Arthur T. Lee

Essential Roles of Drosophila RhoA in the Regulation of Neuroblast Proliferation and Dendritic but Not Axonal Morphogenesis

The pleiotropic functions of small GTPase Rho present a challenge to its genetic analysis in multicellular organisms. We report here the use of the MARCM (mosaic analysis with a repressible cell marker) system to analyze the function of RhoA in the developing Drosophila brain. Clones of cells homozygous for null RhoA mutations were specifically labeled in the mushroom body (MB) neurons of mosaic brains. We found that RhoA is required for neuroblast (Nb) proliferation but not for neuronal survival. Surprisingly, RhoA is not required for MB neurons to establish normal axon projections. However, neurons lacking RhoA overextend their dendrites, and expression of activated RhoA causes a reduction of dendritic complexity. Thus, RhoA is an important regulator of dendritic morphogenesis, while distinct mechanisms are used for axonal morphogenesis.

Microtubule-associated protein 1B: a neuronal binding partner for gigaxonin

Giant axonal neuropathy (GAN), an autosomal recessive disorder caused by mutations in GAN, is characterized cytopathologically by cytoskeletal abnormality. Based on its sequence, gigaxonin contains an NH2-terminal BTB domain followed by six kelch repeats, which are believed to be important for protein–protein interactions (Adams, J., R. Kelso, and L. Cooley. 2000. Trends Cell Biol. 10:17–24.). Here, we report the identification of a neuronal binding partner of gigaxonin. Results obtained from yeast two-hybrid screening, cotransfections, and coimmunoprecipitations demonstrate that gigaxonin binds directly to microtubule-associated protein (MAP)1B light chain (LC; MAP1B-LC), a protein involved in maintaining the integrity of cytoskeletal structures and promoting neuronal stability. Studies using double immunofluorescent microscopy and ultrastructural analysis revealed physiological colocalization of gigaxonin with MAP1B in neurons. Furthermore, in transfected cells the specific interaction of gigaxonin with MAP1B is shown to enhance the microtubule stability required for axonal transport over long distance. At least two different mutations identified in GAN patients (Bomont, P., L. Cavalier, F. Blondeau, C. Ben Hamida, S. Belal, M. Tazir, E. Demir, H. Topaloglu, R. Korinthenberg, B. Tuysuz, et al. 2000. Nat. Genet. 26:370–374.) lead to loss of gigaxonin–MAP1B-LC interaction. The devastating axonal degeneration and neuronal death found in GAN patients point to the importance of gigaxonin for neuronal survival. Our findings may provide important insights into the pathogenesis of neurodegenerative disorders related to cytoskeletal abnormalities.

Osteochondral Lesions of the Talus: Effect of Defect Size and Plantarflexion Angle on Ankle Joint Stresses

Background: Osteochondral lesions of the talus (OLTs) are a common cause of ankle pain and disability. Current clinical guidelines favor autogenous or allogenic osteochondral grafting procedures for lesions larger than 10 mm in diameter because of increased failure rates in these larger lesions with arthroscopic debridement, curettage, and microfracture. There are currently no biomechanical data nor level I clinical data supporting this size threshold. Purpose: The purpose of this study was to determine the effect of OLT defect size on stress concentration, rim stress, and location of peak stress and whether a threshold defect size exists. Study Design: Descriptive laboratory study. Methods: Progressively larger medial OLTs were created (6, 8, 10, and 12 mm) in 8 fresh-frozen cadaveric ankle joints. With a calibrated Tekscan pressure sensor in the tibiotalar joint, an axial load of 686 N was applied, and pressure was recorded in neutral and 15° of plantar flexion with each defect size. Peak stress, contact area, peak and average rim stresses, and location of peak stress were determined. Results: The distance between peak stress and defect rim was significantly decreased with increasing defect size for lesions of 10 mm and larger. Total tibiotalar contact area was significantly decreased with increasing defect size and with ankle plantar flexion. While peak joint stress and peak rim stress were not affected by defect size or plantar flexion, average rim stress was significantly increased by plantar flexion. Conclusion: Reduction in contact area and shift in the location of peak stress with increasing defect size may contribute to articular cartilage degeneration, pain, and defect enlargement in patients with OLTs. There appears to be a threshold of 10 mm after which the distance between the rim of the defect and the peak stress decreases; however, there is no change in peak stress magnitude with increasing defect size. Clinical Relevance: The location of peak stress in the ankle joint becomes closer to the rim of the defect in OLTs at a threshold of 10 mm and greater in diameter. These data may have implications toward OLT size thresholds for surgical decision making in symptomatic lesions (ie, primary osteochondral transplantation procedure vs curettage and debridement). The ultimate goal is to determine whether there is a threshold defect size for primary osteoarticular graft techniques.

