Caspase-1 and the inflammasome promote polycystic kidney disease progression.

We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1ß and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous (PKD1 RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.

Critical Role of Osteopontin in Maintaining Urinary Phosphate Solubility in CKD.

Background: Nephron loss dramatically increases tubular phosphate to concentrations that exceed supersaturation. Osteopontin (OPN) is a matricellular protein that enhances mineral solubility in solution; however, the role of OPN in maintaining urinary phosphate solubility in CKD remains undefined. Methods: Here, we examined (1) the expression patterns and timing of kidney/urine OPN changes in CKD mice, (2) if tubular injury is necessary for kidney OPN expression in CKD, (3) how OPN deletion alters kidney mineral deposition in CKD mice, (4) how neutralization of the mineral-binding (ASARM) motif of OPN alters kidney mineral deposition in phosphaturic mice, and (5) the in vitro effect of phosphate-based nanocrystals on tubular epithelial cell OPN expression. Results: Tubular OPN expression was dramatically increased in all studied CKD murine models. Kidney OPN gene expression and urinary OPN/Cr ratios increased before changes in traditional biochemical markers of kidney function. Moreover, a reduction of nephron numbers alone (by unilateral nephrectomy) was sufficient to induce OPN expression in residual nephrons and induction of CKD in OPN-null mice fed excess phosphate resulted in severe nephrocalcinosis. Neutralization of the ASARM motif of OPN in phosphaturic mice resulted in severe nephrocalcinosis that mimicked OPN-null CKD mice. Lastly, in vitro experiments revealed calcium-phosphate nanocrystals to induce OPN expression by tubular epithelial cells directly. Conclusions: Kidney OPN expression increases in early CKD and serves a critical role in maintaining tubular mineral solubility when tubular phosphate concentrations are exceedingly high, as in late-stage CKD. Calcium-phosphate nanocrystals may be a proximal stimulus for tubular OPN production.

Contribution of phosphate and FGF23 to CKD progression.

PURPOSE OF REVIEW: Progressive forms of chronic kidney disease (CKD) exhibit kidney inflammation and fibrosis that drive continued nephron loss; however, factors responsible for the development of these common pathologic features remain poorly defined. Recent investigations suggest pathways involved in maintaining urinary phosphate excretion in CKD may be contributing to kidney function decline. This review provides an update on recent evidence linking altered phosphate homeostasis to CKD progression. RECENT FINDINGS: High dietary phosphate intake and increased serum concentrations of fibroblast growth factor 23 (FGF23) both increase urinary phosphate excretion and are associated with increased risk of kidney function decline. Recent investigations have discovered high concentrations of tubular phosphate promote phosphate-based nanocrystal formation that drives tubular injury, cyst formation, and fibrosis. SUMMARY: Studies presented in this review highlight important scientific discoveries that have molded our current understanding of the contribution of altered phosphate homeostasis to CKD progression. The collective observations from these investigations implicate phosphaturia, and the resulting formation of phosphate-based crystals in tubular fluid, as unique risk factors for kidney function decline. Developing a better understanding of the relationship between tubular phosphate handling and kidney pathology could result in innovative strategies for improving kidney outcomes in patients with CKD.

Comparison of Lateralizing Calcaneal Osteotomies for Varus Hindfoot Correction.

BACKGROUND: There is limited consensus on the optimal operative technique for correcting heel varus in patients with Charcot-Marie-Tooth (CMT) disease. This comparative study evaluated the ability of 4 lateralizing calcaneal osteotomies, with and without Dwyer wedge resection and coronal rotation of the posterior tuberosity, to correct severe heel varus. METHODS: The computed tomography (CT) scan of a teenage CMT patient with severe hindfoot varus was used to create 3-dimensional (3D)-printed models of the talus, calcaneus, and cuboid. A custom jig facilitated precise replication of the osteotomy cuts. Four different configurations were created: oblique osteotomy with lateralization, oblique osteotomy with lateralization and internal rotation of the posterior tuberosity, Dwyer wedge resection with lateralization, and Dwyer wedge resection with lateralization and internal rotation. CT scans were performed on each model before and after osteotomy. Statistical analysis was used to evaluate differences in several predefined radiographic parameters. RESULTS: The sequential transformations generated increasing lateral translation of the weight-bearing calcaneus. Dwyer wedge osteotomy significantly improved lateralization (effect = 8.0 mm), valgus hindfoot angle (effect = 6.1 degrees), and coronal calcaneal tilt (effect = -17.6 degrees) compared with the oblique osteotomy. Internal rotation of the posterior tuberosity further improved lateralization (effect = 3.3 mm), valgus hindfoot angle (effect = 2.5 degrees), and coronal calcaneal tilt (effect = -11.7 degrees). Dwyer osteotomy models had on average 5-mm shorter posterior tuberosity lengths than the oblique osteotomies. The addition of rotation did not significantly affect length. CONCLUSIONS: Significant lateralization of the posterior tuberosity was achieved in all transformations. The Dwyer wedge osteotomy improved hindfoot valgus angle, coronal calcaneal tilt, and lateralization of the weight-bearing surface compared with oblique osteotomy. Posterior tuberosity internal rotation further lateralized the plantar surface and normalized weight bearing. Lateralization, combined with Dwyer osteotomy and coronal plane internal rotation, achieved the greatest correction of varus heel. CLINICAL RELEVANCE: This study compares multiple lateralizing calcaneal osteotomies and proposes a combined technique of lateralization, Dwyer wedge resection, and coronal plane rotation to address advanced cavovarus hindfoot deformities.

