Abstracts - Table of Contents
Honarary President of IANR for life.
Professor of Neural Regeneration,University College London Director of the Spinal Repair Unit,the Institute of Neurology, Queen Square.
Ying Li, Daqing Li, Geoffrey Raisman
The tissue of the CNS consists of an intimate interweaving of two great networks, glial and neuronal which act as a self-regulating corporate entity. The configuration of astrocytic surfaces is crucial to their participation in the network functions. Re-configuration of the CNS astrocytic network by incorporation of glial cells from the olfactory system produces a situation permissive for the regeneration of severed CNS nerve fibres.
All damage to the nervous system affects both neurons and glia. Yet up to now the majority of efforts at repair have largely concentrated on neurons. After axotomy central neurons do not regenerate their axons. They fail to upregulate the molecular machinery associated with growth and extension of the cytoskeleton. But these events are not necessarily due to an intrinsic failure in the neurons.
That adult neurons retain the ability to grow axons and form new functional connections in the CNS is attested by numerous observations and studies. It has long been recorded that severed central axons sprout, and can form extensive neuromata. The introduction of peripheral nerve Schwann cells into the CNS induces long growth of axons from intrinsic central neurons that otherwise fail to regenerate. After injury to fibre tracts in the CNS, adult axons in both damaged and undamaged tracts sprout new branches which are able to cross great distances through undamaged areas of the CNS and establish functional connections. Above all, our current view of plasticity is that the neural connections in the adult brain are in a state of continuous change.
None of this supports the view that adult central neurons are intrinsically unable to grow axons or make new synaptic connections. Equally, it does not support the view that the astrocytic environment of the adult CNS is intrinsically inhibitory to axon growth. The evidence suggests that the failure of axon regeneration is a local consequence of the reaction of the astrocytes at the injury site and therefore it is to the astrocytic behaviour at this site that repair therapies should be directed.
Hongyun Huang (China)
President,International Association of Neurorestoratology (IANR)
President ,Beijing Hongtianji Neuroscience Academy
Adjunct Professor of Taishan Medical University Member of Editorial Board Cell Transplantation; Chief Editor in Frontiers Neurorestoratology; Associate Editor American Journal of Neuroprotection and neuroregeneration
Hongyun Huang ,Lin Chen, Haitao Xi
Center for Neurorestoratology, Beijing Rehabilitation Center, Beijing
Beijing Hongtianji Neuroscience Academy, Beijing
Neurorestoratology is new independent discipline of neuroscience or medicine; but its development take a long time. Here we summarize its developing history and introduce some new conceptions of Neurorestoratology.
Development history of strategies in Neurorestoratology: tissue and cell transplantation (the earliest tissue transplantation in animal by Thompson in 1890 and the first clinical trial by Backlund and Olson in 1982; the initial OECs transplantation in animal study by Ramón-Cueto, Franklin and Raisamn in 1994,1996,1997,2000 and the earliest clinical trials started by Huang, Lima and Rabinovich in 2001); neurostimulation and neuromodulation (the first electric field affection by Ingvars in 1920 and clinical deep brain stimulation (DBS) by Bechereva in 1972); medicine and growth factor (nerve growth factor found by Levi-Montalcini and Hamburger in1951 and first clinical use by Olson and Backlund in 1991 and high-dose methylprednisolone therapy in animal study in1982 and clinical trial in 1990 by Young); bioengineering and tissue engineering (Garoni found NI-35and NI-250 in 1998 and clinical trial for polymer-encapsulated cells engineered with CNTF by Bloch in 2004); surgery (cordotomy in animal study by Larson in 1965 and in first clinic for patients by Tachibana in 1984 and neurotisation or nerve bridging in animal study by Hueter in 1871 and simultaneously started in clinic by Zhang and Brunelli in 2000).
Tracing the sense development of Neurorestoratology as a discipline, there are Restorative Neurology (Dimitrijevic in 1985), Restorative Neurosurgery (Liberson in 1987), Neuroprostheses (Keith in 1988), Neurorestorative Technique or Therapy (Fernández in 1995 and Jiménez-Jiménez in 1997), Restorative Neuroscience (Andres in 2008) and Neurorestoratology (put forward by Huang and Chen in 2008 and defined by IANR in 2009).
