This review summarizes the current understanding of spinal cord injury pathophysiology and discusses important emerging regenerative approaches that have been translated into clinical trials or have a strong potential to do so. The pathophysiology of spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar. Regenerative approaches to block inhibitory signals including Nogo and the Rho-Rho–associated kinase pathways have shown promise and are in early stages of clinical evaluation. Cell-based strategies including using neural stem cells to remyelinate spared axons are an attractive emerging approach.

Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.

Neural stem cell-based approaches to repair damaged white matter in the central nervous system have shown great promise; however, the optimal cell population to employ in these therapies remains undetermined. A default mechanism of neural induction may function during development, and in embryonic stem cells (ESCs) neural differentiation is elicited in the absence of any extrinsic signaling in minimal, serum-free culture conditions. The default mechanism can be used to derive clonal neurosphere-forming populations of neural stem cells that have been termed leukemia inhibitory factor-dependent primitive neural stem cells (pNSCs), which subsequently give rise to fibroblast growth factor 2-dependent definitive NSCs (dNSCs). Here we characterized the neural differentiation pattern of these two cell types in vitro and in vivo when transplanted into the dysmyelinated spinal cords of shiverer mice. We compared the differentiation pattern to that observed for neural stem/progenitor cells derived from the adult forebrain subependymal zone [adult neural precursor cells (aNPCs)]. dNSCs produced a differentiation pattern similar to that of aNPCs in vitro and in the shiverer model in vivo, where both cell types produced terminally differentiated oligodendrocytes that associated with host axons and expressed myelin basic protein. This is the first demonstration of the in vivo differentiation of NSCs, derived from ESCs through the default mechanism, into the oligodendrocyte lineage. We conclude that dNSCs derived through the default pathway of neural induction are a similar cell population to aNPCs and that the default mechanism is a promising approach to generate NSCs from pluripotent cell populations for use in cell therapy or other research applications.

One strategy for spinal cord repair after injury that has moved quickly from the research laboratory to the clinic is the implantation of olfactory ensheathing cells (OECs). These unique glial cells of the olfactory system have been associated with axonal remyelination and regeneration after grafting into spinalized animals. Despite these promising observations, there remains a lack of direct empirical evidence of the exact fate of OECs after intraspinal implantation, in large part because of a surprising paucity of defined biomarkers that unequivocally distinguish these cells from phenotypically similar Schwann cells. Here we provide direct neurochemical proof that OECs, both in vitro and in vivo, express smooth muscle alpha-actin. That OECs synthesize this contractile protein (and a variety of actin-binding proteins including caldesmon) provides compelling evidence that these cells are, in fact, quite different from Schwann cells. The identification of several smooth muscle-related proteins in OECs points to a new appreciation of the structural and functional features of this population of olfactory glia. These biomarkers can now be used to elucidate the fate of OECs after intraspinal implantation, in particular assessing whether smooth muscle alpha-actin-expressing OECs are capable of facilitating axon remyelination and regeneration.

Core material reactivity worths and control drum reactivity measurements performed In the PAX-GO reactor are compared in this document with predictions calculated by usingiWestinghouse Integrated Standard Design Method (WISDM). Based on this comparison, a drum span normalization factor of 0.90 was generated and will be applied to future R-1 drum span calculations. Calculated material reactivity worths in //Kg as a function of radial position for uranium and carbon are in good agreement with the experimental measurements for these materials. However, the calculated niobium worth overpredicts the experimental curve by approximately 20 percent. The standard design method which preceded WISDM underpredicted the experimental niobium worth by approximately 20 to 30 percent. Consequently, an investigation of the niobium worth discrepancy has been initiated to resolve the inconsistency between calculation and measurement.

Reflector reactivity experiments have been performed in support of the R-1 design on the PAX-Gl, the first nuclear mockup of an 18-drum R-1 design. The first experiment determined the reactivity effects caused by interchanging a 60 reflector sector containing three R-1 type control drums for two 30° sectors, each of which contained one NRX type control drum. Analytical predictions of the worth of the interchange were in excellent agreement with the measurements. The second experiment entailed various measurements of the control drum spans. Two different experimental procedures were employed, both of which yielded very nearly the same results. Comparison of analytical predictions with the experimental data yielded a drum span correction factor of 0.88. Substantial drum interaction effects between the individual R-1 mockup drums were also demonstrated. The third experiment entailed the interchange of an aluminum reflector barrel mockup for a graphite lateral support mockup on the 60 R-1 mockup reflector sector. The effects of the liner segments interchange on the R-1 mockup control drums were also determined. In both cases, the analytical predictions were in good agreement with the experimental data.

An investigation into the increase in Plant Protection System (PPS) alarms at a three-unit US Pressurized Water Reactor (PWR) plant has determined that the alarms are the result, in part, of a hydraulic instability that has developed within the Reactor Coolant System (RCS) following the replacement of the steam generators in all three units of the Palo Verde Nuclear Generating Station (PVNGS). An experimental effort has been established by Arizona Public Service Company and Arizona State University in an attempt to determine the cause of these instabilities. Preliminary investigations have determined that the time scale of these instabilities is consistent with larger scale transient flow processes of the reactor vessel. Accordingly, the flow characteristics were assessed and localized flow measurements made using a one-fifth scale physical model of the upper plenum region of the reactor core of the Combustion Engineering System 80 reactor vessel to verify the postulation that large vortex structures referred to as “precessing” vortices [Ref. 1] affect the core exit flow conditions resulting in the noted flow instabilities. The physical model investigation was complemented by numerical analysis based on a Computational Fluid Dynamics (CFD) code performed for the same geometry. Benchmarking of the CFD model by the scaled physical model is intended to provide increased confidence in the CFD code. If verified, the CFD code may be modified so as to establish corrective actions for this condition, where physical modeling would probably be time consuming and cost prohibitive. The initial results for the physical and computational models demonstrate very good agreement between the measured and calculated flows in the upper-plenum region. The results of the complementary experimental and analytic evaluations do not support the presence of any large scale vortices of appropriate space scales that could affect flow conditions within the upper-plenum region. The elimination of the reactor vessel as the source of the instabilities suggests that the replacement steam generators may be the root cause of the flow instabilities. There is a possibility, however, that frequencies pertinent to vortices may be triggering mechanisms for flow instabilities in the entire system.