Ouabain Regulates CFTR-Mediated Anion Secretion and Na,K-ATPase Transport in ADPKD Cells.

Cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) requires the transepithelial secretion of fluid into the cyst lumen. We previously showed that physiological amounts of ouabain enhance cAMP-dependent fluid secretion and cyst growth of human ADPKD cyst epithelial cells in culture and formation of cyst-like dilations in metanephric kidneys from Pkd1 mutant mice. Here, we investigated the mechanisms by which ouabain promotes cAMP-dependent fluid secretion and cystogenesis. Ouabain (3 nM) enhanced cAMP-induced cyst-like dilations in embryonic kidneys from Pkd1 (m1Bei) mice, but had no effect on metanephroi from Pkd1 (m1Bei) mice that lack expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Similarly, ouabain stimulation of cAMP-induced fluid secretion and in vitro cyst growth of ADPKD cells were abrogated by CFTR inhibition, showing that CFTR is required for ouabain effects on ADPKD fluid secretion. Moreover, ouabain directly enhanced the cAMP-dependent Cl(-) efflux mediated by CFTR in ADPKD monolayers. Ouabain increased the trafficking of CFTR to the plasma membrane and up-regulated the expression of the CFTR activator PDZK1. Finally, ouabain decreased plasma membrane expression and activity of the Na,K-ATPase in ADPKD cells. Altogether, these results show that ouabain enhances net fluid secretion and cyst formation by activating apical anion secretion via CFTR and decreasing basolateral Na(+) transport via Na,K-ATPase. These results provide new information on the mechanisms by which ouabain affects ADPKD cells and further highlight the importance of ouabain as a non-genomic stimulator of cystogenesis in ADPKD.

The ability of massive osteochondral allografts from the medial tibial plateau to reproduce normal joint contact pressures after glenoid resurfacing: the effect of computed tomography matching.

BACKGROUND: Current techniques for resurfacing of the glenoid in the treatment of arthritis are unpredictable. Computed tomography (CT) studies have demonstrated that the medial tibial plateau has close similarity to the glenoid. The purpose of this study was to assess contact pressures of transplanted massive tibial osteochondral allografts to resurface the glenoid without and with CT matching. METHODS: Ten unmatched cadaveric tibiae were used to resurface 10 cadaveric glenoids with osteochondral allografts. Five cadaveric tibiae and glenoids were CT matched and studied. An internal control group of 4 matched pairs of glenoids, with the contralateral glenoid transplanted to the opposite glenoid, was also included as a best-case scenario to measure the effects of the surgical technique. All glenoids were tested before and after grafting at different abduction and rotation angles, with recording of peak contact pressures. RESULTS: Peak contact pressures were not different from the intact state in the autografted group but were increased in both allografted groups. CT-matched tibial grafts had lower peak pressures than unmatched grafts. Peak pressures were on average 24.8% (range [18.3%, 29.6%]) greater than in the native glenoids for unmatched allografts, 21.8% ([17.0%, 25.5%]) greater for the matched allografts, and 4.9% ([3.8%, 5.5%]) greater for matched autografts. CONCLUSION: Osteochondral grafting from the medial tibial plateau to the glenoid is feasible but results in increased peak contact pressures. The technique is reproducible as defined by the autografted group. Contact pressures between native and allografted glenoids were significantly different. The clinical significance remains unknown. Peak pressures experienced by the glenoid seem highly sensitive to deviations from the native glenoid shape.

