gluteus medius and minimus from the greater trochanter or greater trochanteric osteotomy.


Assuntos
Acetábulo/cirurgia , Neoplasias Ósseas/cirurgia , Procedimentos Ortopédicos/métodos , Acetábulo/patologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Marcha , Articulação do Quadril/cirurgia , Humanos , Osteotomia , Ossos Pélvicos/cirurgia , Suporte de Carga
10.
Skeletal Radiol ; 38(8): 791-6, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19277645

RESUMO

OBJECTIVES: The objective of this study was to evaluate by cross-sectional imaging the prevalence and degree of cortical scalloping by small eccentric chondromas correlated with histologic diagnosis and patient history. MATERIALS AND METHODS: From 122 patients with histologically proven enchondromas and two patients without histology but with radiologic and clinical follow-up, 11 patients with small, eccentrically located chondromas in the long bones had cross-sectional imaging available. The lesions were evaluated for location, size, presence, and degree of cortical scalloping. The patient's medical charts and microscope slides were reviewed for relevant clinical history, clinical management, and histology. RESULTS: The chondromas ranged in size from 1.6 to 3.8 cm (mean 2.3 cm). Two lesions were located in the proximal femoral diaphysis, two in the distal femoral diaphysis, six in the distal femoral metaphysis, and one in the proximal tibial epimetaphysis. The lesions were curetted due to diagnostic uncertainty, continued pain, marked radiologic cortical penetration, or due to patient insistence on biopsy. All 11 lesions were benign, nine histologically, and two by stability over 4 and 7 years. The prevalence of cortical scalloping among eccentric chondromas was 100%. Cortical scalloping or occupancy ranged from 50 to 100% (mean 75%). CONCLUSIONS: All small eccentric chondromas in this study were associated with an appearance of cortical scalloping of varying degree. All curetted lesions were histologically bland without nuclear atypia. Based on the benign histology of nine lesions and lack of growth of two lesions over several years, the degree of cortical scalloping is felt to be a result of lesion location within the endosteum rather than biological activity or malignancy.


Assuntos
Neoplasias Ósseas/diagnóstico , Condroma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Lesões Pré-Cancerosas/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anatomia Transversal/métodos , Diagnóstico Diferencial , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tíbia/diagnóstico por imagem , Tíbia/patologia
11.
J Clin Endocrinol Metab ; 93(3): 901-4, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18089698

RESUMO

CONTEXT: Preimplantation genetic diagnosis (PGD) enables the selection of embryos without mutations for implantation and has not been described to our knowledge for mutations in GNAS. Phocomelia in a patient with Albright hereditary osteodystrophy (AHO) has also not been previously described. OBJECTIVE: The aim of this study was to identify a GNAS mutation in a patient with a severe form of AHO and pseudohypoparathyroidism type 1a with phocomelia and to perform PGD on embryos derived by in vitro fertilization to deliver an unaffected infant. DESIGN: A proband and his family are described clinically, the GNAS gene was sequenced to identify a novel mutation in the proband, and PGD was performed on embryos. SETTING: The setting was in a tertiary-care hospital. PATIENTS: The patients were from a single family in which the proband has a severe form of AHO. INTERVENTIONS: Interventions were PGD and in vitro fertilization. MAIN OUTCOME MEASURES: The main outcome measures were the clinical phenotypes and GNAS gene sequences of the proband, embryos, and family members. RESULTS: After PGD, three genotypically normal embryos were transferred back to the mother. Pregnancy ensued, and a healthy male infant was delivered at 36.5 wk gestation. The GNAS genes in the baby were confirmed as wild-type, and the infant is free of any signs of AHO. CONCLUSIONS: We describe herein a proband with AHO and severe skeletal deformities (including phocomelia) related to a novel GNAS mutation and the delivery of a male infant with homozygous normal GNAS genotype after PGD.


