Novel interactions of LDL-receptor 1 (LRP1) with components of CNS myelin reveal LRP1 as a novel regulator of CNS regenerative failure after injury /

There are an estimated 12,000 to 20,000 new cases of spinal cord injury (SCI) each year and 1.28 million people in the United States are paralyzed in some form due to SCI. Currently, there are no clinically available treatments that target degraded myelin, one of the primary causes of regenerative failure in the central nervous system (CNS) after acute SCI. Contrary to conventional wisdom, neurons of the central nervous system (CNS) possess substantial regenerative capacity after trauma such as spinal cord injury (SCI). The failure of these neurons to regenerate is therefore not due to intrinsic inability, but rather to inhibitory cues within the CNS microenvironment, including myelin-associated inhibitors (MAIs) and the chondroitin sulfate proteoglycans within the glial scar. While these potent molecular obstacles have been well characterized, the neuronal receptors mediating their ability to blunt neuroregeneration have remained elusive. In this work, I identify LRP1 as a novel receptor of MAG (and likely other MAIs) that mediates inhibition of neurite outgrowth and the inhibitory signaling in neurons. In response to exposure to MAIs, LRP1 forms a signaling complex with p75, which leads to activation of RhoA. Additionally, treatment of myelin with soluble fragments of LRP1, which contain the sequence necessary for MAI binding, also attenuate neuronal growth inhibition. These effects are due to the ability of LRP1 to facilitate MAI-mediated activation of RhoA, which is the necessary and sufficient cellular signal for cessation of axonal extension. Antagonism of LRP1 also attenuates RhoA activation in vivo in rat models of spinal cord injury. LRP1 and p75 also selectively associate from lesion extracts from injured rat spinal cord, and this effect is blocked by infusion of RAP into the lesion site. In total, this work identifies LRP1 as a novel and exciting potential therapeutic target in the regeneration of neurons after damage to the spinal cor

Post-Exertional Malaise in Women with Chronic Fatigue Syndrome

OBJECTIVE: Postexertional malaise (PEM) is a defining characteristic of chronic fatigue syndrome (CFS) that remains a source of some controversy. The purpose of this study was to explore the effects of an exercise challenge on CFS symptoms from a patient perspective. METHODS: This study included 25 female CFS patients and 23 age-matched sedentary controls. All participants underwent a maximal cardiopulmonary exercise test. Subjects completed a health and well-being survey (SF-36) 7 days postexercise. Subjects also provided, approximately 7 days after testing, written answers to open-ended questions pertaining to physical and cognitive responses to the test and length of recovery. SF-36 data were compared using multivariate analyses. Written questionnaire responses were used to determine recovery time as well as number and type of symptoms experienced. RESULTS: Written questionnaires revealed that within 24 hours of the test, 85% of controls indicated full recovery, in contrast to 0 CFS patients. The remaining 15% of controls recovered within 48 hours of the test. In contrast, only 1 CFS patient recovered within 48 hours. Symptoms reported after the exercise test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands. A significant multivariate effect for the SF-36 responses (p \u3c 0.001) indicated lower functioning among the CFS patients, which was most pronounced for items measuring physiological function. CONCLUSIONS: The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls

Post-exertional symptomology in Chronic Fatigue Syndrome

Symptom exacerbation following physical stress has been documented in illnesses such as multiple sclerosis (MS), lupus and rheumatoid arthritis (RA). Similar phenomenology has been reported in CFS but is not well understood. PURPOSE: The purpose of this study was to explore symptom exacerbation following an exercise challenge in CFS patients relative to a sedentary control population. METHODS: Forty female subjects (n=40), 20 CFS and 20 matched sedentary controls served as subjects. All participants underwent a graded maximal cardiopulmonary exercise test (CPX). Two questionnaires, Short Form-36 (SF-36) and a series of open-ended questions, were completed 7 days after the exercise challenge to assess post-exertional differences between groups. The open-ended questions pertained to symptoms experienced following the test and time taken to recover from any testing effects. SF-36 data were analyzed using a multivariate analysis. Written questionnaire responses were evaluated by determining recovery time in days as well as number and type of symptoms experienced. RESULTS: SF-36 analysis found statistical significance across all 8 health domains measured between groups (p \u3c.01), but no effects were found for the exercise test. Analysis of the open-ended questionnaires revealed that within 24 hours of the exercise challenge, 85% of controls indicated full recovery in contrast to 0% of CFS patients. The remaining 15% of controls recovered within 48 hours of the test as opposed to only one CFS patient. Clear differences in number and type of reported symptoms were also found between groups. CONCLUSIONS: The results of this study indicate that CFS patients suffer symptom exacerbation following physical stress. As with MS, lupus and RA, post-exertional symptom exacerbation appears to be both a real and incapacitating feature of the syndrome. The delayed recovery response evoked by a single bout of exercise stress is distinctly different from that of sedentary control