Trapezium Trabecular Morphology in Carpometacarpal Arthritis

PURPOSE In thumb carpometacarpal osteoarthritis, current evidence suggests that degenerative, bony remodeling primarily occurs within the trapezium. Nevertheless, the pathomechanics involved and the most common sites of wear remain controversial. Quantifying structural bone morphology characteristics with high-resolution computed tomography CT (micro-CT) infer regions of load transmission. Using micro-CT, we investigated whether predominant trabecular patterns exist in arthritic versus normal trapeziums. METHODS We performed micro-CT analysis on 13 normal cadaveric trapeziums and 16 Eaton stage III to IV trapeziums. We computationally divided each specimen into 4 quadrants: volar-ulnar, volar-radial, dorsal-radial, and dorsal-ulnar. Measurements of trabecular bone morphologic parameters included bone volume ratio, connectivity, trabecular number, and trabecular thickness. Using analysis of variance with post hoc Bonferroni/Dunn correction, we compared osteoarthritic and normal specimen quadrant measurements. RESULTS No significant difference existed in bone volume fraction between the osteoarthritic and normal specimens. Osteoarthritic trapeziums, however, demonstrated significantly higher trabecular number and connectivity than nonosteoarthritic trapeziums. Comparing the volar-ulnar quadrant of osteoarthritis and normal specimens collectively, this quadrant in both consistently possessed significantly higher bone volume fraction, trabecular number, and connectivity than the dorsal-radial and volar-radial quadrants. CONCLUSIONS The significantly greater trabecular bone volume, thickness, and connectivity in the volar-ulnar quadrant compared with the dorsal-radial and dorsal-ulnar quadrants provides evidence that the greatest compressive loads at the first carpometacarpal joint occur at the volar-ulnar quadrant of the trapezium, representing a consistently affected region of wear in both normal and arthritic states. CLINICAL RELEVANCE These findings suggest that trapezial trabecular morphology undergoes pathologic alteration. This provides indirect evidence that changes in load transmission occur with thumb carpometacarpal joint arthritis development.

Biomechanical Comparison of Blade Plate and Intramedullary Nail Fixation for Tibiocalcaneal Arthrodesis

Background: Tibiocalcaneal arthrodesis is an uncommon salvage procedure used for complex problems of the ankle and hindfoot. A biomechanical evaluation of the fixation constructs of this procedure has not been studied previously. The purpose of this study was to compare intramedullary nail to blade plate fixation in a deformity model in fatigue endurance testing and load to failure. Materials and Methods: Nine matched pairs of fresh frozen cadaveric legs underwent talectomy followed by fixation with a blade plate and 6.5-mm fully threaded cancellous screw or an ankle arthrodesis intramedullary nail. The specimens were loaded to 270 N at a rate of 3 Hz for a total of 250,000 cycles, followed by loading to failure. Results: Intramedullary nail fixation demonstrated greater mean stiffness throughout the fatigue endurance testing, from cycles 10 through 250,000 (blade plate versus intramedullary nail; cycle 10, 93 ± 34 N/mm versus 117 ± 40 N/mm (t = 2.33, p = 0.04); cycle 100, 89 ± 34 N/mm versus 118 ± 42 N/mm (t = 3.16, p = 0.01); cycle 1000, 86 ± 32 N/mm versus 120 ± 45 N/mm (t = 3.52, p = 0.01); cycle 10,000, 83 ± 36 N/mm versus 128 ± 50 N/mm (t = 3.80, p = 0.01); cycle 100,000, 82 ± 34 N/mm versus 126 ± 52 N/mm (t = 3.70, p = 0.01); cycle 250,000, 80 ± 31 N/mm versus 125 ± 49 N/mm (t = 4.2, p = 0.003). There was no statistically significant difference between the intramedullary nail and blade plate fixation in cycle one or in load to failure; cycle 10, blade plate 70 ± 38 N/mm and intramedullary nail 67 ± 20 N/mm (t = 0.60, p = 0.56); load to failure, blade plate 808 ± 193 N, IMN 1074 ± 290 N) (p = 0.15). Conclusion: Intramedullary nail fixation was biomechanically superior to blade plate and screw fixation in a tibiocalcaneal arthrodesis construct. Clinical Relevance: The ankle arthrodesis intramedullary nail provides greater stiffness for fixation in tibiocalcaneal arthrodesis, which may improve healing.

Single column locking plate fixation is inadequate in two column acetabular fractures. A biomechanical analysis

BackgroundThe objective of this study was to determine whether one can achieve stable fixation of a two column (transverse) acetabular fracture by only fixing a single column with a locking plate and unicortical locking screws. We hypothesized that a locking plate applied to the anterior column of a transverse acetabular fracture would create a construct that is more rigid than a non-locking plate, and that this construct would be biomechanically comparable to two column fixation.MethodsUsing urethane foam models of the pelvis, we simulated transverse acetabular fractures and stabilized them with 1) an anterior column plate with bicortical screws, 2) an anterior locking plate with unicortical screws, 3) an anterior plate and posterior column lag screw, and 4) a posterior plate with an anterior column lag screw. These constructs were mechanically loaded on a servohydraulic material testing machine. Construct stiffness and fracture displacement were measured.Result and DiscussionWe found that two column fixation is 54% stiffer than a single column fixation with a conventional plate with bicortical screws. There was no significant difference between fixation with an anterior column locking plate with unicortical screws and an anterior plate with posterior column lag screw. We detected a non-significant trend towards more stiffness for the anterior locking plate compared to the anterior non-locking plate.ConclusionIn conclusion, a locking plate construct of the anterior column provides less stability than a traditional both column construct with posterior plate and anterior column lag screw. However, the locking construct offers greater strength than a non-locking, bicortical construct, which in addition often requires extensive contouring and its application is oftentimes accompanied by the risk of neurovascular damage.