Main associations or societies in or related with Neurorestedoratology are below: International Association of Neurorestoratology (IANR), Global College of Neuroprotection and Neuroregeneration (GCNN), American Society for Neural Therapy and Repair (ASNTR), International Society of Restorative Neurology (ISRN), International Neuromodulation Society (INS), The Society For The Study Of Neuroprotection And Neuroplasticity (SSNN), Cell Transplant Society (CTS), International Conference on Neuroprotective Agenda, Network of European CNS Transplantation and Restoration (NECTAR), Asia Pacific Symposium on Neural Regeneration (APSNR) and so on.
Main journals in the field of Neurorestoratology include Cell Transplantation, Restorative Neurology and Neuroscience, Neuromodulation, Frontiers in Neurorestoratology, Ameican Journal of Neuroprotection and Neuroregeneration, Stem cells, Clinical transplantation and so on.
Most important new conceptions in Neurorestoratology list below: second generation of neurorestorative therapy (2G- neurorestorative therapy), active movement-target enhancement-rehabilitation therapy (AMTENT), key point for neural network restoration (KPNNR), pain Neurorestoratology, epilepsy Neurorestoratology.
Ziad.M.AL Zoubi (Jordan)
President of IANR;Director, Jordan Ortho & Spinal Centre;Founder, Jordan Spine Society; Founder，Pan Arab Spine Society; Chairman, Association for Spinal Cord Injury Care
Abstract：Research on cell therapy for the treatment of chronic untreatable diseases is tremendous .extensive x-vivo, animal experiment and the clinical trials are now published in journals. Probably the chronic neuronal diseases like chronic spinal cord injuries are the most difficult to treat. Hundreds of clinical trials are running now in many centers all over the world , this interest in cell therapy raised many questions about the seriousness of this huge number of research work and this leads automatically to establish many research centers , societies, associations .etc
This lecture will discusse the need for some form of accreditation rules , classification of these centers, and groups of research centers to help the researchers and the demanding patients .
Long-term Follow-up Observation on 24 Patients with Spinal Cord Injury Receiving Olfactory Ensheathing Cell Transplantation
He Xijing1，Wang Dong 1，Li Haopeng 1，Xu Siyue 1，Yang Pinglin 1，
Wang Guoyu 1，Wu Fei 1，Pei Leilei 2
1、NO.2 Orthopedics Department, Second Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an, Shaanxi Province 710004, China.
2、Statistical Learning and Research Department of Medical School of Xi’an Jiaotong University, Xi’an, Shaanxi Province 710004, China.
Abstract：Olfactory ensheathing cell transplantation (OECT) has been used to treat patients with spinal cord injury (SCI). But it is still unclear about its long-term curative efficacy and safety. This study was retrospectively to analyze the long-term changes in sensory level, muscle strength, neural function and individual self-evaluations of 24 patients with SCI (male/female 20/4; average age 32.4 years, age range 19~45) who received OECT in our hospital from September 2005 to March 2010. The changes in neural function were estimated based on the ASIA scores. ANOVA was used to do statistical analysis. Successful transplantation and follow-up (averagely 3.2 years, range 0.5 to 5.2) were conducted and no apparent complications were found in all the 24 patients. Postoperatively, 9 patients with total paralysis showed the sensory level descended to 1-2 spinal segments below the SCI level, and 1 patient had no change; among the 13 patients with quadriplegia 11 presented with two-spinal-segment descending of sensory level, 2 with three-spinal-segment descending, especially 1 of the 2 patients showing an improvement of flexor function and the emergence of thumb long extensor dorsiflexion movement (muscle strength 2 degrees). No mass or cavity formation was detected at the sites of cell transplantation by MRI. The self-evaluations of 2 patients for OECT were excellent, 9 good, 12 poor, and 1 very poor. The excellent and good-evaluation rate was 50%. ANOVA showed there was no obviously difference in ASIA scores between before and after OECT (P<0.05). In short, the transplantation of olfactory ensheathing cells derived from allogeneic embryonic olfactory bulb induction is a safe therapy for spinal cord injury. But the long-term therapeutic effect of OECT on SCI is not perfect. This technique still needs further observation and exploration.