Assuntos
Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação , Diagnóstico Pré-Implantação , Adulto , Cromograninas , Displasia Fibrosa Poliostótica/diagnóstico , Humanos , Masculino
12.
Biochem Biophys Res Commun ; 371(4): 644-8, 2008 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-18440306

RESUMO

Heterozygous activating mutations in exon 9 of SH3BP2 have been found in most patients with cherubism, an unusual genetic syndrome characterized by excessive remodeling of the mandible and maxilla due to spontaneous and excessive osteoclastic bone resorption. Osteoclasts differentiate after binding of sRANKL to RANK induces a number of downstream signaling effects, including activation of the calcineurin/NFAT (nuclear factor of activated T cells) pathway. Here, we have investigated the functional significance of SH3BP2 protein on osteoclastogenesis in the presence of sRANKL. Our results indicate that SH3BP2 both increases nuclear NFATc1 in sRANKL treated RAW 264.7 preosteoclast cells and enhances expression of tartrate resistant acid phosphatase (TRAP), a specific marker of osteoclast differentiation. Moreover, overexpression of SH3BP2 in RAW 264.7 cells potentiates sRANKL-stimulated phosphorylation of PLCgamma1 and 2, thus providing a mechanistic pathway for the rapid translocation of NFATc1 into the nucleus and increased osteoclastogenesis in cherubism.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diferenciação Celular , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Fosfatase Ácida/análise , Fosfatase Ácida/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Humanos , Isoenzimas/análise , Isoenzimas/metabolismo , Camundongos , Osteoclastos/química , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Fosfatase Ácida Resistente a Tartarato
13.
Pediatr Endocrinol Rev ; 4 Suppl 4: 380-5, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17982384

RESUMO

McCune-Albright syndrome (MAS) is characterized by the clinical triad of polyostotic fibrous dysplasia, café-au-lait pigmented skin lesions and endocrinopathy (1,2) The molecular lesion in MAS is a postzygotic mutation in the GNAS gene that leads to activation of Gsalpha, the alpha chain of the heterotrimeric G protein, Gsalpha. Cells that carry the activating mutation are distributed in a mosaic pattern. A clinical diagnosis of MAS can be made when a patient is found to have at least two features of the classical triad (3). Because of the restricted pattern of distribution of the GNAS mutation, termed gsp, initial molecular analyses were limited to lesional tissue, but recent techniques such as peptide nucleic acid clamping have improved the sensitivity of current assays and now enable the detection of gsp mutations in circulating cells from many patients with MAS.


Assuntos
Displasia Fibrosa Poliostótica/diagnóstico , Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Testes Genéticos , Cromograninas , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Humanos
14.
Orthopedics ; 30(3): 227-34, 2007 03.
Artigo em Inglês | MEDLINE | ID: mdl-17375550

RESUMO

The records of 63 patients surgically treated for liposarcoma at the Cleveland Clinic between 1975 and 1995 were examined. Both metastatic disease (Enneking stage IIl) and an abdominal location were found to be poor prognosticants for survival. Age, gender, or tumor size, setting, or grade did not have any prognostic significance. The 5-year disease-specific survival for extremity tumors was 92% (95% confidence interval [CI]; range: 84%-100%), while general 5-year survival for extremity tumors was 66% (95% Cl; range: 48%-85%).


Assuntos
Lipossarcoma/cirurgia , Neoplasias de Tecidos Moles/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Lipossarcoma/mortalidade , Lipossarcoma/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Taxa de Sobrevida
15.
Hum Mutat ; 27(7): 717-8, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16786512

RESUMO

We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw. Two siblings and the father were carriers but lacked phenotypic features. Transient expression of p.D419N (c.1255G>A), as well as three previously described exon 9 mutations from cherubism patients (p.R415Q (c.1244G>A), p.D420E (c.1259G>A), and p.P418R (c.1253C>G)) increased activity of NFAT (nuclear factor of activated T-cells), an osteoclastogenic mediator, indicating that cherubism results from gain of function mutations in SH3BP2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Querubismo/genética , Mutação de Sentido Incorreto , Fatores de Transcrição NFATC/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Querubismo/diagnóstico por imagem , Querubismo/metabolismo , Pré-Escolar , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Células Jurkat , Masculino , Mutagênese Sítio-Dirigida , Linhagem , Radiografia
16.
World J Orthop ; 7(3): 149-55, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-27004161

RESUMO

Articular cartilage repair techniques are challenging. Human embryonic stem cells and induced pluripotent stem cells (iPSCs) theoretically provide an unlimited number of specialized cells which could be used in articular cartilage repair. However thus far chondrocytes from iPSCs have been created primarily by viral transfection and with the use of cocultured feeder cells. In addition chondrocytes derived from iPSCs have usually been formed in condensed cell bodies (resembling embryoid bodies) that then require dissolution with consequent substantial loss of cell viability and phenotype. All of these current techniques used to derive chondrocytes from iPSCs are problematic but solutions to these problems are on the horizon. These solutions will make iPSCs a viable alternative for articular cartilage repair in the near future.

