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Thread: Dr. Wise, Help Please?

  1. #11
    Dr.Young, the bone marrow stem cell studies that the SCS Australia did were done by the following researchers: Stuart Hodgetts, Paul Simmons, David Haylock and Giles W Plant. The results were also presented at the National Stem Cell Center in Australia. They are now investigated ways to further enhance recovery by combined the BMSC with Decorin and doind multiple injections of BMSC in the spinal cord, first at 7 days, then after one month. The use of Decorin is only going to be used on chronic rats.

  2. #12

    Smile Thanks

    Quote Originally Posted by Wise Young
    Schmeky, I hope that people are not getting the impression that there is a cure now and that there is not a lot more work to do. I am very concerned that people are signing up for unproven therapies based on third party anecdotal data. Some people appear disappointed that there is no secret cure that is applied somewhere in the world. It is important that people treat their spinal cord injury rather than treating their emotions.

    Wise.
    Thank you very much Dr. Wise for laminating the strategies lying in the road to cure, and of informing us of how much work it requires to get a complete therapy working.

    But I sensed that you're just enthusiastic for Dr. Park's procedure in Korea as it combines two strategies of therapy.

    Why don't researches use these strategies combined on human subjects remains a matter of time and courage I think!

  3. #13
    Quote Originally Posted by zokarkan
    Dr.Young, the bone marrow stem cell studies that the SCS Australia did were done by the following researchers: Stuart Hodgetts, Paul Simmons, David Haylock and Giles W Plant. The results were also presented at the National Stem Cell Center in Australia. They are now investigated ways to further enhance recovery by combined the BMSC with Decorin and doind multiple injections of BMSC in the spinal cord, first at 7 days, then after one month. The use of Decorin is only going to be used on chronic rats.
    I don't know the bone marrow studies that you mention. The following are all the papers published in 2005 with the keywords of "bone marrow transplant" and "spinal":



    Yano S, Kuroda S, Lee JB, Shichinohe H, Seki T, Ikeda J, Nishimura G, Hida K, Tamura M and Iwasaki Y (2005). In vivo fluorescence tracking of bone marrow stromal cells transplanted into a pneumatic injury model of rat spinal cord. J Neurotrauma 22: 907-18. Recent experimental studies have shown that bone marrow stromal cells (BMSC) differentiate into neural cells and reduce neurological deficits when transplanted into traumatized spinal cord. These findings have been derived primarily from histological analyses. We conducted a study directed chiefly at developing a non-invasive system for tracking BMSC transplanted into the spinal cord of living animals. In this study, we induced spinal cord injury (SCI) in rats with a pneumatic device. BMSC were harvested from transgenic mice expressing green fluorescence protein (BMSC-GFP), and were transplanted stereotactically into a control group of rats without SCI (n = 6) and a group with SCI (n = 3). At 2 and 4 weeks after transplantation, the dura mater was exposed and green fluorescence derived from the transplanted BMSC-GFP was observed. The distribution and differentiation of the transplanted cells were subsequently evaluated with immunohistochemistry. Green fluorescence could be detected around the transplantation site in three of six of the control rats. In all three rats subjected to SCI, green fluorescence was shown to spread from the site of BMSC-GFP injection toward the injury site, suggesting that the transplanted cells had migrated toward the lesion within the 4-week post-transplantation period. Histological evaluation suggested that the detected green fluorescence was emitted by cells that had distributed in the dorsal white matter, and demonstrated that some of the transplanted cells expressed neuronal or astrocytic markers. These results suggest the possibility of tracking BMSC transplanted into the spinal cord in living animals. Such noninvasive bioimaging techniques would be valuable for monitoring the fate of these transplanted cells and assessing the safety and efficacy of their transplantation. Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16083357

