Weight-Bearing CT Scan After Tibial Pilon Fracture Demonstrates Significant Early Joint-Space Narrowing.

BACKGROUND: Posttraumatic osteoarthritis (PTOA) is a common and early sequela of tibial pilon fractures resulting in substantial long-term disability. New approaches are needed to objectively and reliably quantify early disease progression in order to critically assess the impact of interventions aimed at preventing or mitigating PTOA. Weight-bearing computed tomography (WBCT) scans provide a means for measuring joint space while the ankle is in a loaded, functional position. We assessed the interrater and intrarater reliability of a standardized, regional method to quantify joint-space loss following tibial pilon fracture compared with the uninjured contralateral ankle. METHODS: We prospectively enrolled 20 patients with intra-articular tibial pilon fractures that were surgically treated at 1 of 2 level-I trauma centers. Six months after injury, bilateral ankle WBCT scans were obtained. Joint space was measured by 4 reviewers at 9 discrete regions of the tibiotalar articulation on sagittal images. Measurements were repeated by reviewers 2 weeks later. To characterize the measurement method, interrater correlation coefficient estimates and test-retest reproducibility were calculated. RESULTS: The mean tibiotalar joint space was 21% less in the injured ankles compared with the contralateral uninjured ankles (p < 0.0001). The middle-lateral and middle-central regions of the joint demonstrated the greatest decrease in joint space between injured and uninured ankles. The interrater correlation coefficient of the measurement technique was 0.88, and the test-retest reproducibility was 0.80, indicating good reliability and reproducibility of the method. CONCLUSIONS: We developed a simple, standardized, and reliable technique to quantify tibiotalar joint space following tibial pilon fracture on WBCT. Significant loss of joint space is seen 6 months after the injury. This tool can be used to longitudinally quantify loss of joint space following pilon fracture and assess the impact of interventions to reduce PTOA.

Rare Post Traumatic Kyphoscoliosis of the Thoracolumbar Spine After Posterior Fusion for Adolescent Idiopathic Scoliosis: A Case Report and Review of the Literature.

Background: Vertebral fracture after posterior arthrodesis and instrumentation for idiopathic scoliosis is a rare occurrence with limited reported cases in the literature. Case Presentation: A 16-year-old female patient surgically treated for adolescent idiopathic scoliosis with T2-L1 posterior spinal fusion was in a low-energy fall resulting in fracture of L1 and new kyphosis and scoliosis of the thoracolumbar spine at the distal aspect of the fusion. The fracture was initially managed conservatively, however pain persisted and thus she was indicated for extension of the fusion and correction of the post-traumatic kyphosis. Conclusions: Fractures after posterior spinal fusion for idiopathic scoliosis are rare and evidence for the appropriate management remains limited in the literature.Level of Evidence: V.

Surgical modifications of the Kasai hepatoportoenterostomy minimize invasiveness without compromising short- and medium-term outcomes.

BACKGROUND: Biliary atresia (BA) causes progressive fibrosis and obliteration of the biliary tree, resulting in bile stasis and eventual liver dysfunction. It affects 1 in 10,000-18,000 infants, and if left untreated, universally leads to liver failure. The Kasai hepatoportoenterostomy (KPE) was developed as an effective surgical therapy for BA and can restore bile drainage into the intestine. Traditionally, the KPE procedure extra-corporealizes the liver to expose the portal plate. Here, we describe modifications to the procedure via a smaller incision in which the liver remains within the abdominal cavity and we compare the outcomes of this technique to previous institutional outcomes and to contemporary international series. MATERIALS AND METHODS: We identified all patients who underwent KPE for BA at a single institution between 1994 and 2012. Patient outcomes after the modified KPE performed from 2004 to 2012 were compared to data from infants who underwent the traditional KPE from 1994 to 2003. RESULTS: Ninety-nine patients were identified. Fifty-two were in the traditional KPE group and 47 in the modified KPE group. There was no difference in mean age at surgery. Median follow-up was 64 months (traditional KPE) and 46 months (modified KPE). The rate of native liver survival (39.1% vs 48.5%), overall survival (89.2% vs 97.8%), liver transplant occurring under one year of age (36.5% vs 40.4%) and median time to liver transplant (188 vs 172 days) were not statistically different between groups (p > 0.05 for all comparisons). The results of the modified KPE compared favorably to published outcomes. CONCLUSION: The described modifications to the KPE appear to yield equivalent outcomes when compared to the traditional KPE procedure and compare well with published outcomes in the literature. It is possible that the procedure described here results in less scarring and technically easier liver transplant procedures. LEVEL OF EVIDENCE: Level III.

Leland G. Hawkins, MD-His Life and Orthopaedic Legacy: Talus Fractures and the Hawkins Classification.

The long history of excellence and continued success of the University of Iowa Department of Orthopedics and Rehabilitation is due to the dedication and talent of generations of faculty, residents and staff. Many former Iowa Orthopedic residents have made significant contributions and become leaders in Orthopedic surgery. An orthopedic surgeon and scholar with roots at the University of Iowa deserving of tribute is Dr. Leland Greene Hawkins. His seminal investigation and interest in fractures of the talus established the well-known Hawkins Classification for talar neck fractures, which revolutionized treatment and quantified the risk of progression to avascular necrosis, earning him attention and respect worldwide.

Additive manufacturing of hydrogel-based materials for next-generation implantable medical devices.

