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Ready-to-Wear Neural Network By: Dee Rapposelli A"mini-nervous system" that has been grown in culture by researchers at the Center for Brain Injury and Repair at the University of Pennsylvania School of Medicine can be transplanted intact into rodent models of spinal cord injury (SCI). The researchers accomplished this feat through a novel tissue-engineering technique described in a paper published online December 5, 2005 (Epub ahead of print) on the Journal of Neuroscience Methods. Further proof-of-principle research about the in vivo viability of the in vitro-grown nervous system appeared online on February 15 in the online-ahead-of-print version of Tissue Engineering. Dorsal root ganglia neurons are placed in nutrient-fortified plates where they vigorously sprout axons. The axon tracts themselves are mechanically elongated and placed in a collagen matrix, rolled up, and as recounted in the more recent of the 2 online research articles, are ready for implantation into an SCI model. Senior author of the study, Douglas H. Smith, MD, director of the Center for Brain Injury and Repair and a professor in the Department of Neurosurgery at the University of Pennsylvania, refers to the neural product as a "nervous-tissue construct." Within 7 days, the axon-rich nervous tissues stretch to about 10 mm in length. Indeed, the researchers call the phenomenon "a process of extreme axon stretch growth." The work demonstrates a promising alternative to techniques that focus on promoting in vivo axonal bridges over crushed and severed nerves. In the earlier research, axons in nutrient-rich plates grew out to mesh with each other-a very good sign. "We have designed a geometrical arrangement that looks similar to the longitudinal arrangement that the spinal cord had before it was damaged. The long bundles of axons span 2 populations of neurons, and these neuron constructs can grow axons in 2 directions-toward each other and into the host spinal cord at each side. That way they can integrate and connect the 'cables' to the host tissue to bridge a spinal cord lesion," Smith explained in a statement to the press. The subsequent study put this to the test, and the researchers were vindicated by the findings. The engineered nervous-tissue constructs were transplanted into a 1-cm cavity within the spinal cords of rodents that functioned as experimental models of SCI. Transplantation was performed 10 days after SCI, and the animals were euthanized and examined 4 weeks after the transplantation procedure. The researchers found that the axon tracts thrived in vivo and, as expected, had extended out of the transplant and into the host spinal cord tissue. The next test, currently under way, will examine the neuronal electrical conductivity of the engineered bridge and whether and to what degree function is restored. For more information about this research see: Iwata A, Browne KD, Pfister BJ, et al. Long-term survival and outgrowth of mechanically engineered nervous tissue constructs implanted into spinal cord lesions. Tissue Eng. 2006;12:101-110. Pfister BJ, Iwata A, Taylor AG, et al. Development of transplantable nervous tissue constructs comprised of stretch-grown axons. J Neurosci Methods. 2005 Dec 5; [Epub ahead of print]. ALS Biomarkers Found By: Dee Rapposelli Measuring concentration levels of 3 proteins within cerebrospinal fluid (CSF) may be a definitive method for identifying amyotrophic lateral sclerosis (ALS). In search of possible biomarkers, a multicenter team of investigators headed by Giulio Pasinetti, MD, PhD, professor of psychiatry, neuroscience, and geriatrics and adult development at the Mount Sinai School of Medicine in New York City, discovered that compared with healthy controls, patients with ALS had significantly lower levels of 3 protein species: 4.8 kiloDalton (kDa), 6.7 kDa, and 13.4 kDa cystatin in their CSF. A subsequent validation study that included patients with ALS, healthy controls, and patients with peripheral neuropathy confirmed the findings. It also showed that measurement of the protein markers could help distinguish between ALS and multifocal motor neuropathy with conduction block, a condition often misdiagnosed as ALS. Furthermore, analysis of the biomarkers proved efficient for identifying early-stage ALS. They displayed their unique characteristics within 1.5 years of symptom onset. The proteins were identified using high-throughput surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Analysis of all 3 proteins-"a 3-protein model"-proved to be a highly accurate (accuracy, 95%), sensitive (sensitivity, 91%), and specific (specificity, 97%) way to identify patients with ALS. Clinical application of this technology, used as an adjunct diagnostic procedure, may assist clinicians in differential diagnosis and early detection of ALS, the researchers concluded. The biomarkers may also shed light on disease etiology and progression and may also inspire novel therapeutic trials. The study was posted February 15 on the online version of Neurology. The citation is Pasinetti GM, Ungar LH, Lange DJ, et al. Identification of potential CSF biomarkers in ALS. Neurology. 