Characterization of robotic system passive path repeatability during specimen removal and reinstallation for in vitro knee joint testing.

Robotic testing systems are commonly utilized for the study of orthopaedic biomechanics. Quantification of system error is essential for reliable use of robotic systems. Therefore, the purpose of this study was to quantify a 6-DOF robotic system's repeatability during knee biomechanical testing and characterize the error induced in passive path repeatability by removing and reinstalling the knee. We hypothesized removing and reinstalling the knee would substantially alter passive path repeatability. Testing was performed on four fresh-frozen cadaver knees. To determine repeatability and reproducibility, the passive path was collected three times per knee following the initial setup (intra-setup), and a single time following two subsequent re-setups (inter-setup). Repeatability was calculated as root mean square error. The intra-setup passive path had a position repeatability of 0.23 mm. In contrast, inter-setup passive paths had a position repeatability of 0.89 mm. When a previously collected passive path was replayed following re-setup of the knee, resultant total force repeatability across the passive path increased to 28.2N (6.4N medial-lateral, 25.4N proximal-distal, and 10.5 N anterior-posterior). This study demonstrated that removal and re-setup of a knee can have substantial, clinically significant changes on our system's repeatability and ultimately, accuracy of the reported results.

Altered tibiofemoral contact mechanics due to lateral meniscus posterior horn root avulsions and radial tears can be restored with in situ pull-out suture repairs.

BACKGROUND: An avulsion of the posterior root attachment of the lateral meniscus or a radial tear close to the root attachment can lead to degenerative knee arthritis. Although the biomechanical effects of comparable injuries involving the medial meniscus have been studied, we are aware of no such study involving the lateral meniscus. We hypothesized that in situ pull-out suture repair of lateral meniscus root avulsions and of complete radial tears 3 and 6 mm from the root attachment would increase the contact area and decrease mean and peak tibiofemoral contact pressures, at all knee flexion angles, relative to the corresponding avulsion or tear condition. METHODS: Eight human cadaveric knees underwent biomechanical testing. Eight lateral meniscus conditions (intact, footprint tear, root avulsion, root avulsion repair, radial tears at 3 and 6 mm from the posterior root, and repairs of the 3 and 6-mm tears) were tested at five different flexion angles (0°, 30°, 45°, 60°, and 90°) under a compressive 1000-N load. RESULTS: Avulsion of the posterior root of the lateral meniscus or an adjacent radial tear resulted in significantly decreased contact area and increased mean and peak contact pressures in the lateral compartment, relative to the intact condition, in all cases except the root avulsion condition at 0° of flexion. In situ pull-out suture repair of the root avulsion or radial tear significantly reduced mean contact pressures, relative to the corresponding avulsion or tear condition, when the results for each condition were pooled across all flexion angles. CONCLUSIONS: Posterior horn root avulsions and radial tears adjacent to the root attachment of the lateral meniscus significantly increased contact pressures in the lateral compartment. In situ pull-out suture repairs of these tears significantly improved lateral compartment joint contact pressures. CLINICAL RELEVANCE: In situ repair may be an effective treatment to improve tibiofemoral contact profiles after an avulsion of the posterior root of the lateral meniscus or a complete radial tear adjacent to the root. In situ repairs should be further investigated clinically as an alternative to partial lateral meniscectomy.

Biomechanical consequences of a complete radial tear adjacent to the medial meniscus posterior root attachment site: in situ pull-out repair restores derangement of joint mechanics.