    Sakai M, Ohashi K, Kobayashi T, Yamashita T, Akiyama H, Nemoto T, Kishida S, Kamata N and Sakamaki H (2005). Meningeal hematopoiesis following radiation myelitis in a hematopoietic stem-cell transplant recipient. Am J Hematol 79: 291-3. Extramedullary meningeal hematopoiesis (EMH) represents an uncommon finding after stem-cell transplantation. We describe the case of an allogeneic bone marrow transplantation (BMT) recipient who developed EMH 1 month after radiation myelitis had been diagnosed. A 39-year-old man with multiple myeloma underwent matched unrelated BMT following a myeloablative conditioning regimen of cyclophosphamide and total-body irradiation (200 cGy x 6). This was followed by delivery of 40 Gy of involved-field radiation to an extramedullary plasmacytoma compressing the spinal cord. Although transplantation went extremely well, the patient developed radiation myelitis 7 months after transplantation, and EMH ensued 1 month later. Because the patient was not in a disease state known to cause EMH, it is tempting to speculate that radiation-related neural injuries might cause donor cells to migrate to the central nervous system. Am. J. Hematol. 79:291-293, 2005. (c) 2005 Wiley-Liss, Inc. Hematology Division, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16044440

    Kuh SU, Cho YE, Yoon DH, Kim KN and Ha Y (2005). Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien) There have been many efforts to recover neuronal function from spinal cord injuries, but there are some limitations in the treatment of spinal cord injuries.The neural stem cell has been noted for its pluripotency to differentiate into various neural cell types. The human umbilical cord blood cells (HUCBs) are more pluripotent and genetically flexible than bone marrow neural stem cells. The HUCBs could be more frequently used for spinal cord injury treatment in the future.Moderate degree spinal cord injured rats were classified into 3 subgroups, group A: media was injected into the cord injury site, group B: HUCBs were transplanted into the cord injury site, and group C: HUCBs with BDNF (Brain-derived neutrophic factor) were transplanted into the cord injury site. We checked the BBB scores to evaluate the functional recovery in each group at 8 weeks after transplantation. We then, finally checked the neural cell differentiation with double immunofluorescence staining, and we also analyzed the axonal regeneration with retrograde labelling of brain stem neurons by using fluorogold. The HUCBs transplanted group improved, more than the control group at every week after transplantation, and also, the BDNF enabled an improvement of the BBB locomotion scores since the 1 week after its application (P<0.05). 8 weeks after transplantation, the HUCBs with BDNF transplanted group had more greatly improved BBB scores, than the other groups (P<0.001). The transplanted HUCBs were differentiated into various neural cells, which were confirmed by double immunoflorescence staining of BrdU and GFAP & MAP-2 staining. The HUCBs and BDNF each have individual positive effects on axonal regeneration. The HUCBs can differentiate into neural cells and induce motor function improvement in the cord injured rat models. Especially, the BDNF has effectiveness for neurological function improvement due to axonal regeneration in the early cord injury stage. Thus the HUCBs and BDNF have recovery effects of a moderate degree for cord injured rats. Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16010451

    Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH and Park HS (2005). Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 11: 913-22. Transplantation of bone marrow cells into the injured spinal cord has been found to improve neurologic functions in experimental animal studies. However, it is unclear whether bone marrow cells can similarly improve the neurologic functions of complete spinal cord injury (SCI) in human patients. To address this issue, we evaluated the therapeutic effects of autologous bone marrow cell transplantation (BMT) in conjunction with the administration of granulocyte macrophage-colony stimulating factor (GM-CSF) in six complete SCI patients. BMT in the injury site (1.1 x 10(6) cells/microL in a total of 1.8 mL) and subcutaneous GM-CSF administration were performed on five patients. One patient was treated with GM-CSF only. The follow-up periods were from 6 to 18 months, depending on the patients. Sensory improvements were noted immediately after the operations. Sensory recovery in the sacral segment was noted mainly 3 weeks to 7 months postoperatively. Significant motor improvements were noted 3 to 7 months postoperatively. Four patients showed neurologic improvements in their American Spiral Injury Association Impairment Scale (AIS) grades (from A to C). One patient improved to AIS grade B from A and the last patient remained in AIS grade A. No immediate worsening of neurologic symptoms was found. Side effects of GMCSF treatment such as a fever (>38 degrees C) and myalgia were noted. Serious complications increasing mortality and morbidity were not found. The follow-up study with magnetic resonance imaging 4-6 months after injury showed slight enhancement within the zone of BMT. Syrinx formation was not definitely found. BMT and GM-CSF administration represent a safe protocol to efficiently manage SCI patients, especially those with acute complete injury. To demonstrate the full therapeutic value of this protocol, long-term and more comprehensive case-control clinical studies are required. Department of Neurosurgery, Inha University College of Medicine, Inchon, South Korea. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15998231