Key words：spinal cord injury; transplantation; olfactory ensheathing cells; efficacy evaluation
Hari Shanker Sharma (Sweden)
President Elect of IANR；President of GCNN
Laboratory of Cerebrovascular Research, Dept. of Surgical Science, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University
Hari S Sharma, Ph D, Dr Med Sci
Central nervous system (CNS) injury is caused by a variety of external and internal factors leading to serious mental and physical dysfunction [1-3]. The science of Neurorestoratologyestablished in recent years by Huang and his International group from Beijing, China focused on restoration of all kinds of mental and physical dysfunctions caused by disordersof the CNS . Thus, CNS injuries caused by external factors e.g., trauma and/or neurodegenerative diseases i.e., Parkinson’s, Alzheimer’s, Huntington’s Diseases, Multiple sclerosis, stroke, ischemia, infarction or other kinds neurological injuries require extensive restoration using pharmacotherapy in combination to neuroregenerative approaches e.g., treatment with stem cells, neurorehabilitation including exercise and training as therapy in combination with other suitable therapeutic measures [1-5]. Thus, the science of Neurorestoratology combines all forms of physical, chemical and cellulartreatments to restore functions of the CNS in patients . Our laboratory is engaged in neuroregenerative therapy in different animal models of CNS injuries [5-8]. Our observations shows that multiple combinations of neurotrophic factors derived from neurons, e.g., brain derived neurotrophic factor (BDNF), or glia derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) when administered exogenously following CNS injury caused by trauma or hyperthermia induces remarkable restoration of neuronal, glial and endothelial cell structure and functions [1-3, 5-8]. However, other combination of neurotrophic factors is not that effective in identical situations. This suggests that suitable combination of neuroregenerative therapy using neurotrophic factors leads to marked neurorestoration. Interestingly, the therapeutic efficiency of these neurotrophic factors is further enhances when they are administered using nanowired technology . However, nanowired drug delivery did not alter the fundamental principles of neurotrophic factor therapy. Thus, this combination of neurotrophicfactors that did not influence neurorestorationisstill not altered following their nanodrug delivery. However, nanowired drug delivery of neurotrophins that Inducesprofoundneurorestorationismark
edlyenhancedusing nano-drug delivery. The functional significance of neurorestorative therapy using neurotrophic factors with or without nanodrug delivery is discussed.
Arthur M. Sherwood (USA)
Professor, Department of Physical Medicine and Rehabilitation, Baylor College of Medicine; Science and Technology Advisor, National Institute on Disability and Rehabilitation Research Department of Education
Arthur M. Sherwood1*, W. Barry McKay2, and Milan R. Dimitrijevic3
1Department of Physical Medicine and Rehabilitation and Research, Baylor College of Medicine, Houston;2The Shepherd Center;3Department of Physical Medicine and Rehabilitation and Research, Baylor College of Medicine, USA
The ability to reliably, objectively and quantitatively characterize motor control within the surviving, or pre-treatment spinal cord, and then to sensitively monitor changes brought by any intervention attempt is essential to the evaluation of protocols designed to ameliorate the consequences of spinal cord injury. This presentation will describe a method that measures the spinal motor output in the form of multiple-muscle surface-recorded electromyographic activity that is produced in response to a standard set of reflex and volitional activities attempted under controlled conditions. Calculated from this recorded activity, selected parameters and indices are used to quantitatively describe residual motor control and intervention effects. The theoretical basis and practical aspects of designing appropriate tasks, presenting them to test subjects, quantifying output, calculating indices, and interpreting results will be presented, with emphasis on the practical implementation in a clinical context. In addition to the objective quantification of reflex and volitional tasking, this measurement tool provides an opportunity to monitor neuromodulatory effects of unpatterned stimulation. Presented here will be the effects of epidural or transcutaneous electrical stimulationof dorsal root afferents that appear as multisegmental, motor unit outputvarying according to the distribution and parameters of the stimulation. These output patterns, including particularly locomotor-like activity, provide evidence of the function of the “spinal brain”.