BACKGROUND: Complete radial tears near the medial meniscus posterior root attachment site disrupt the circumferential integrity of the meniscus (similar to a posterior root avulsion). These tears can compromise the circumferential integrity, and they have been reported in biomechanical studies to be comparable with the meniscectomized state. PURPOSE: To quantify the tibiofemoral contact pressure and contact area changes that occur in cadaveric knees from complete posterior horn radial tears and subsequent repairs of the medial meniscus adjacent to the posterior root attachment site. STUDY DESIGN: Controlled laboratory study. METHODS: Six nonpaired fresh-frozen human cadaveric knees each underwent 45 different testing conditions: 9 medial meniscus conditions (intact, root avulsion, root repair, serial radial tear at 3, 6, and 9 mm from the root attachment site, and in situ repair at the same 3 distances from the root attachment site) at 5 flexion angles (0°, 30°, 45°, 60°, and 90°), under a 1000-N axial load. Tekscan sensors were used to measure contact area and pressure in the medial and lateral compartments. RESULTS: The medial meniscus root avulsion and all radial tear conditions resulted in significantly decreased contact area and increased mean contact pressure compared with the intact state for knee flexion angles beyond 0° (P < .05). The root repair and in situ repairs restored contact area and pressure to levels statistically indistinguishable from those of the intact meniscus and increased contact area and decreased contact pressure compared with the corresponding tear conditions. CONCLUSION: Posterior horn radial tears adjacent to the medial meniscus root that extend to the meniscocapsular junction can lead to derangement of the loading profiles of the medial compartment that are similar to a root avulsion. Repair of these radial tears with an in situ pull-out technique restored joint mechanics to the intact state. CLINICAL RELEVANCE: Complete radial tears of the posterior horn of the medial meniscus, which occur relatively frequently, are biomechanically equivalent to root avulsions and could potentially lead to medial compartment arthrosis. An in situ repair offers an alternative treatment to meniscectomy and can reestablish the posterior anchor point, thus improving load distribution in the medial compartment. Future clinical studies of these repairs are recommended.

The hip fluid seal--Part I: the effect of an acetabular labral tear, repair, resection, and reconstruction on hip fluid pressurization.

PURPOSE: The acetabular labrum is theorized to be important to normal hip function by creating intra-articular fluid pressurization through the hip fluid seal. However, the effect of a labral tear or partial labral resection, and interventions including labral repair and labral reconstruction, on the hip fluid seal remains to be defined. The purpose of this study was to characterize intra-articular fluid pressurization in six labral conditions: intact, tear, repair (looped vs. through sutures), partial resection, reconstruction with iliotibial band, and complete resection. METHODS: Eight cadaveric hips with a mean age of 47.8 years (SD 4.3, range 41-51) were included in the study. For each labral condition, the hip was compressed with a force of 2.7 times body weight (2,118 N) while intra-articular pressure was continuously measured with 1.0 × 0.3 mm pressure transducers. Peak intra-articular pressure measurements for each condition were normalized relative to the intact state. Statistical analyses were performed utilizing linear mixed-effects models with repeated measures analysis. RESULTS: Intra-articular fluid pressurization of the intact state varied from 78 to 422 kPa (mean 188 kPa ± SD 120). Labral tear, partial resection, and complete resection resulted in average pressurization of 75 ± 33, 53 ± 37, and 24 ± 18 %, respectively compared with the intact state. Through type labral repair resulted in significantly greater increases in pressurization from the labral tear state, compared with the looped type repair (median increase; +46 vs. -12 %, p = 0.029). Labral reconstruction resulted in a mean pressurization of 110 ± 38 % relative to intact state, with a significant 56 ± 47 % improvement in pressurization compared with partial labral resection (p = 0.009). CONCLUSIONS: Partial labral resection caused significant decreases in intra-articular fluid pressurization. Through type labral suture repair restored the fluid pressurization better than looped type repairs. Labral reconstruction significantly improved pressurization to levels similar to the intact state. This study demonstrated the effect of labral tears and partial resections on intra-articular fluid pressurization via the hip fluid seal, and it also demonstrated improvements in pressurization seen with through type labral repairs and labral reconstructions.

The hip fluid seal--Part II: The effect of an acetabular labral tear, repair, resection, and reconstruction on hip stability to distraction.

PURPOSE: The acetabular labrum is theorized to be important to normal hip function by providing stability to distraction forces through the suction effect of the hip fluid seal. The purpose of this study was to determine the relative contributions of the hip capsule and labrum to the distractive stability of the hip, and to characterize hip stability to distraction forces in six labral conditions: intact labrum, labral tear, labral repair (looped vs. through sutures), partial resection, labral reconstruction with iliotibial band, and complete resection. METHODS: Eight cadaveric hips with a mean age of 47.8 years (SD 4.3, range 41-51 years) were included. For each condition, the hip seal was broken by distracting the hip at a rate of 0.33 mm/s while the required force, energy, and negative intra-articular pressure were measured. For comparisons between labral conditions, measurements were normalized to the intact labral state (percent of intact). RESULTS: The relative contribution of the labrum to distractive stability was greatest at 1 and 2 mm of displacement, where it was significantly greater than the role of the capsule and accounted for 77 % (SD 27 %, p = 0.006) and 70 % (SD 7 %, p = 0.009) of total distractive stability, respectively. The relative contribution of the capsule to distractive stability increased with progressive displacement, providing 41 % (SD 49 %) and 52 % (SD 53 %) of distractive stability at 3 and 5 mm of distraction, respectively. The maximal distraction force required to break the hip seal in the intact labral state (capsule removed) varied from 124 to 150 N. Labral tear, partial resection, and complete resection resulted in average maximal distraction forces of 76 % (SD 34 %), 29 % (SD 26 %), and 27 % (SD 22 %), respectively, compared to the intact state. Through type labral repairs resulted in significantly greater improvements (from the labral tear state) in maximal negative pressure generated, compared to looped type repairs (median increase; +32 vs. -9 %, p = 0.029). Labral reconstruction resulted in a mean maximal distraction force of 66 % (SD 35 %), with a significant improvement of 37 % compared to partial labral resection (p < 0.001). CONCLUSION: The acetabular labrum was the primary hip stabilizer to distraction forces at small displacements (1-2 mm). Partial labral resection significantly decreased the distractive strength of the hip fluid seal. Labral reconstruction significantly improved distractive stability, compared to partial labral resection. The results of this study may provide insight into the relative importance of the capsule and labrum to distractive stability of the hip and may help to explain hip microinstability in the setting of labral disease.