    Tashjian RZ, Bradley MP and Lucas PR (2005). Spinal epidural hematoma after a pathologic compression fracture: an unusual presentation of multiple myeloma. Spine J 5: 454-6. BACKGROUND CONTEXT: Spinal epidural hematoma can result from traumatic and atraumatic etiologies. Atraumatic spinal epidural hematomas have been reported as an initial presentation of multiple myeloma. There are no other reports previously describing spinal epidural hematoma after a pathologic spinal fracture. PURPOSE: To present the first reported case of a spinal epidural hematoma after a pathologic fracture and a very unusual initial presentation of multiple myeloma in a young patient. STUDY DESIGN/SETTING: Case report. METHODS: A healthy asymptomatic 37-year-old male was struck in the head with a ball while playing soccer. Initial symptoms included severe back pain without neurologic symptoms. Complete motor paralysis developed over the next 24 hours in the lower extremities with a sensory level of T10. Magnetic resonance imaging evaluation of the spine revealed a T6 compression fracture with a dorsal T3 to T10 epidural hematoma. The patient underwent surgical T2 to T8 posterior spinal decompression with evacuation of the hematoma. Serum and urine electrophoresis and bone marrow biopsy were performed. RESULTS: The results of the electrophoresis revealed an immunoglobulin A monoclonal spike. The bone marrow biopsy was positive for plasma cell myeloma. Recovery of some motor function was noted in both lower extremities postoperatively. The patient was subsequently started on steroids and chemotherapy for myeloma. The patient has also undergone bone marrow transplant, and his myeloma is currently in remission. CONCLUSION: This is the first reported case of spinal epidural hematoma after a pathologic spinal fracture. Also, this case represents an unusual initial presentation of multiple myeloma in a young patient. Brown Medical School, Rhode Island Hospital, Department of Orthopaedic Surgery, 2 Dudley Street, Providence, RI 02905, USA. Rztashjian@hotmail.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15996616

    Sykova E and Jendelova P (2005). Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord. Ann N Y Acad Sci 1049: 146-60. Stem cells are a promising tool for treating brain and spinal cord injury. Magnetic resonance imaging (MRI) provides a noninvasive method to study the fate of transplanted cells in vivo. We studied implanted rat bone marrow stromal cells (MSCs) and mouse embryonic stem cells (ESCs) labeled with iron-oxide nanoparticles (Endorem(R)) and human CD34(+) cells labeled with magnetic MicroBeads (Miltenyi) in rats with a cortical or spinal cord lesion. Cells were grafted intracerebrally, contralaterally to a cortical photochemical lesion, or injected intravenously. During the first week post transplantation, transplanted cells migrated to the lesion. About 3% of MSCs and ESCs differentiated into neurons, while no MSCs, but 75% of ESCs differentiated into astrocytes. Labeled MSCs, ESCs, and CD34(+) cells were visible in the lesion on MR images as a hypointensive signal, persisting for more than 50 days. In rats with a balloon-induced spinal cord compression lesion, intravenously injected MSCs migrated to the lesion, leading to a hypointensive MRI signal. In plantar and Basso-Beattie-Bresnehan (BBB) tests, grafted animals scored better than lesioned animals injected with saline solution. Histologic studies confirmed a decrease in lesion size. We also used 3-D polymer constructs seeded with MSCs to bridge a spinal cord lesion. Our studies demonstrate that grafted adult as well as embryonic stem cells labeled with iron-oxide nanoparticles migrate into a lesion site in brain as well as in spinal cord. D.Sc., Institute of Experimental Medicine ASCR, Videska 1083, 140 20 Prague 4, Czech Republic. sykova@biomed.cas.cz. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15965114