2006 Feb 15; [Epub ahead of print]. Cleavage Product of Cystatin C Identified as Biomarker for MS By: Dee Rapposelli In a related article, published in the February issue of Annals of Neurology, unique expression of 12.5 kiloDalton (kDa) protein, a cleavage product of 13.4 kDa cystatin-also known as cystatin C-was 100% specific and 66% sensitive for multiple sclerosis (MS) and clinically isolated syndromes (CIS). Using high-throughput surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-MS), researchers from The Johns Hopkins University in Baltimore analyzed protein species in the cerebrospinal fluid (CSF) of 29 patients with MS or CIS, 27 patients with transverse myelitis, 50 patients with HIV, and 27 patients with other neurologic diseases. SELDI-MS revealed elevated 12.5 kDa peaks in the CSF of 19 of the patients with either MS or CIS. No such pattern was seen in the CSF of patients with transverse myelitis and other neurologic disorders. Characteristic peaking was seen in the CSF of some patients with HIV, but the levels were significantly lower than those seen in the CSF of patients with MS and CIS. In addition, elevated 12.5 kDa peaks correlated with diminished 13.6 kDa peaks in the CSF spectrometry analysis of patients with MS and CIS. Patients who had the highest levels of 12.5 kDa also had the highest inhibition of cathepsin B, a cysteine protease inhibited by cystatin C and associated with demyelination. The unique presence of 12.5 kDa in some patients with MS and CIS, in the form of cleavage of the carboxy terminus of cystatin C, may be an adaptive host response, the researchers conjectured. They concluded that the protein fragment may act as a biomarker for a subset of patients with MS and may aid in the differential diagnosis of MS and other inflammatory diseases. For more information about this research, see Irani DN, Anderson C, Gundry R, et al. Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis. Ann Neurol. 2006;59:237-247. Neuroprotective Noble Gas Safe in Humans By: Dee Rapposelli After many years studying the neuroprotective effects of xenon in animal models of hypoxic ischemia, researchers from the Imperial College and Chelsea and Westminster Hospital in London demonstrated that the noble gas could be safely used in humans undergoing hypothermic cardiopulmonary artery bypass during coronary artery bypass grafting (CABG). For the research team, headed by Mervyn Maze, MB, ChB, head of the Division of Surgery, Oncology, Reproductive Biology, and Anaesthesiology, and Nicholas Franks, PhD, chair in biophysics and anesthetics at Imperial College, the open-label dose-escalation trial was a preliminary step before forging on to randomized trials of xenon as a neuroprotective agent in patients undergoing procedures, such as CABG, that carry postoperative risks of neurocognitive complications. Experimental studies strongly suggest that xenon, used as an anesthetic but better known as the stuff of fanciful neon lights, blocks glutamate receptors implicated in nerve-cell death following stroke, spinal cord injuries, and other events in which hypoxic ischemia occurs. A recent study in which the British team studied the effects of xenon preconditioning in rodent models of neonatal asphyxia showed that brain damage could be ameliorated. Infarction size was reduced in neonatal rat pups subjected to hypoxic isch-emic injury after xenon preconditioning, and improvement in neurologic function was sustained 30 days after injury. Indeed, xenon up-regulated the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor, the researchers reported in their study, presented this past October at the annual meeting of the American Society of Anesthesia and published in the Journal of Cerebral Blood Flow Metabolism this past February. The findings suggest that xenon could be used prophylactically and therapeutically to either prevent or ameliorate brain damage in patients in whom stroke or spinal cord injury occurs. Before launching into randomized trials in humans, however, the British researchers needed to rule out the risk of bubble embolism from the prophylactic procedure. They acquired informed consent from 16 patients scheduled for CABG who during the surgical procedure received xenon through a standard anesthetic breathing circuit and an oxygenator. No evidence of increased emboli was detected on transcranial Doppler ultrasonography of the middle cerebral artery. Nor was major organ dysfunction found. The researchers concluded that use of xenon for neuroprotective prophylaxis during surgery was safe and they called to move on to studying the neuroprotective effect of xenon in large placebo-controlled, randomized trials. For more information about this research, see: Lockwood G, Franks NP, Downie NA, et al. Feasibility and safety of delivering xenon to patients undergoing coronary artery bypass graft surgery while on cardiopulmonary bypass: phase I study. Anesthesiology. 