Bone cement improves suture anchor fixation.

Suture anchor fixation failure can occur if the anchor pulls out of bone. We hypothesized that suture anchor fixation can be augmented with polymethylmethacrylate cement, and that polymethylmethacrylate can be used to improve fixation in a stripped anchor hole. Six matched cadaveric proximal humeri were used. On one side, suture anchors were placed and loaded to failure using a ramped cyclic loading protocol. The stripped anchor holes then were injected with approximately 1 cc polymethylmethacrylate, and anchors were replaced and tested again. In the contralateral humerus, polymethylmethacrylate was injected into anchor holes before anchor placement and testing. In unstripped anchors, polymethylmethacrylate increased the number of cycles to failure by 34% and failure load by 71% compared with anchors not augmented with polymethylmethacrylate. Polymethylmethacrylate haugmentation of stripped anchors increased the cycles to failure by 31% and failure load by 111% compared with unstripped uncemented anchors. No difference was found in cycles to failure or failure load between cemented stripped anchors and cemented unstripped anchors. Polymethylmethacrylate can be used to augment fixation, reducing the risk of anchor pull-out failure, regardless whether the suture anchor hole is stripped or unstripped.

Treatment of thumb carpometacarpal arthritis with arthroscopic hemitrapeziectomy and interposition arthroplasty.

The carpometacarpal joint of the thumb is a common site of degenerative arthritis. Several surgical treatments exist, but arthroscopic management offers the potential benefit of earlier recovery. The current study evaluated the early clinical outcomes of a procedure involving arthroscopic hemitrapeziectomy with Artelon spacer (Artimplant, Västra Frölunda, Sweden) interposition arthroplasty into the newly created carpometacarpal space.A chart review of 9 patients treated with thumb carpometacarpal arthroscopic hemitrapeziectomy and Artelon spacer interposition arthroplasty between September 2005 and January 2009 was performed for postoperative complications, range of motion, and pinch strength (percentage of the contralateral limb). Subjective outcomes were analyzed by the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire and the Patient-rated Wrist Evaluation. Mean follow-up was 23.4 months (range, 13-33 months). All patients maintained full range of motion. By the 1-year follow-up, mean pinch strength returned to 59%± 19.1% of the contralateral limb strength. The Quick Disabilities of the Arm, Shoulder, and Hand and the Patient-rated Wrist Evaluation scores were 12.3 ± 7.6 and 26.8 ± 23.5, respectively. No significant complications occurred, and 1 patient with symptoms of synovitis was successfully treated with a corticosteroid injection. This study revealed excellent short-term results at the minimum 1-year follow-up for a less invasive treatment option that is appropriate for select patients with moderate thumb carpometacarpal arthritis (Eaton stages 2 and 3). The authors demonstrated a comparably good outcome of arthroscopic hemitrapeziectomy with Artelon spacer interposition arthroplasty with no evidence of foreign-body reaction. The authors also demonstrated the potential role of corticosteroid injections in the setting of a postoperative inflammatory reaction.

Massive spontaneous epidural hematoma in a high-level swimmer: a case report.

A twenty-two-year-old Olympic-caliber collegiate swimmer presented to the emergency department with complaints of progressive weakness in both lower extremities. Two days earlier, the patient had noted sharp pain in the neck and the middle part of the back on waking; however, he was able to complete his morning swimming practice. He could not recall a traumatic event, but he had participated in a rigorous swim practice the day before. One day before presentation, the pain completely resolved. However, on the day of presentation, the patient had awoken from a nap with searing interscapular back pain and decreased strength in the legs. He reported no bladder or bowel difficulties at that time. He was unable to stand and was immediately taken to the emergency department. The medical history was unremarkable for any previous spine trauma. The surgical history was noncontributory, and the patient reported no previous bleeding dyscrasias. He was not taking any medications, and he reported no history of illicit drug use. Manual motor testing revealed normal strength throughout both upper extremities. The patient had strong biceps, triceps, and brachioradialis reflexes and had no difficulty with rapid fine alternating motions. He had a negative Hoffman reflex, a negative inverted radial reflex, and no upper motor neuron findings in the upper extremities. In the lower extremities, however, the patient had no strength in the iliopsoas, quadriceps, hamstrings, tibialis anterior, extensor hallucis longus, or gastrocnemius/soleus muscles. The patient had absent patellar and Achilles tendon reflexes bilaterally, and he had no rectal tone. He had no sensation to light touch, pain, or temperature from the nipple line down to the toes. Blood tests were unremarkable, with a hematocrit of 42.4%, an international normalized ratio of 1.1, a prothrombin time of 13.8 seconds, a partial thromboplastin time of 26.3 seconds, a C-reactive protein level …