    Orii H, Sotome S, Chen J, Wang J and Shinomiya K (2005). Beta-tricalcium phosphate (beta-TCP) graft combined with bone marrow stromal cells (MSCs) for posterolateral spine fusion. J Med Dent Sci 52: 51-7. Macaque lumber posterolateral spine fusion (PLF) was performed by using beta-TCP graft combined with bone marrow derived stromal cells (MSCs), to evaluate whether a beta-TCP/MSCs hybrid can be used for PLF instead of autogenous bone graft. Nine crab-eating macaque underwent bilateral PLF at L4-L5. The implants were divided into three groups: 1) beta-TCP/MSCs hybrid, 2) autogenous bone, and 3) beta-TCP. Six monkeys were sacrified at 12 weeks and three monkeys were sacrificed at 24 weeks after implantation. Manual palpation, radiography, micro computed tomography, peripheral quantitative computed tomography (pQCT), and histology were used to assess bone formation. Manual palpation and X-ray showed that 83.3% of hybrid groups and 66.7% of autogenous groups achieved solid spine fusion, whereas none of other groups fused. Histological analysis showed that all of the hybrid groups achieved massive bone formation. Bone mineral density (BMD) evaluated with pQCT in the hybrid groups increased by additional new bone. Beta-TCP/MSCs hybrid can be used for PLF instead of autogenous bone graft. Thus it can be hypothesized that the monkey PLF can simulate human PLF. Department of Orthopedics and Spinal Surgery, Graduate School, Tokyo Medical and Dental University, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15868741

    Phinney DG and Isakova I (2005). Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system. Curr Pharm Des 11: 1255-65. Mesenchymal stem cells resident in adult bone marrow are best characterized by their capacity to differentiate into connective tissue cell types such as adipocytes, chondrocytes, osteoblasts and hematopoiesis-supporting stroma. Accordingly, these cells are being evaluated in human clinical trials for efficacy in treating genetic diseases of bone, to speed hematopoietic recovery after bone marrow transplantation and reduce the severity of graft versus host disease. In the past few years MSCs have also been reported to exhibit a broad degree of plasticity commensurate with other adult stem cell populations, including the ability to differentiate in vitro and in vivo into non-mesodermal cell types such as neurons and astrocytes. MSCs have also been reported to promote repair and regeneration of nervous tissue within the central and peripheral nervous system, although the mechanism by which this occurs remains indeterminate. Herein, we review evidence purporting the differentiation of MSCs into neural cell lineages and evaluate the utility of MSCs as cellular vectors for treating neurological disorders and spinal cord injury. Based on our analysis of their transcriptome, we also theorize how the varied functions of MSCs and their progeny in bone marrow may extrapolate to a therapeutic benefit in models of neurological disease. Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA. dphinne@tulane.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15853682

    Sigurjonsson OE, Perreault MC, Egeland T and Glover JC (2005). Adult human hematopoietic stem cells produce neurons efficiently in the regenerating chicken embryo spinal cord. Proc Natl Acad Sci U S A 102: 5227-32. Hematopoietic stem cells (HSCs) have been proposed as a potential source of neural cells for use in repairing brain lesions, but previous studies indicate a low rate of neuronal differentiation and have not provided definite evidence of neuronal phenotype. To test the neurogenic potential of human HSCs, we implanted CD34+ HSCs from adult human bone marrow into lesions of the developing spinal cord in the chicken embryo and followed their differentiation by using immunohistochemistry, retrograde labeling, and electrophysiology. We find that human cells derived from the implanted population express the neuronal markers NeuN and MAP2 at substantially higher rates than previously reported. We also find that these cells exhibit neuronal cytoarchitecture, extend axons into the ventral roots or several segments in length within the spinal white matter, are decorated with synaptotagmin+ and GABA+ synaptic terminals, and exhibit active membrane properties and spontaneous synaptic potentials characteristic of functionally integrated neurons. Neuronal differentiation is accompanied by loss of CD34 expression. Careful examination with confocal microscopy reveals no signs of heterokaryons, and human cells never express a chicken-specific antigen, suggesting that fusion with host chicken cells is unlikely. We conclude that the microenvironment in the regenerating spinal cord of the chicken embryo stimulates substantial proportions of adult human HSCs to differentiate into full-fledged neurons. This may open new possibilities for a high-yield production of neurons from a patient's own bone marrow. Institute of Immunology, Rikshospitalet University Hospital and University of Oslo Rikshospitalet, 0027 Oslo, Norway. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15790679

    von Ungern-Sternberg BS, Erb TO and Frei FJ (2005). Jaw thrust can deteriorate upper airway patency. Acta Anaesthesiol Scand 49: 583-5. Upper airway obstruction is a frequent problem in spontaneously breathing children undergoing anesthesia or sedation procedures. Failure to maintain a patent airway can rapidly result in severe hypoxemia, bradycardia, or asystole, as the oxygen demand of children is high and oxygen reserve is low. We present two children with cervical masses in whom upper airway obstruction exaggerated while the jaw thrust maneuver was applied during induction of anesthesia. This deterioration in airway patency was probably caused by medial displacement of the lateral tumorous tissues which narrowed the pharyngeal airway. Department of Anesthesia, University Children's Hospital Basel, Basel, Switzerland. bvonungern@uhbs.ch http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15777312