Stability of mid-shaft clavicle fractures after plate fixation versus intramedullary repair and after hardware removal.

PURPOSE: Operative treatment for middle-third clavicle fractures has been increasing as recent data has demonstrated growing patient dissatisfaction and functional deficits after non-operative management. A controlled biomechanical comparison of the characteristics of locked intramedullary (IM) fixation versus superior pre-contoured plating for fracture repair and hardware removal is warranted. Therefore, the purpose of the present study was to investigate potential differences between these devices in a biomechanical model. METHODS: Thirty fourth-generation composite clavicles were randomized to one of five groups with 6 specimens each and tested in a random order. The groups tested were intact, repair with plate, repair with IM device, plate removal, and IM device removal. The lateral end of the clavicles was loaded to failure at a rate of 60 mm/min in a cantilever bending setup. Failure mechanism, energy (J), and torque (Nm) at the site of failure were recorded. RESULTS: Failure torque of the intact clavicle (mean ± standard deviation) was 36.5 ± 7.3 Nm. Failure torques of the IM repair (21.5 ± 9.0 Nm) and plate repair (18.2 ± 1.6 Nm) were not significantly different (n.s.) but were significantly less than the intact group (P < 0.05). Failure torque following IM device removal (30.2 ± 6.5 Nm) was significantly greater than plate removal (12.9 ± 2.0 Nm) (P < 0.05). No significant differences were observed between the intact and IM device removal groups (n.s.). CONCLUSION: The results of the current study demonstrate that IM and plate devices provide similar repair strength for middle-third clavicle fractures. However, testing of the hardware removal groups found the IM device removal group to be significantly stronger than the plate removal group.

Functional bracing of ACL injuries: current state and future directions.

PURPOSE: Functional braces are commonly prescribed to treat anterior cruciate ligament (ACL) injury. The results of the existing literature on functional brace use are mixed. The purpose of this study was to evaluate the history and current state of functional ACL bracing and to identify design criteria that could improve upon current bracing technologies. METHODS: A literature search was performed through the PubMed MEDLINE database in April 2013 for the keywords "anterior cruciate ligament" and "brace". Articles published between January 1, 1980, and April 4, 2013, were retrieved and reviewed. Current functional braces used to treat ACL injury were identified. The function of the native ACL was carefully studied to identify design requirements that could improve upon current bracing technologies. RESULTS: Biomechanical evaluations of functional brace effects at time zero have been mixed. Functional brace use reportedly does not improve long-term patient outcomes following ACL reconstruction, but has been shown to reduce subsequent injury rates while skiing in both ACL-deficient and reconstructed skiers. In situ force in the ACL varies with flexion angle and activity. Currently, no brace has been designed and validated to replicate the force-flexion behavior of the native ACL. CONCLUSIONS: Biomechanical and clinical evidence suggests current functional bracing technologies do not sufficiently restore normal biomechanics to the ACL-deficient knee, protect the reconstructed ACL, and improve long-term patient outcomes. Further research into a functional brace designed to apply forces to the knee joint similar in magnitude to the native ACL should be pursued. LEVEL OF EVIDENCE: III.

Biomechanical evaluation of knotless anterior and posterior Bankart repairs.

PURPOSE: The value of modern tape-like suture materials and the influence of the number of anchors inserted for arthroscopic Bankart repairs compared to the intact state have yet to be investigated. It was hypothesised: (1) suture-tape repairs will show higher biomechanical strength than common suture repairs, (2) four anchors will be stronger than three, and (3) the strength of the native capsulolabral complex will be greater than repairs. METHODS: Six matched-paired cadaveric shoulders received Bankart lesions/reconstructions and three underwent intact state testing. Anteroinferior repairs compared suture and suture-tape repairs using three anchors, while posteroinferior repairs compared three and four suture anchors using common sutures. An established testing protocol was run for biomechanical testing. RESULTS: There was no significant difference in the maximum loads, loads at 2 mm displacement, stiffness or energy between repair groups or between repairs and the intact state (n.s.). However, failure modes were different: 16/24 (66.7%) of the repair groups showed glenoid labrum detachment compared to 2/12 (16.7%) within the intact state group (P = 0.012). CONCLUSIONS: While biomechanical parameters of repairs and intact states showed equivalence, failure-mode analysis reaffirms previous findings that capsulolabrum complex refixation is weaker than the native attachment. Therefore, in daily clinical practice, type of suture is secondary and insertion of a fourth anchor will be unlikely to add strength but may confer additional risk and cost.

Fracture mechanics of the femoral neck in a composite bone model: effects of platen geometry.

Load applicator (platen) geometry used for axial load to failure testing of the femoral neck varies between studies and the biomechanical consequences are unknown. The purpose of this study was to determine if load application with a flat versus a conical platen results in differing fracture mechanics. Femurs were aligned in 25° of adduction and an axial compressive force was applied to the femoral heads at a rate of 6 mm/min until failure. Load application with the conical platen resulted in an average ultimate failure load, stiffness, and energy to failure of 9067 N, 4033 N/mm, and 12.12 J, respectively. Load application with the flat platen resulted in a significant (p<0.05) reduction in ultimate failure load (7620 N) and stiffness (2924 N/mm). Energy to failure (12.30 J) was not significantly different (p=0.893). Different fracture patterns were observed for the two platens and the conical platen produced fractures more similar to clinical observations. Use of a flat platen underestimates the strength and stiffness of the femoral neck and inaccurately predicts the associated fracture pattern. These findings must be considered when interpreting the results of prior biomechanical studies on femoral neck fracture and for the development of future femoral neck fracture models.

Normal curvature of glenoid surface can be restored when performing an inlay osteochondral allograft: an anatomic computed tomographic comparison.

PURPOSE: The purpose of this study was to quantitatively measure the morphology of the glenoid and to assess feasibility of using the medial tibial plateau surface as a donor for osteoarticular allograft reconstruction of the glenoid. METHODS: Using computed tomography (CT), 10 tibias and 10 scapular models from our database (5 males and 5 females in each group) were randomly selected. Commercial software (Mimics, Materialize, Inc., Plymouth, MI) was used to extract the bone contours from the CT images and to reconstruct the 3-dimensional (3D) geometry of the scapula and tibia. By utilizing the software Creo Elements/Pro 5.0 (Parametric Technology Corp., Needham, MA), mean length and width of both the glenoid and medial tibial plateau were calculated. Radius of curvature was then measured in each 3D CT model at three intermediate segment points that were established within the length line at 25, 50, and 75 percent from superior to inferior in the glenoid and from posterior to anterior in the medial tibial plateau. Statistical analysis was performed and determined to be significant for P < 0.05. RESULTS: The mean (± SD) radius of curvature values at the established 25, 50, and 75 percent segments of the glenoid were 47.4 ± 17.5 mm, 51.2 ± 12.4 mm, and 45.9 ± 17.0 mm, respectively. For the medial tibial plateau, the radius of curvature at 25, 50, and 75 percent were 43.5 ± 9.7 mm, 37.4 ± 14.3 mm and 52.3 ± 21.5 mm, respectively. Values of the glenoid length were 34.0 ± 2.9 mm, and width values were 24.4 ± 2.3 mm. For the medial tibial plateau, the length was 42.6 ± 2.7 mm, and the width was 23.3 ± 4.3 mm. There was no statistical difference in the radius of curvature and dimensional surface area between the glenoid and medial tibial plateau surfaces. CONCLUSION: The 3D CT-based anatomic study found that there is a statistically similar relationship in the radius of curvature of the glenoid and the medial tibial plateau surface. This concept may allow the medial tibial plateau to be used as a donor for osteoarticular allograft reconstruction of the glenoid, especially in young patients where previous studies have demonstrated that the success rate in shoulder replacements is not as good as in older patients.

Cam lesion femoral osteoplasty: in vitro biomechanical evaluation of iatrogenic femoral cortical notching and risk of neck fracture.

PURPOSE: To investigate the effect of femoral cortical notching at different depths on the peak compressive load and energy required to cause a femoral neck fracture in composite femurs. METHODS: Thirty fourth-generation composite femurs were divided into 5 groups: (1) intact with an inherent alpha angle of 61°, (2) resection of inherent cam lesion by reducing the alpha angle from 61° to 45°, (3) cam resection and cortical notching of a 5.5-mm spherical diameter by 2.00-mm (grade I) depth, (4) cam resection with cortical notching of 4.00-mm (grade II) depth, and (5) cam resection with cortical notching of 6.00-mm (grade III) depth. The specimens were loaded in the position of midstance during gait and tested until failure using a dynamic tensile testing machine at a rate of 6 mm/min. RESULTS: Grade II and grade III cortical notching depths with cam resections resulted in a significant decrease in the ultimate load to failure and energy (P < .05) compared with the intact state. The grade II and grade III cortical notching groups with cam resection failed at a significantly lower ultimate load and with significantly lower energy when compared with the cam resection group alone. CONCLUSIONS: The findings of this study demonstrated significant decreases in ultimate load and energy to failure between the intact group and the grade II and grade III femoral cortical notching groups with cam resection. CLINICAL RELEVANCE: Iatrogenic cortical notching may lead to an increased risk of postsurgical complications, specifically femoral neck fracture. Thus, surgical intervention for a cam lesion femoral osteoplasty should strive for precision, especially around the femoral neck.

Overexpression of the polycystin-1 C-tail enhances sensitivity of M-1 cells to ouabain.

Cells derived from renal cysts of patients with autosomal dominant polycystic kidney disease (ADPKD) are abnormally sensitive to ouabain, responding to physiological ouabain concentrations with enhanced proliferation and increased forskolin-induced transepithelial fluid secretion. This requires activation of the epidermal growth factor receptor (EGFR), Src kinase and the extracellular signal-regulated kinases MEK and ERK. Here, we have determined if the ADPKD phenotype obtained in mouse cortical collecting duct cells by stable overexpression of the C-terminal domain of polycystin-1 (PC-1 C-tail) also elicits the ADPKD-like response to ouabain in the cells. M-1 C20 cells expressing the PC-1 C-tail and M-1 C17 cells lacking expression of this construct were treated with physiological concentrations of ouabain, and cell proliferation, activation of the EGFR-Src-MEK-ERK pathway, forskolin-induced transepithelial Cl(-) secretion and the sensitivity of Na,K-ATPase to ouabain were explored. M-1 C20 cells responded to ouabain with increased cell proliferation and ERK phosphorylation. Ouabain also augmented forskolin-induced and cystic fibrosis transmembrane conductance regulator-mediated apical secretion of Cl(-) in M-1 C20 cells. These effects required activation of EGFR, Src and MEK. In contrast, ouabain had no significant effects on M-1 C17 cells. Interestingly, approximately 20% of the Na,K-ATPase from M-1 C20 cells presented an abnormally increased sensitivity to ouabain. Overexpression of PC-1 C-tail in M-1 C20 cells is associated with an ouabain-sensitive phenotype and an increased ability of the cells to proliferate and secrete anions upon ouabain stimulation. This phenotype mimics the ouabain sensitivity of ADPKD cells and may help promote their cystogenic potential.

Biomechanical comparison of anatomic single- and double-bundle anterior cruciate ligament reconstructions: an in vitro study.