2006;104: 458-465. Ma D, Hossain M, Pettet GK, et al. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab. 2006;26:199-208. New Insights on Retraining Techniques By: Dee Rapposelli Scrutiny of different types of retraining techniques is providing researchers and clinicians with insights about rehabilitation needs of patients recuperating from spinal cord injury (SCI) and stroke. A recent study, appearing in the February 28 issue of Neurology debunked the popular assumption, primarily based on animal studies, that body weight-supported treadmill training (BWSTT) is superior to conventional mobility rehabilitation (standing/stepping training). Another study, published in the online version of Stroke (posted March 3), showed that constraint-induced movement (CI) therapy was associated with significant and sustained improvement in function in patients living with chronic stroke. In what Jonathan R. Wolpaw, MD, professor and chief of the Laboratory of Nervous System Disorders at the Wadsworth Center in Albany, NY, called a "tightly controlled single-blind, multicenter trial" in his accompanying editorial, a research team, led by Bruce H. Dobkin, MD, professor of neurology at the University of California, Los Angeles (UCLA) School of Medicine, discovered that conventional mobility rehabilitation is just as effective as BWSTT in helping patients with partial SCIs walk again. Dobson and colleagues did not expect this would be the result; they set out to definitively establish that BWSTT was a superior rehabilitation program. The UCLA study included 117 patients who had sustained partial SCIs within the past 8 weeks. The patients were graded according to the American Spinal Injury Association Impairment Scale as B, C, or D, with B designating most impairment and D designating least impairment. Patients were randomly assigned to receive either BWSTT or conventional mobility therapy for 12 weeks. At the end of the study, 33% of grade B patients who had received BWSTT were ambulatory, compared with 58% of grade B patients who had received conventional therapy. Results were more dramatic for grade C and D patients. Most were walking independently-regardless of the type of therapy they received-and no difference in walking speed (average, 1.1 meters per second) was seen between the 2 groups. The researchers did note that those patients who received therapy sooner (less than 4 weeks after injury) were able to walk faster and longer than patients who had more of a delay between injury and the start of rehabilitation. The researchers concluded that the choice of whether to use BWSTT or conventional therapy can be a matter of personal preference and that future research might look at how to improve outcomes in grade B and C patients who have chronic motor deficits. The citation for the published study is Dobkin B, Apple D, Barbeau H, et al. Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI. Neurology. 2006;66:484-493. The citation for the editorial is Wolpaw JR. Treadmill training after spinal cord injury: good but not better. Neurology. 2006;66:466-467. A placebo-controlled trial of CI therapy, a neurorehabilitative technique to restore upper limb function in patients recovering from stroke, proved the therapy to be quite valuable. Forty-one volunteers were randomly assigned to receive either CI therapy, consisting of a specific protocol that focuses on training a paretic arm while restraining the contralateral arm, or placebo, consisting of a general fitness program. Duration of treatment was 6 hours a day for 10 consecutive weekdays. Significantly greater functional improvement was achieved in patients receiving CI therapy, compared with patients receiving placebo. The mean increase in motor activity log arm use was 1.8 points in the active-treatment group, whereas no change was seen in the placebo group. Furthermore, improvements were sustained at a 2-year follow-up. The research article includes an appendix that describes the CI therapy protocol. For more information see: Taub E, Uswatte G, King DK, et al. A placebo-controlled trial of constraint-induced movement therapy for upper extremity after stroke. Stroke. 2006 March 2 [Epub ahead of print]. Taub E, Miller NE, Novack TA, et al. Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil. 1993;74:347-354.

 
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