17.
Orthopedics ; 39(3): e423-9, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27064780

RESUMO

This study attempted to determine whether patients undergoing cemented long-stem proximal femoral replacement had: (1) an increased short-term mortality rate; (2) greater intraoperative hemodynamic instability; (3) a greater need for resuscitation; and (4) a decreased risk of periprosthetic fracture. The current study reviewed intraoperative and short-term events related to clinical outcomes in 24 consecutive patients who were treated at a single institution over a 5-year period. These patients underwent primary long-stem (≥250 mm, n=13) vs short-stem (<250 mm, n=11) cemented proximal femoral replacement. Other than stem length, the 2 groups were not significantly different in terms of patient age, sex, height, weight, body mass index, diagnosis, or preoperative American Society of Anesthesiologists functional score. Primary outcomes were intraoperative death, blood loss, blood transfusions, fluid resuscitation, hypotension, oxygen desaturation, mortality up to 1 year, and need for revision surgery. At 1 year, a significantly increased mortality rate (77% vs 27%, P=.03) was noted in patients receiving long-stem vs short-stem arthroplasty. Patients who received longer stems also required more intraoperative blood transfusions and fluid resuscitation (P=.04) for greater hypotension (P=.04) and oxygen desaturation (P=.04). Two intraoperative deaths occurred in the long-stem group, and none occurred in the short-stem group. The findings suggest that there is an increased risk of intraoperative hemodynamic instability with long-stem vs short-stem proximal femoral replacement, with a need for greater resuscitative efforts and an increased risk of mortality at 1 year. [Orthopedics. 2016; 39(3):e423-e429.].


Assuntos
Artroplastia de Quadril/efeitos adversos , Neoplasias Femorais/secundário , Prótese de Quadril/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Femorais/cirurgia , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/cirurgia , Fraturas do Quadril/etiologia , Fraturas do Quadril/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas Periprotéticas/etiologia , Falha de Prótese/efeitos adversos , Reoperação/efeitos adversos , Reoperação/estatística & dados numéricos
18.
J Bone Joint Surg Am ; 87(11): 2489-94, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16264125

RESUMO

BACKGROUND: The somatic nature of mutations in the GNAS gene in McCune-Albright syndrome and isolated fibrous dysplasia makes their identification difficult. Conventional methods for the detection of mosaic mutations of GNAS have required polymerase chain reaction analysis of genomic DNA from affected tissues or multiple rounds of tandem polymerase chain reaction and endonuclease digestion to enrich for mutant alleles in genomic deoxyribonucleic acid (DNA) from other tissues. Peptide nucleic acid (PNA) primers specifically block synthesis from the nonmutant or wild-type allele. We therefore used PNA-clamping to detect low copy numbers of mutant GNAS alleles in DNA from peripheral blood cells from patients with McCune-Albright syndrome and fibrous dysplasia. METHODS: We applied the PNA-clamping method to the analysis of genomic DNA from peripheral blood cells of thirteen patients with McCune-Albright syndrome and three patients with isolated fibrous dysplasia. Polymerase chain reaction was performed in the presence and absence of PNA, and the polymerase chain reaction products were sequenced. In the absence of PNA, a strong 325 base-pair polymerase chain reaction band was generated from all samples; in the presence of PNA, there was an approximately 50% to 90% reduction in the intensity of this polymerase chain reaction product. RESULTS: In the absence of PNA, direct sequencing of the polymerase chain reaction products demonstrated R201 mutations in GNAS alleles of three of the thirteen patients with McCune-Albright syndrome and none of the three patients with fibrous dysplasia. In contrast, in the presence of PNA, R201 mutations were detected in eleven of the thirteen patients with McCune-Albright syndrome and in all three of the patients with fibrous dysplasia. In mixing experiments involving the use of wild-type and mutant DNA samples, we were able to determine the presence of a mutant GNAS allele in the equivalent of one cell in 1000 to 5000 cells. CONCLUSIONS: Inclusion of a specific PNA primer in the polymerase chain reaction for GNAS exon 8 allows the selective amplification of low numbers of mutant alleles, and it permits detection of activating mutations in genomic DNA from peripheral blood cells in patients with McCune-Albright syndrome and fibrous dysplasia.