BACKGROUND: Arthroscopic identification of the anteromedial (AM) and posterolateral (PL) bundle locations of the anterior cruciate ligament (ACL) has facilitated an improved quantitative description of ACL anatomy. Few studies have directly compared the biomechanical laxity of anatomic single-bundle (SB) versus anatomic double-bundle (DB) ACL reconstruction techniques based on precise anatomic descriptions. HYPOTHESIS: Anatomic tunnel positioning for SB and DB reconstructions would produce comparable anterior-posterior and rotatory knee laxity. STUDY DESIGN: Controlled laboratory study. METHODS: Nine matched pairs of cadaveric knees were evaluated for the kinematics of intact, ACL-deficient, and either anatomic SB or anatomic DB ACL-reconstructed knees. Reconstruction tunnels were placed either centrally in the ACL footprint or within the AM and PL footprints. A 6 degrees of freedom robotic system was used to assess knee laxity with an 88-N anterior tibial load and a simulated pivot-shift test of combined 10-N · m valgus and 5-N · m internal tibial torques. Rotational motion was measured with internal and external torques of 5 N · m along with varus and valgus torques of 10 N · m. One-sample and 2-sample independent t tests were used to compare between groups (P < .05). RESULTS: No significant differences were found between anatomic SB and DB reconstruction groups during anterior tibial loading. Anterior tibial translations during simulated pivot shift had no significant differences between anatomic reconstruction groups. Tibial rotation for internal/external and varus/valgus torques showed no significant differences between anatomic reconstructions, with the exception of small (<3°) but statistically significant differences in internal rotation at 20° and 30° of flexion. Despite the similar behavior between the 2 anatomic reconstruction groups, neither technique was able to reproduce the intact state during an anterior tibial load. CONCLUSION: No significant differences in anterior translation were found between the anatomic SB and anatomic DB ACL reconstructions for simulated pivot shift or anterior tibial loading. CLINICAL RELEVANCE: Although significant differences between reconstructions were observed for internal rotation, the small magnitude of these differences (<3°) may not have clinical significance.

Biomechanical comparison of interference screws and combination screw and sheath devices for soft tissue anterior cruciate ligament reconstruction on the tibial side.

BACKGROUND: The tibial fixation site has been reported to be the weakest point in anterior cruciate ligament (ACL) reconstructions. Numerous interference screws and combination screw and sheath devices are available for soft tissue fixation, and a biomechanical comparison of these devices is necessary. HYPOTHESIS: Combination screw and sheath devices would provide superior soft tissue fixation properties compared with interference screws in a porcine model. STUDY DESIGN: Controlled laboratory study. METHODS: Eight different intratunnel tibial soft tissue fixation devices were biomechanically tested in a porcine model with bovine tendons, with 10 specimens per group. The soft tissue fixation devices included 3 interference screws-the Bio-Interference Screw, BIOSURE PK, and RCI Screw-and 5 combination screw and sheath devices (combination devices)-the AperFix II, BIOSURE SYNC, ExoShape, GraftBolt, and INTRAFIX. The specimens were subjected to cyclic (1000 cycles, 50-250 N, 0.5 Hz) and pull-to-failure loading (50 mm/min) with a dynamic tensile testing machine. Ultimate failure load (N), cyclic displacement (mm), pull-out stiffness (N/mm), displacement at failure (mm), load at 3 mm displacement (N), and mechanism of failure were recorded. RESULTS: The ultimate failure loads were highest for the GraftBolt (1136 ± 115.6 N), followed by the INTRAFIX (1127 ± 155.0 N), AperFix II (1122 ± 182.9 N), BIOSURE PK (990.8 ± 182.1 N), Bio-Interference Screw (973.3 ± 95.82 N), BIOSURE SYNC (829.5 ± 172.4 N), RCI Screw (817.7 ± 113.9 N), and ExoShape (814.7 ± 178.8 N). The AperFix II, GraftBolt, and INTRAFIX devices were significantly stronger than the BIOSURE SYNC, RCI Screw, and ExoShape. Although the 3 strongest devices were combination screw and sheath devices, no significant differences were observed between the ultimate failure strengths of the screw and combination devices when compared as groups. The least amount of cyclic displacement after 1000 cycles was observed for the GraftBolt (1.38 ± 0.27 mm), followed by the AperFix II (1.58 ± 0.21 mm), Bio-Interference Screw (1.61 ± 0.22 mm), INTRAFIX (1.63 ± 0.15 mm), ExoShape (1.68 ± 0.30 mm), BIOSURE PK (1.72 ± 0.29 mm), BIOSURE SYNC (1.92 ± 0.59 mm), and RCI Screw (1.97 ± 0.39 mm). The GraftBolt allowed significantly less displacement than did the BIOSURE SYNC and RCI Screw. Similarly, no significant differences were observed between the cyclic displacements of the screws and combination devices when compared as groups. CONCLUSION: The combination screw and sheath devices did not provide superior soft tissue fixation properties compared with the interference screws alone in a porcine model. Although the highest ultimate failure loads and least amounts of cyclic displacement were observed for combination devices, group comparisons of screw and combination devices did not result in any significant differences for ultimate failure load and cyclic displacement. CLINICAL RELEVANCE: It is important to consider that these results represent device performance in an in vitro animal model and are not directly transferrable to an in vivo clinical situation. The combination of a sheath and screw did not consistently result in improved fixation characteristics compared with interference screw fixation.