    Muschler GF, Matsukura Y, Nitto H, Boehm CA, Valdevit AD, Kambic HE, Davros WJ, Easley KA and Powell KA (2005). Selective retention of bone marrow-derived cells to enhance spinal fusion. Clin Orthop Relat Res 242-51. Connective tissue progenitors can be concentrated rapidly from fresh bone marrow aspirates using some porous matrices as a surface for cell attachment and selective retention, and for creating a cellular graft that is enriched with respect to the number of progenitor cells. We evaluated the potential value of this method using demineralized cortical bone powder as the matrix. Matrix alone, matrix plus marrow, and matrix enriched with marrow cells were compared in an established canine spinal fusion model. Fusions were compared based on union score, fusion mass, fusion volume, and by mechanical testing. Enriched matrix grafts delivered a mean of 2.3 times more cells and approximately 5.6 times more progenitors than matrix mixed with bone marrow. The union score with enriched matrix was superior to matrix alone and matrix plus marrow. Fusion volume and fusion area also were greater with the enriched matrix. These data suggest that the strategy of selective retention provides a rapid, simple, and effective method for concentration and delivery of marrow-derived cells and connective tissue progenitors that may improve the outcome of bone grafting procedures in various clinical settings. Department of Orthopaedic Surgery, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. muschlg@ccf.org http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15738828

    de Haro J, Zurita M, Ayllon L and Vaquero J (2005). Detection of 111In-oxine-labeled bone marrow stromal cells after intravenous or intralesional administration in chronic paraplegic rats. Neurosci Lett 377: 7-11. Recent studies suggested that bone marrow stromal cells (BMSC) may have a therapeutic role in the treatment of paraplegia secondary to severe spinal cord injury (SCI). For this reason, we have studied the possibility of using nuclear medicine imaging techniques to evaluate the permanency and migration of BMSC after transplantation procedures in chronic paraplegic Wistar rats. After intravenous administration of 111In-oxine-labeled BMSC, gammagraphic images showed that the activity distributed all over the organism, but in the spinal cord only scarce activity was identified. When 111In-oxine-labeled BMSC were injected within the traumatic centromedullary cavity of paraplegic animals, the gammagraphic images showed persistent activity in the lesion zone, without any activity migrating to the rest of the organism, at least during the whole time of the study (10 days after transplantation procedures). Our results show the utility of 111In labeling for to know the permanency and distribution of BMSC after grafting procedures, and suggest the convenience of the intralesional administration of BMSC, instead of the intravenous administration, in the treatment of chronic traumatic paraplegia. Neuroscience Research Unit, Mapfre-Medicine Foundation, Neurosurgical and Nuclear Medicine Services, Puerta de Hierro Hospital, Autonomous University, San Martin de Porres, 4, 28035 Madrid, Spain. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15722177

    Schultz SS (2005). Adult stem cell application in spinal cord injury. Curr Drug Targets 6: 63-73. The mechanical force incurred by spinal cord injury results in degenerative neural tissue damage beyond the site of initial injury. By nature, the central nervous system (CNS) does not regenerate itself. Cell therapy, in particular, stem cell implantation has become a possible solution for spinal cord injury. Embryonic stem cells and fetal stem cells are the forefathers of the field of stem cell therapy. Isolation and preparation of specific populations of adult stem cells have evolved to the point of stable, long-term culturing with the capability to differentiate into neural phenotypes from all three of the neural lineages: neurons, astrocytes, and oligodendrocytes. Thus, adult stem cells will transcend ethical concerns, technical difficulties, and probably immunorejection. A variety of adult stem cells have been implanted in a rat model of spinal cord injury, ranging from olfactory ensheathing cells, cultured spinal cord stem cells, bone marrow derived stem cells, dermis derived stem cells, and a few others. Although no definite decisions on which adult stem cells are most effective for this CNS injury, their ability to incorporate into the spinal cord, differentiate, and to improve locomotor recovery hold promise for a cure. Department of Neuroscience, Albert Einstein School of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. sherrischultz5000@yahoo.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15720214

    Kamada T, Koda M, Dezawa M, Yoshinaga K, Hashimoto M, Koshizuka S, Nishio Y, Moriya H and Yamazaki M (2005). Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after complete transection of adult rat spinal cord. J Neuropathol Exp Neurol 64: 37-45. The aim of this study was to evaluate whether transplantation of Schwann cells derived from bone marrow stromal cells (BMSC-SCs) promotes axonal regeneration and functional recovery in completely transected spinal cord in adult rats. Bone marrow stromal cells (BMSCs) were induced to differentiate into Schwann cells in vitro. A 4-mm segment of rat spinal cord was removed completely at the T7 level. An ultra-filtration membrane tube, filled with a mixture of Matrigel (MG) and BMSC-SCs (BMSC-SC group) or Matrigel alone (MG group), was grafted into the gap. In the BMSC-SC group, the number of neurofilament- and tyrosine hydroxylase-immunoreactive nerve fibers was significantly higher compared to the MG group, although 5-hydroxytryptamine- or calcitonin gene-related peptide-immunoreactive fibers were rarely detectable in both groups. In the BMSC-SC group, significant recovery of the hindlimb function was recognized, which was abolished by retransection of the graft 6 weeks after transplantation. These results demonstrate that transplantation of BMSC-SCs promotes axonal regeneration of lesioned spinal cord, resulting in recovery of hindlimb function in rats. Transplantation of BMSC-SCs is a potentially useful treatment for spinal cord injury. Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15715083

    Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G and Fischer I (2005). Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 1035: 73-85. Bone marrow stromal cells (MSC) are non-hematopoietic support cells that can be easily derived from bone marrow aspirates. Human MSC are clinically attractive because they can be expanded to large numbers in culture and reintroduced into patients as autografts or allografts. We grafted human MSC derived from aspirates of four different donors into a subtotal cervical hemisection in adult female rats and found that cells integrated well into the injury site, with little migration away from the graft. Immunocytochemical analysis demonstrated robust axonal growth through the grafts of animals treated with MSC, suggesting that MSC support axonal growth after spinal cord injury (SCI). However, the amount of axon growth through the graft site varied considerably between groups of animals treated with different MSC lots, suggesting that efficacy may be donor-dependent. Similarly, a battery of behavioral tests showed partial recovery in some treatment groups but not others. Using ELISA, we found variations in secretion patterns of selected growth factors and cytokines between different MSC lots. In a dorsal root ganglion explant culture system, we tested efficacy of conditioned medium from three donors and found that average axon lengths increased for all groups compared to control. These results suggest that human MSC produce factors important for mediating axon outgrowth and recovery after SCI but that MSC lots from different donors vary considerably. To qualify MSC lots for future clinical application, such notable differences in donor or lot-lot efficacy highlight the need for establishing adequate characterization, including the development of relevant efficacy assays. Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15713279

    Lu P, Jones LL and Tuszynski MH (2005). BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191: 344-60. Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery. Department of Neurosciences and Center for Neural Repair, University of California at San Diego, La Jolla, CA 92093-0626, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15649491

    Fuehrer M, Gerusel-Bleck M, Konstantopoulos N, Bender-Goetze C and Walther JU (2005). FISH analysis of native smears from bone marrow and blood for the monitoring of chimerism and clonal markers after stem cell transplantation in children. Int J Mol Med 15: 291-7. After stem cell transplantation (SCT) close follow-up of chimerism and/or clonal disease markers is essential for early treatment of graft failure or relapse. We wanted to assess the sensitivity, clinical reliability and practicability of inter-phase FISH on untreated, native smears of BM or PB for this purpose. We investigated 23 children after SCT with sex mismatch (MM) and/or clone specific markers (monosomy 7, trisomy 8, MLL rearrangement, bcr-abl, TEL-AML-1). Diagnoses were ALL (8), AML (6), MDS (2), CML (2), large cell anaplastic lymphoma (1) and SAA (4). Eighteen children were transplanted from sex-mismatched donors, seven among them had shown a clonal marker at diagnosis. The remaining five patients with sex matched donors also had a clonal marker. For FISH, we used commercial probes on fresh or stored unmanipulated smears of PB or BM. Cut-off levels for clonal markers were established on control probands without hematologic disease, for host sex on probands of the opposite sex, respectively (mean +3 SD). The presence of host cells and/or clonal markers established at diagnosis by conventional karyotyping was followed up after SCT at regular intervals by FISH. Nineteen of the 23 patients studied achieved and maintained complete continuous hematologic remission with corresponding absence of host and/or disease markers. In one of them, a fatal extramedullary relapse occurred. The associated mixed chimerism was confirmed by FISH. In all four cases with hematological relapse, the respective marker (MLL, bcr-abl, Mo 7) reappeared and was successfully monitored during DLI and repeat SCT in two as well as parallelled by simultaneous demonstration of host cells in the two sex mismatched cases among them. We demonstrate the usefulness of FISH on native smears for clinical routine follow-up of SCT patients. FISH allowed identification of cell origin in non-hematologic material (spinal fluid, pericardial effusion). Chimerism analysis in BM was slightly more sensitive than in PB. FISH was feasible on frozen stored smears as well. Kinderklinik und Poliklinik der Ludwig-Maximillians Universitat Munchen, D-80337 Munchen, Germany. monika.fuehrer@med.uni-muenchen.de http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15647846

  4. #14
    Senior Member
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    Dr. Young

    Dr. Young-

    Would you call me a fool if I thought there hasn't been great strides in SCI research progress ( more effective therapy options being studied ) in the past 5 years?
    sherman brayton

  5. #15
    sbdspray - A fool, no.

    However, depending on definition, there have been great strides in research, awarenewss, education, advocacy, etc.

    Although our perception may be that science has move slowly in the world of sci progress, particularly in the area of clinical trial application, if you delve into the "research forum", investigate some of the more active clinical institutions (Miami Project, UC Irvine, UCSD, etc.) and reflect back to where they were just 5 years ago I think you'll find that the steps made, the forecasts predicted, the urgency sustained, and the excitement generated are head and shoulders ahead of even the most optimistic of visions.

    Imo, the critical juncture we are now facing is consistent funding, legislative reecognition and clinical trial infrastructure. With these tools and the application of the above mentioned efforts we are nearing the finish line of this marathon.

    Onward and upward...www.unite2fightparalysis.org

  6. #16
    Quote Originally Posted by sbdspray
    Dr. Young-

    Would you call me a fool if I thought there hasn't been great strides in SCI research progress ( more effective therapy options being studied ) in the past 5 years?
    Sherman, you know that I would never call you a fool. I agree with Chris Chappell that we have made significant progress. Let me innumerate the positive steps. I'm sure that I can come out with more if I took a little time to think about it more.