Implantable microdevices often have static components rather than moving parts, and exhibit limited biocompatibility. This paper demonstrates a fast manufacturing method which can produce features in biocompatible materials down to tens of microns in scale, with intricate and composite patterns in each layer. By exploiting unique mechanical properties of hydrogels, we developed a "locking mechanism" for precise actuation and movement of freely moving parts, which can provide functions such as valves, manifolds, rotors, pumps, and delivery of payloads. Hydrogel components could be tuned within a wide range of mechanical and diffusive properties, and can be controlled after implantation without a sustained power supply. In a mouse model of osteosarcoma, triggering of release of doxorubicin from the device over ten days showed high treatment efficacy and low toxicity, at one-tenth of a standard systemic chemotherapy dose. Overall, this platform, called "iMEMS", enables development of biocompatible implantable microdevices with a wide range of intricate moving components that can be wirelessly controlled on demand, in a manner that solves issues of device powering and biocompatibility.

Optimal internal fixation of anatomically shaped synthetic bone grafts for massive segmental defects of long bones.

BACKGROUND: Large segmental bone defects following tumor resection, high-energy civilian trauma, and military blast injuries present significant clinical challenges. Tissue engineering strategies using scaffolds are being considered as a treatment, but there is little research into optimal fixation of such scaffolds. METHODS: Twelve fresh-frozen paired cadaveric legs were utilized to simulate a critical sized intercalary defect in the tibia. Poly-ε-caprolactone and hydroxyapatite composite scaffolds 5 cm in length with a geometry representative of the mid-diaphysis of an adult human tibia were fabricated, inserted into a tibial mid-diaphyseal intercalary defect, and fixed with a 14-hole large fragment plate. Optimal screw fixation comparing non-locking and locking screws was tested in axial compression, bending, and torsion in a non-destructive manner. A cyclic torsional test to failure under torque control was then performed. FINDINGS: Biomechanical testing showed no significant difference for bending or axial stiffness with non-locking vs. locking fixation. Torsional stiffness was significantly higher (P=0.002) with the scaffold present for both non-locking and locking compared to the scaffold absent. In testing to failure, angular rotation was greater for the non-locking compared to locking constructs at each torque level up to 40 N-m (P<0.05). The locking constructs survived a significantly higher number of loading cycles before reaching clinical failure at 30 degrees of angular rotation (P<0.02). INTERPRETATION: The presence of the scaffold increased the torsional stiffness of the construct. Locking fixation resulted in a stronger construct with increased cycles to failure compared to non-locking fixation.

Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential.

The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).

CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways.

The osteoclast is an integral cell of bone resorption. Since osteolytic disorders hinge on the function and dysfunction of the osteoclast, understanding osteoclast biology is fundamental to designing new therapies that curb osteolytic disorders. The identification and study of lysosomal proteases, such as cathepsins, have shed light on mechanisms of bone resorption. For example, Cathepsin K has already been identified as a collagen degradation protease produced by mature osteoclasts with high activity in the acidic osteoclast resorption pits. Delving into the mechanisms of cathepsins and other osteoclast related compounds provides new targets to explore in osteoclast biology. Through our anti-osteoclastogenic compound screening experiments we encountered a modified version of the Cathepsin B inhibitor CA-074: the cell membrane-permeable CA-074Me (L-3-trans-(Propylcarbamoyl) oxirane-2-carbonyl]-L-isoleucyl-L-proline Methyl Ester). Here we confirm that CA-074Me inhibits osteoclastogenesis in vivo and in vitro in a dose-dependent manner. However, Cathepsin B knockout mice exhibited unaltered osteoclastogenesis, suggesting a more complicated mechanism of action than Cathepsin B inhibition. We found that CA-074Me exerts its osteoclastogenic effect within 24 h of osteoclastogenesis stimulation by suppression of c-FOS and NFATc1 pathways.

A review of osteocyte function and the emerging importance of sclerostin.

➤ Osteocytes, derived from osteoblasts, reside within bone and communicate extensively with other bone cell populations to regulate bone metabolism. The mature osteocyte expresses the protein sclerostin, a negative regulator of bone mass.➤ In normal physiologic states, the protein sclerostin acts on osteoblasts at the surface of bone and is differentially expressed in response to mechanical loading, inflammatory molecules such as prostaglandin E2, and hormones such as parathyroid hormone and estrogen.➤ Pathologically, sclerostin dysregulation has been observed in osteoporosis-related fractures, failure of implant osseous integration, metastatic bone disease, and select genetic diseases of bone mass.➤ An antibody that targets sclerostin, decreasing endogenous levels of sclerostin while increasing bone mineral density, is currently in phase-III clinical trials.➤ The osteocyte has emerged as a versatile, indispensable bone cell. Its location within bone, extensive dendritic network, and close communication with systemic circulation and other bone cells produce many opportunities to treat a variety of orthopaedic conditions.

Tau mutants bind tubulin heterodimers with enhanced affinity.

Tau is a microtubule binding protein that forms pathological aggregates in the brain in Alzheimer's disease and other tauopathies. Disease etiology is thought to arise from loss of native interactions between tau and microtubules, as well as from gain of toxicity tied to tau aggregation, although neither mechanism is well understood. Here we investigate the link between function and disease using disease-associated and disease-motivated mutants of tau. We find that mutations to highly conserved proline residues in repeats 2 and 3 of the microtubule binding domain have differential effects on tau binding to tubulin and the capacity of tau to enhance tubulin polymerization. Notably, mutations to these residues result in an increased affinity for tubulin dimers while having a negligible effect on binding to stabilized microtubules. We measure conformational changes in tau on binding to tubulin that provide a structural framework for the observed altered affinity and function. Additionally, we find that these mutations do not necessarily enhance aggregation, which could have important implications for tau therapeutic strategies that focus solely on searching for tau aggregation inhibitors. We propose a model that describes tau binding to tubulin dimers and a mechanism by which disease-relevant alterations to tau impact its function. Together, these results draw attention to the interaction between tau and free tubulin as playing an important role in mechanisms of tau pathology.