CSPGs (chondroitin sulfate proteoglycans) are a family of extracellular matrix molecules with various functions in regulating tissue morphogenesis, cell division and axon guidance. A number of CSPGs are highly upregulated by reactive glial scar tissues after injuries and form a strong barrier for axonal regeneration in the adult vertebrate CNS. Although CSPGs may negatively regulate axonal growth via binding and altering activity of other growth-regulating factors, the molecular mechanisms by which CSPGs restrict axonal elongation are not well understood. Here, we identified a novel receptor mechanism whereby CSPGs inhibit axonal growth via interactions with neuronal transmembrane LAR (the leukocyte common antigen-related phosphatase). CSPGs bind LAR with high affinity in transfected COS-7 cells and co-immunoprecipitate with LAR expressed in various tissues including the brain and spinal cord. CSPG stimulation enhances activity of LAR phosphatase in vitro. Deletion of LAR in knockout mice or blockade of LAR with sequence-selective peptides significantly overcomes neurite growth restrictions of CSPGs in neuronal cultures. Intracellularly, CSPG-LAR interaction mediates axonal growth inhibition of neurons partially via inactivating Akt and activating RhoA signals. Systemic treatments with LAR-targeting peptides in mice with thoracic spinal cord transection injuries induce significant axon growth of descending serotonergic fibers in the vicinity of the lesion and beyond in the caudal spinal cord and promote locomotor functional recovery. Identification of LAR as a novel CSPG functional receptor provides a therapeutic basis for enhancing axonal regeneration and functional recovery after CNS injuries in adult mammals.
In severe traumatic injuries to the lower extremity, it is often a difficult decision to attempt heroic efforts aimed at limb salvage or to amputate primarily. To answer this question, the authors performed a 5-year review of 70 limbs in 67 patients. Patients were identified as presenting with major lower extremity trauma and an associated arterial injury. Nineteen (27%) of the 70 limbs were amputated. Limb salvage was not related to the presence or absence of shock and order of repair (orthopedic or vascular). No statistical difference was noted between the time of injury to operative repair in either the amputated or limb salvage group. Limb salvage was related to warm ischemia time and the quantitative degree of arterial, nerve, bone, muscle, skin, and venous injury. A limb salvage index (LSI) was formulated based on the degree of injury to these systems. All 51 patients with an LSI score of less than 6 had successful limb salvage (p less than 0.001). All 19 patients with an LSI score of 6 or greater had amputations (p less than 0.001). Although statistics cannot replace clinical judgment, this index can be a valuable objective tool in the evaluation of the patient with a severely traumatized extremity.
Commonly used positive end-expiratory pressure by clinicians is inadequate for optimal mechanical ventilation of morbidly obese patients. A recruitment maneuver followed by end-expiratory pressure titration was found to significantly improve lung volumes, respiratory system elastance, and oxygenation.
The Neurospora RNA-dependent RNA polymerase QDE-1 is an RNA polymerase that can use both RNA and DNA as templates, suggesting a new mechanism for small RNA production.
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