Michael Darowish

Smad3-Deficient Chondrocytes Have Enhanced BMP Signaling and Accelerated Differentiation

Smad3 deficiency accelerates chondrocyte maturation and leads to osteoarthritis. Primary chondrocytes without Smad3 lack compensatory increases of TGF‐β signaling factors, but BMP‐related gene expression is increased. Smad2 or Smad3 overexpression and BMP blockade abrogate accelerated maturation in Smad3−/− chondrocytes. BMP signaling is increased in TGF‐β deficiency and is required for accelerated chondrocyte maturation.

Cervical Intervertebral Disc Degeneration Induced by Unbalanced Dynamic and Static Forces: A Novel in Vivo Rat Model

Study Design. Establishment of a novel in vivo animal model of cervical spondylosis. Objective. To investigate apoptotic, degenerative, and inflammatory changes occurring in the cervical intervertebral discs of rats. Summary of Background Data. Cervical degeneration occurs as the result of imbalance of both static and dynamic spinal stabilizers. The disc degeneration that occurs is characterized by increased local inflammation and increased apoptosis of intervertebral disc cells. Methods. By excising the paraspinal musculature and posterior cervical spinal ligaments of rats, both static and dynamic cervical stabilizers were disrupted. The resultant biomechanical imbalance resulted in biochemical and histologic changes, which were characterized by light microscopy, electron microscopy, immunostaining, enzyme-linked immunosorbent assay, polymerase chain reaction, and in situ hybridization. Results. Histologic analysis showed characteristic degenerative changes of the intervertebral discs and vertebral endplates following surgery. Ultrastructural examination revealed apoptotic changes, which were verified by immunostaining. Instability also resulted in significant up-regulation of inflammatory factors, as shown by enzyme-linked immunosorbent assay, polymerase chain reaction, and in situ hybridization. Conclusions. By creating static and dynamic posterior instability of the cervical spine, this novel model of cervical spondylosis results in rapid intervertebral disc degeneration characterized by increased apoptosis and local inflammation, such as that seen clinically.

Intramedullary nailing in open tibia fractures: a comparison of two techniques

We analyzed 51 patients with open tibial fractures treated with intramedullary nailing. In 29 patients the nailing was performed without reaming and in 22 after the “reamed-to-fit” technique. There was no statistically significant difference in the rate of union. The nonreamed group required a greater number of secondary procedures to achieve union and had a higher but not statistically significant incidence of infection. Analysis of the operative and anesthesia cost associated with the additional procedures revealed that on average, patients receiving nonreamed nailing incurred a cost of

Reduction of particle-induced osteolysis by interleukin-6 involves anti-inflammatory effect and inhibition of early osteoclast precursor differentiation

4,900 more per fracture than patients of the reamed-to-fit technique. The healing rates of open tibia fractures using either minimally reamed or nonreamed techniques of intramedullary nailing are comparable. No increase in the rate of infection with the reamed-to-fit technique was found. A significant increase in the number of secondary procedures required to achieve union was found with the nonreamed nailing technique.RésuméNous avons analysé 51 malades avec une fracture tibiale ouverte traitée par enclouage centromédullaire. Pour 29 malades l’enclouage a été exécuté sans alésage et pour 22 avec la technique d’alésage adapté. Il n’y avait aucune différence statistique dans le taux de consolidation. Le groupe sans alésage a exigé un plus grand nombre de gestes secondaires pour obtenir la consolidation et avait un plus grande fréquence d’infection sans que cela soit statistiquement significatif. L’analyse du coût opératoire et de l’anesthésie, associée aux procédures supplémentaires montre qu’en moyenne un malade traité sans alésage a un coût de €4,100 de plus par fracture que le malade avec la technique d’alésage adapté. es taux de consolidation des fractures tibiales ouvertes en utilisant l’enclouage avec alésage adapté ou les techniques sans alésage sont comparables. Aucune augmentation dans le taux d’infection avec la technique d’alésage adapté n’a été trouvée. Une augmentation notable du nombre de procédures secondaires nécessaires pour obtenir la consolidation a été notée avec la technique de l’enclouage sans alésage.

Insulin-like growth factor-1 treatment prevents anti-Fas antibody-induced apoptosis in endplate chondrocytes.

The goal of this study was to define the anti-osteoclastogenic and/or anti-inflammatory role of IL-6 in inflammatory bone resorption using in vivo and in vitro methods. To this end, titanium particles were placed on murine calvaria, and bone resorption and osteoclast formation quantified in wild-type and IL-6(-/-) mice. In this model, calvarial bone loss and osteoclast formation were increased in titanium-treated IL-6(-/-) mice. Although basal numbers of splenic osteoclast precursors (OCP) were similar, IL-6(-/-) mice treated with particles in vivo had increased splenic OCP suggesting an enhanced systemic inflammatory response. In vitro osteoclastogenesis was measured using splenic (OCP) at various stages of maturation, including splenocytes from WT, IL-6(-/-) and TNFalpha transgenic mice. ELISA was used to measure TNFalpha production. IL-6 inhibited osteoclastogenesis in early OCP obtained from wild-type and IL-6(-/-) spleens. Pre-treatment of OCP with M-CSF for three days increased the CD11b(high)/c-Fms+ cell population, resulting in an intermediate staged OCP. Osteoclastogenesis was unaffected by IL-6 in M-CSF pre-treated and TNFalpha transgenic derived OCP. IL-6(-/-) splenocytes secreted greater concentrations of TNFalpha in response to titanium particles than WT; addition of exogenous IL-6 to these cultures decreased TNFalpha expression while anti-IL-6 antibody increased TNFalpha. While IL-6 lacks effects on intermediate staged precursors, the dominant in vivo effects of IL-6 appear to be related to strong suppression of early OCP differentiation and an anti-inflammatory effect targeting TNFalpha. Thus, the absence of IL-6 results in increased inflammatory bone loss.