Assuntos
Displasia Fibrosa Monostótica/genética , Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Reação em Cadeia da Polimerase/métodos , Células Sanguíneas , Cromograninas , Humanos , Mutação
19.
J Orthop Res ; 20(6): 1240-5, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12472235

RESUMO

The utility of cortical allografts in repairing large bone defects is limited by their slow and incomplete incorporation into host bone. In order to determine the effects of recombinant human osteogenic protein-1 (rhOP-1) impregnation on allograft incorporation, we used a canine intercalary bone defect model. Bilateral resection of a 4 cm segment of the femoral diaphysis and reconstruction with structural bone allografts were performed. In one limb, the allograft was soaked in solution with rhOP-1 for 1 h before implantation. In the other limb, the allograft was soaked in the same solution without rhOP-1. Dynamic load-bearing, radiographic analysis, biomechanical testing, and histomorphometric analysis were conducted. Radiographic analysis showed significantly larger periosteal callus area in the rhOP-1 treated group at week 2. The rhOP-1 significantly increased allograft bone porosity and significantly increased the number of active osteons in the allografts. There were no significant differences between the rhOP-1 treated and non-treated allografts in load bearing and biomechanical analyses. These findings indicate that rhOP- I increases intercalary allograft remodeling without deleterious effects in mechanical and functional strength.


Assuntos
Proteínas Morfogenéticas Ósseas/farmacologia , Transplante Ósseo , Fraturas do Fêmur/tratamento farmacológico , Fraturas do Fêmur/cirurgia , Fator de Crescimento Transformador beta , Animais , Proteína Morfogenética Óssea 7 , Modelos Animais de Doenças , Cães , Fraturas do Fêmur/diagnóstico por imagem , Fixadores Internos , Radiografia , Proteínas Recombinantes/farmacologia , Anormalidade Torcional , Transplante Homólogo , Suporte de Carga
20.
Reg Anesth Pain Med ; 28(4): 271-8, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12945019

RESUMO

BACKGROUND AND OBJECTIVES: The effect of postoperative epidural analgesia (vs. systemic analgesia) on patient outcomes is unclear. Available randomized controlled trials (RCTs) have focused on the intraoperative period and not properly examined the effect of postoperative epidural analgesia (EA) on outcomes. METHODS: A 5% nationally random sample of Medicare beneficiaries from 1994 to 1999 was analyzed to identify patients undergoing total hip arthroplasty (Common Procedural Terminology [CPT] code 27130, 27132, 27134, 27137, 27138). Patients were divided into 2 groups depending on the presence or absence of postoperative EA based on the CPT coding (01996). The rate of major morbidity (acute myocardial infarction, deep venous thrombosis, pulmonary embolism, angina, respiratory failure, heart failure, cardiac dysrhythmias, pneumonia, pulmonary edema, sepsis, acute renal failure, paralytic ileus, acute cerebrovascular event) and death at 7 and 30 days after the procedure were compared. Multivariate regression analysis was performed to determine if the presence of postoperative (EA) had an independent effect on mortality or major morbidity. Data were reported as an odds ratio with 95% confidence intervals (CI) when appropriate. RESULTS: The unadjusted 7- and 30-day death rate was significantly lower for EA versus no EA (1.9/1000 [95% CI: 0.2-3.6] vs. 3.9/1000 [95% CI: 3.0-6.2] at 7 days [P =.04] and 5.8/1000 [95% CI: 2.9-8.7] vs. 9.9/1000 [95% CI: 8.6-11.3] at 30 days [P = 0.01]). However, multivariate regression analysis revealed that there was no difference between the groups with regard to mortality or major morbidity with the exception of an increase in deep venous thrombosis in patients who received EA. CONCLUSIONS: The use of postoperative EA was not associated a lower incidence of mortality and major morbidity in Medicare patients undergoing total hip arthroplasty. However, the results should be interpreted with caution because of limitations in using the Medicare claims data for analysis. Further trials using other properly conducted and designed studies (e.g., RCTs) would be ideal to validate these results.


Assuntos
Analgesia Epidural , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/mortalidade , Dor Pós-Operatória/terapia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Revisão da Utilização de Seguros , Tempo de Internação , Masculino , Medicare , Estudos Retrospectivos , Estados Unidos/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA