Large scale segmental bone defect healing through the combined delivery of VEGF and BMP-2 from biofunctionalized cortical allografts.

Large scale cortical allografts suffer from poor incorporation and healing and often end in graft failure 5-10 years after implantation. To reduce these failures we have developed a growth-factor loaded cortical allograft capable of delivering one or two factors with a degree of temporal control and precision that permits the early release of one growth factor followed by the later and more sustained release of the other. We have loaded vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2), both critical components of bone formation and repair, onto cortical long bone allografts such that the VEGF is released first and followed shortly by BMP-2.

Notch in skeletal physiology and disease.

Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4.

Approach-based Comparative and Predictor Analysis of 30-day Readmission, Reoperation, and Morbidity in Patients Undergoing Lumbar Interbody Fusion Using the ACS-NSQIP Dataset.

Study Design: A retrospective cohort study.

Objective: The aim of this study was to determine the difference in 30-day readmission, reoperation, and morbidity for patients undergoing either posterior or anterior lumbar interbody fusion.

Summary Of Background Data: Despite increasing utilization of lumbar interbody fusion to treat spinal pathology, few studies compare outcomes by surgical approach, particularly using large nationally represented cohorts.

The lateral meningocele syndrome mutation causes marked osteopenia in mice.

Lateral meningocele syndrome (LMS) is a rare genetic disorder characterized by neurological complications and osteoporosis. LMS is associated with mutations in exon 33 of leading to a truncated protein lacking sequences for NOTCH3 degradation and presumably causing NOTCH3 gain of function. To create a mouse model reproducing human LMS-associated mutations, we utilized CRISPR/Cas9 to introduce a tandem termination codon at bases 6691-6696 (ACCAAG→TAATGA) and verified this mutation ( ) by DNA sequencing of F1 mice.

Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo.

Nuclear factor of activated T cells (NFAT) c2 is important for the immune response and it compensates for NFATc1 for its effects on osteoclastogenesis, but its role in this process is not established. To study the function of NFATc2 in the skeleton, Nfatc2 mice, where the Nfact2 exon 2 is flanked by loxP sequences, were created and mated with mice expressing the Cre recombinase under the control of the Lyz2 promoter. Bone marrow-derived macrophage (BMM) from Lyz2 ;Nfatc2 mice cultured in the presence of macrophage-colony stimulating factor and receptor activator of NF-κB ligand exhibited a decrease in the number and size of osteoclasts and a smaller sealing zone when compared to BMMs from Nfatc2 littermate controls.

Biomechanical Comparison of Epiphyseal Anterior Cruciate Ligament Fixation Using a Cortical Button Construct Versus an Interference Screw and Sheath Construct in Skeletally Immature Cadaveric Specimens.

Background: Anterior cruciate ligament (ACL) ruptures have become increasingly common in pediatric and adolescent athletes. While multiple methods exist, all-epiphyseal ACL reconstruction is a popular technique in the skeletally immature patient. Given the high rate of reruptures in this population and the increasing number of commercially available fixation devices, biomechanical testing is crucial to understand the performance of these devices in pediatric epiphyseal bone.

Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis.

Osteoarthritis is a joint disease characterized by cartilage degradation, altered gene expression and inflammation. NOTCH1 and NOTCH2 receptors and the JAGGED1 ligand regulate chondrocyte biology; however, the contribution of Notch signaling to osteoarthritis is controversial. Hajdu Cheney Syndrome (HCS) is a rare genetic disorder affecting the skeleton and associated with NOTCH2 mutations that lead to NOTCH2 gain-of-function.

Glucocorticoids inhibit notch target gene expression in osteoblasts.

Glucocorticoids in excess suppress osteoblast function and cause osteoporosis. We demonstrated that cortisol induces the expression of selected Notch receptors in osteoblasts, revealing a potential mechanism for the skeletal effects of glucocorticoids. However, it remains to be determined whether increased expression of Notch receptors results into enhanced signaling.

Induction of the Hajdu-Cheney Syndrome Mutation in CD19 B Cells in Mice Alters B-Cell Allocation but Not Skeletal Homeostasis.

Mice harboring Notch2 mutations replicating Hajdu-Cheney syndrome (Notch2) have osteopenia and exhibit an increase in splenic marginal zone B cells with a decrease in follicular B cells. Whether the altered B-cell allocation is responsible for the osteopenia of Notch2 mutants is unknown. To determine the effect of NOTCH2 activation in B cells on splenic B-cell allocation and skeletal phenotype, a conditional-by-inversion (COIN) Hajdu-Cheney syndrome allele of Notch2 (Notch2) was used.

MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis.

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts.

The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the Splenic Marginal Zone.

The neurogenic locus notch homolog protein (Notch)-2 receptor is a determinant of B-cell allocation, and gain-of-NOTCH2-function mutations are associated with Hajdu-Cheney syndrome (HCS), a disease presenting with osteoporosis and acro-osteolysis. We generated a mouse model reproducing the HCS mutation (Notch2HCS), and heterozygous global mutant mice displayed gain-of-Notch2 function. In the mutant spleen, the characteristic perifollicular rim marking the marginal zone (MZ), which is the interface between the nonlymphoid red pulp and the lymphoid white pulp, merged with components of the white pulp.

Management of a Tibial Plafond Lung Cancer Metastasis Using an Intramedullary Hindfoot Fusion Nail.

Unlabelled: Metastatic disease to the tibial plafond is rare with few reports in the literature. No consensus exists regarding surgical reconstruction of large structural defects of the ankle due to these lesions, as each treatment must be tailored to the individual patient's goals and prognosis. Cancer metastases pose a unique challenge to limb salvage as there is often bone loss and poor soft tissue quality combined with the need for postoperative adjuvant therapy.

Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders.

Background: There are four Notch transmembrane receptors that determine the fate and function of cells. Notch is activated following its interactions with ligands of the Jagged and Delta-like families that lead to the cleavage and release of the Notch intracellular domain (NICD); this translocates to the nucleus to induce the transcription of Notch target genes. Genetic disorders of loss- and gain-of-NOTCH function present with severe clinical manifestations.

Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes.

Parathyroid hormone (PTH) and Notch receptors regulate bone formation by governing the function of osteoblastic cells. To determine whether PTH interacts with Notch signaling as a way to control osteoblast function, we tested the effects of PTH on Notch activity in osteoblast- and osteocyte-enriched cultures. Notch signaling was activated in osteoblast-enriched cells from wild-type C57BL/6J mice following exposure to the Notch ligand Delta-like (Dll)1 or by the transient transfection of the Notch intracellular domain (NICD), the transcriptionally active fragment of Notch1.

Research Pearls: The Significance of Statistics and Perils of Pooling. Part 3: Pearls and Pitfalls of Meta-analyses and Systematic Reviews.

Within the health care environment, there has been a recent and appropriate trend towards emphasizing the value of care provision. Reduced cost and higher quality improve the value of care. Quality is a challenging, heterogeneous, variably defined concept.

Research Pearls: The Significance of Statistics and Perils of Pooling. Part 1: Clinical Versus Statistical Significance.

Patient-reported outcomes (PROs) are increasingly being used in today's rapidly evolving health care environment. The value of care provision emphasizes the highest quality of care at the lowest cost. Quality is in the eye of the beholder, with different stakeholders prioritizing different components of the value equation.

An Antibody to Notch2 Reverses the Osteopenic Phenotype of Hajdu-Cheney Mutant Male Mice.

Notch receptors play a central role in skeletal development and bone remodeling. Hajdu-Cheney syndrome (HCS), a disease characterized by osteoporosis and fractures, is associated with gain-of-NOTCH2 function mutations. To study HCS, we created a mouse model harboring a point 6955C>T mutation in the Notch2 locus upstream of the proline, glutamic acid, serine, and threonine domain, leading to a Q2319X change at the amino acid level.

Regeneration of Articular Cartilage by Human ESC-Derived Mesenchymal Progenitors Treated Sequentially with BMP-2 and Wnt5a.

The success of cell-based therapies to restore joint cartilage requires an optimal source of reparative progenitor cells and tight control of their differentiation into a permanent cartilage phenotype. Bone morphogenetic protein 2 (BMP-2) has been extensively shown to promote mesenchymal cell differentiation into chondrocytes in vitro and in vivo. Conversely, developmental studies have demonstrated decreased chondrocyte maturation by Wingless-Type MMTV Integration Site Family, Member 5A (Wnt5a).

Hairy and Enhancer of Split-Related With YRPW Motif-Like (HeyL) Is Dispensable for Bone Remodeling in Mice.

Notch induces Hairy Enhancer of Split (Hes)1 and Hes-related with YRPW motif (Hey) Hey1, Hey2 and Hey-like (HeyL) expression in osteoblasts, but it is not known whether any of these target genes mediates the effect of Notch in the skeleton. We demonstrated that Notch1 activation in osteoblasts/osteocytes induces Hes1, Hey1, Hey2, and HeyL, but HeyL was induced to a greater extent than other target genes. To characterize HeyL null mice for their skeletal phenotype, microcomputed tomography (µCT) and histomorphometric analysis of HeyL null and sex-matched littermate controls was performed.

Effects of Sex and Notch Signaling on the Osteocyte Cell Pool.

Osteocytes play a fundamental role in mechanotransduction and skeletal remodeling. Sex is a determinant of skeletal structure, and female C57BL/6J mice have increased osteoblast number in cancellous bone when compared to male mice. Activation of Notch in the skeleton causes profound cell-context dependent changes in skeletal physiology.

Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab.

Notch receptors play a central role in skeletal development and homeostasis. Hajdu Cheney Syndrome (HCS) is a rare disease associated with mutations of NOTCH2 that lead to the translation of a truncated, presumably stable, NOTCH2 protein. As a consequence, a gain-of-NOTCH2 function is manifested.

Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations.

Notch plays an important function in skeletal homeostasis, osteoblastogenesis, and osteoclastogenesis. Hajdu-Cheney syndrome (HCS) is a rare disease associated with mutations in NOTCH2 leading to the translation of a truncated NOTCH2 stable protein. As a consequence, a gain-of-NOTCH2 function is manifested.

Shoulder Stiffness: Current Concepts and Concerns.

Unlabelled: Shoulder stiffness can be caused by various etiologies such as immobilization, trauma, or surgical interventions. The Upper Extremity Committee of ISAKOS defined the term "frozen shoulder" as idiopathic stiff shoulder, that is, without a known cause. Secondary stiff shoulder is a term that should be used to describe shoulder stiffness with a known cause.

Notch Signaling and the Skeleton.

Notch 1 to 4 receptors are important determinants of cell fate and function, and Notch signaling plays an important role in skeletal development and bone remodeling. After direct interactions with ligands of the Jagged and Delta-like families, a series of cleavages release the Notch intracellular domain (NICD), which translocates to the nucleus where it induces transcription of Notch target genes. Classic gene targets of Notch are hairy and enhancer of split (Hes) and Hes-related with YRPW motif (Hey).