Radial nerve transposition with humeral fracture fixation: preliminary results.

Study Design. In vitro investigation of vertebral endplate chondrocyte apoptosis. Objectives. To determine whether Fas antibody caused apoptosis in endplate chondrocytes, and whether insulin-like growth factor-1 (IGF-1) inhibited this effect. Integrin-ā1 and focal adhesion kinase (FAK) expression in conjunction with apoptosis was also investigated. Summary of Background Data. Binding of Fas antibody to Fas mimics Fas-FasL ligation, which causes apoptosis. IGF-1 has been shown to have anti-apoptotic effects. Materials and Methods. Rat cervical endplate chondrocytes were cultured and treated with Fas antibody, with or without IGF-1. Cellular morphology was examined by microscopy. Apoptotic changes were evaluated by transmission electron microscopy, TUNEL staining, and immunostaining. Apoptosis-induced changes in the expression of integrin-ā1 chain and FAK were also investigated. Results. Endplate chondrocytes were able to be cultured; a chondrocytic phenotype was maintained. Fas antibody induced apoptosis in endplate chondrocytes; this was confirmed by TUNEL staining. Bcl-2 expression was decreased by Fas antibody, while Bax expression increased. Integrin-ā1 and FAK expression was decreased by Fas antibody. IGF-1 treatment inhibited these Fas antibody-induced changes. Conclusions. Fas antibody induces apoptosis and decreases Integrin-ā1 and FAK expression in cultured endplate chondrocytes; IGF-1 is protective against these changes.

Basic science of bone healing.

Humeral shaft fractures traditionally have been managed with closed treatment. In patients with polytrauma, open fractures, and patients at risk for nonunion, open reduction and internal fixation and intramedullary nailing have been advocated. The current study describes a technique used in humeral shaft fractures that reduces the risk of iatrogenic radial nerve injury during plate osteosynthesis in fracture patterns at high risk of nonunion (highly comminuted, transverse fractures). Ten patients who had radial nerve transposition were reviewed retrospectively using the electronic records database at the authors’ institution. The average age of the patients was 27 years and average followup was 25 months. All had humeral shaft fractures, AO class A3.2 in four patients, B3.2 in five patients, and C2.2 in one patient. All fractures were deemed to be at high risk for nonunion. There were no iatrogenic nerve palsies as a result of the transposition, and no infections. Two patients had delayed or nonunion, who achieved healing after a second intervention. Transposition of the radial nerve is a useful adjunct to plating of humeral shaft fractures in patients at high risk for nonunion. The technique is safe, does not cause iatrogenic injury, and protects the radial nerve during all subsequent approaches to the fracture site.

Q:What is cell phone elbow, and what should we tell our patients?

Bone healing is a complex process that can be influenced by both host and environmental factors. In this article, we review the biology involved in the regeneration of new bone after fracture, and factors influencing bone healing, including diabetes, smoking, NSAID use, and bisphosphonates.

Fracture related ulnar and sciatic nerve transections: a report of two cases and literature review

With prolonged cellular telephone use, people may note the onset of aching, burning, numbness, or tingling in the ulnar forearm and hand. This constellation of symptoms, termed “cell phone elbow” by the lay press, is known medically as cubital tunnel syndrome—the second most common nerve compression syndrome in the upper extremities after carpal tunnel syndrome. In most cases, treatment consists simply of modifying the activity and avoiding activities that aggravate the symptoms. Switching hands frequently while talking on the phone or using a hands-free headset can help. Other daily activities that produce cubital tunnel syndrome include leaning on an elbow while driving or working, and sitting at a computer workstation that requires elbow flexion greater than 90 degrees. Making ergonomic adjustments to these activities is beneficial. For patients who have nocturnal symptoms, a simple elbow pad worn anteriorly or a towel wrapped around the elbow to prevent flexion while sleeping can be very efficacious. Occasionally, anti-inflammatory injections can be given to quiet an inflamed ulnar nerve and reduce symptoms.1 Surgical interventions, discussed below, are available for patients with severe, persistent symptoms. What is cubital tunnel syndrome? ■

Catastrophic intramedullary fragmentation of a tinel reamer.

IntroductionCase reports, case series, and case control studies have looked at the incidence of complete nerve transection in the setting of fracture and the need for surgical exploration dating back to the 1920s. We present two cases of nerve laceration accompanying traumatic fracture with a thorough review of the literature.MethodsWe used the following search terms: “ulnar nerve” OR “sciatic nerve” AND “laceration” OR “transection” AND “fracture.” Results were reviewed and included for discussion if they specifically reported ulnar or sciatic nerve laceration accompanying traumatic fracture.ResultsOur search yielded 15 papers reporting a total of 10 ulnar nerve lacerations and nine sciatic nerve lacerations. We present two additional cases. The first is a patient with a humerus fracture and complete ulnar nerve transection. The second case is a patient who suffered a femur fracture and complete transection of the sciatic nerve.ConclusionNerve laceration accompanying traumatic fracture is rare. We review the reported cases of nerve laceration and present two cases treated at our institution. Though uncommon, nerve laceration should be considered in the setting of traumatic fracture with neurological injury, particularly open fractures.