    1. Combination therapies. Five years ago, the concept of combination therapies was just a gleam in our eyes. Now, it has become clear that it must be one of the major objective of clinical trials. Five years ago, we hoped that the cell transplants alone would be sufficient and it is clear that they are not. Now, several laboratories have come out with clear evidence indicating the combination therapies are better than individual therapies.
    2. Growth factors. There was a great deal of confusion concerning growth factors. Five years ago, I think that most scientists were thinking in terms of BDNF and NT-3 as the main candidates for growth factor stimulation. Attention has shifted to GDNF and other growth factors.
    3. Nogo/CSPG. Five years ago, the effects of Nogo blockade was known and we really had only one option, i.e. using IN-1 to bind Nogo. Today, we not only have IN-1 going into clinical trial but we have several alternative approaches to blocking Nogo effects, including Nogo receptor blockade and use of Cethrin to block the second messenger systems for Nogo. Chondroitinase has been shown to stimulate regeneration.
    4. Cell transplants. Five years ago, we had only one cell transplant that had been tried in humans: mixed fetal cells (Russia and Gainesville). Today, we have clinical experience with activated macrophages, fetal olfactory ensheathing glia, nasal mucosa, pig fetal neural stem cells, bone marrow stem cells, and umbilical cord blood stem cells. We know now that none of the transplants alone are producing dramatic return in function although many people have had significant return of sensory function and modest return of 1-2 levels of motor function. We also know the cell transplantation into the spinal cord is safe. Despite hundreds (perhaps even thousands, if we include the Russian experience) of patients receiving a variety of cell transplants, we have had almost no reports of mortality, tumor formation, or significant loss of function from transplants (all feared complications). It also seems that none of the cell transplants are producing significant increases in severe and long-term neuropathic pain (another feared complication).
    5. Availability of cells. We are making some progress in having cells available for transplant. Five years ago, only fetal neural cells were available. Now in various places around the world, we have at fetal OEG cells, nasal mucosa, bone marrow autografts, umbilical cord blood stem cell heterografts, fetal neural stem cells, embryonic stem cells (even cloned embryonic stem cells), and others.
    6. Clinical trials. Five years ago, we had perhaps three or four clinical trials going on around the world. Today, we have dozens of trials going on overseas. We also have a clinical trial network in China that is poised to start trials. Congress is seriously considering funding clinical trials in the United States through the Christopher Reeve Paralysis Act. There are many clinicians who are doing cell transplants around the world and even some in the United States who have had experience transplanting cells.
    7. Funding. Five years ago, we had relatively little funding for clinical trials of therapies.
      1. Industry investment. In 2000, there was only Acorda (4-AP), Proneuron (activated macrophage), and Diacrin (fetal pig stem cells) funding spinal cord injury trials. Today, we have
        • Acorda (4-AP),
        • Proneuron (activated macrophages),
        • Novartis (Nogo antibodies),
        • Aventis (HP184),
        • Bioaxone (Cethrin),
        • Medtronics (alternating electrical current).
      2. Countries. In 2000, we had only one country doing significant spinal cord injury clinical trials for chronic spinal cord injury (Russia) and a few scattered efforts here in the United States with omentum transplant and fetal stem cell transplants. In 2005, we have the following countries:
        • Russia: Moscow (fetal neural cells) and Novosibirsk (fetal neural cells)
        • U.S.: Purdue (alternating current)
        • Canada: Toronto and some U.S. cities (Cethrin)
        • China: Beijing (fetal OEG cells), Kunming (fetal schwann cells), Zhengzhou (bone marrow stem cell autografts)
        • Portugal: Nasal mucosa autografts
        • Australia: Nasal OEG autografts
        • New Zealand: Nasal mucosa autografts
        • Korea: bone marrow stem cells, umbilical cord blood stem cells
        • Turkey: bone marrow stem cells
      3. Current Clinical Trials on subacute or chronic spinal cord injury
        • Activated macrophage transplants (Proneuron)
        • Bone marrow stem cell transplants (Turkey, Korea, China, Russia)
        • Umbilical cord blood stem cell transplans (Korea)
        • Cethrin (Bioaxone)
        • Nogo antibody (Novartis)
        • HP184 (Aventis)
        • Fetal OEG (Beijing, China)
        • Fetal Schwann cells (Kunming China)
        • Nasal mucosa transplants (Lisbon)


    Many clinical trials are being planned, including of course ChinaSCINet. In short, we are making progress. Spinal cord injury research is following what some people in Wall Street might call a "hockey stick" curve. In 2000, we were at the leading edge of the hockey stick near the bottom of the graph. We have moved out of the flat part of the hockey stick and have begun to move up the handle.

    Wise.
    Last edited by Wise Young; 08-26-2005 at 01:58 AM.

  7. #17
    Senior Member Schmeky's Avatar
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    Dr. Y,

    Great write up.

    Incidentally, the hockey stick graph appears to have a complete transection at about the T-6 level.

  8. #18
    schmeky, I put the break in there to remind myself and others that it can break any time and that we should not be complacent. Wise.

  9. #19
    Senior Member Schmeky's Avatar
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    Dr Y,

    Please don't think I am being flippant. I am trying to hold on to what sense of humor I have left.

    With Best Regards,

    Schmeky

  10. #20
    Quote Originally Posted by Schmeky
    Dr Y,

    Please don't think I am being flippant. I am trying to hold on to what sense of humor I have left.

    With Best Regards,

    Schmeky
    Schmeky, I know and thanks for what you are and do. Wise.

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