Department of Anatomy, The State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, Hong Kong SAR China; JNU-HKU Joint Laboratory of Brain Function and Health, Jinan University, Guangzhou, China
Functional neurons are generated from adult neural precursors throughout life in adult mammals. Adult neurogenesis has attracted a lot of interest in the past decade. Our laboratory focuses on the role of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle on sexual function and psychiatric condition including depression. Enhancing endogenous neurogenesis including proliferation and differentiation of new neurons by various treatments could be a useful approach in regenerative medicine in the injured brain and spinal cord.
Abstract：We have established a model of SCI in the neonatal mouse that provides the opportunity to implant human stem cells of various types in a context of dynamic functional recovery where they can be assessed for survival, proliferation, differentiation, and functional integration.
The model involves a compression injury at thoracic levels followed by stem cell implantation and/or high-throughput functional imaging using calcium-mediated activity probes. In this model, functional deficits as assessed with behavioral tests are evident during the first day after injury and dramatic functional improvement occurs during the ensuing few days. During this period, it is possible to record synaptic activity in spinal neurons using calcium imaging such that descending inputs can be assessed above and below the lesion at different times during the recovery process. In this model we have begun to test the capacity for human fetal neural progenitor cells to survive and integrate into the spinal cord. So far we have found that these cells can survive for at least 15 days during which time they begin to differentiate and elaborate neurites. We are now testing whether they are able to receive inputs from specific descending pathways originating in the brain stem.
Stereotaxic implantation of Olfactory ensheathing cells （OECs）for stroke patients
Key words：olfactory ensheathing cells (OECs), old stroke, early phase clinical trial, stem cells
Based on our previous preclinical study (Shyu WC, Journal of Clinical Investigation 2008; 118:2482–2495), we thus held the phase Ib/IIa clinical trial study. We will recruit 6 patients (between 35 and 70 years of age) who have suffered from old cerebral infarction over middle cerebral artery territory for over 6 months to 5 years with the severity measured by the National Institute of Health stroke scale (NIHSS) from 5 to 15 scales. Recruited patients should be received the endoscopic surgery for picking the olfactory mucosa 1 to 2 months before transplantation. The OECs will be cultured and expanded under the rule of GTP. Then, quality control of OECs should be done by immunohistochemical staining positive for GFAP, S100, and P75. Finally, we perform stereotaxic transplantation of the OECs (about 2 to 8 ´106 cells in saline) into the peri-infarcted area. All patients will be followed for one year. The primary outcome end points are set to analyze scores of the NIH-stroke scale (NIHSS), European stroke scale (ESS), and European stroke motor subscale (EMS). In addition, we also measure the quantitative results of diffusion tensor image (DTI) using MRI and motor evoke potential (MEP) by transcranial magnetic stimulation (TMS) as the secondary end point.
Department of Stem Cell Biology and Histology and Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japanmdezawa@med.tohoku.ac.jp
Since pluripotent stem cells are able to generate all kinds of ectodermal, mesodermal and endodermal cells, they are expected to be applicable to various kinds of diseases. While ES cells and iPS cells are well known pluripotent stem cells, they have risk of tumorigenicity. Adult stem cells are natural cells residing in our living body and normally do not show tumorigenic proliferation. However, they typically generate the cell types of the tissue in which they reside and thus the range of their differentiation capabilities is considered limited.
We newly found a unique type of stem cells which we named Multilineage differentiating Stress Enduring (Muse) cells (Kuroda et al., PNAS, 2010). They are adult stem cells that reside in adult human mesenchymal tissues and are pluripotent. They can be isolated as cells double positive for mesenchymal marker CD105 and human ES cell marker SSEA-3 from bone marrow, skin and fat tissues or from commercially available human cultured mesenchymal cells. Muse cells were found as stress tolerant cells, and express pluripotent stem cell markers, self-renew and generate cells representative of all three germ layers from a single cell. Most importantly, they do not show tumorigenic proliferation, a trait that is consistent with the fact that they reside in adult tissues. Furthermore, they are shown to migrate and home into damaged tissues when infused into peripheral blood. When human Muse cells are infused into tail vein of Nog-mouse suffering from spinal cord injury, fulminant hepatitis, diabetes mellitus and skin injury, human Muse cells integrated into those damaged tissues, differentiated into neuronal cells, hepatocytes, insulin-producing cells and keratinocytes, and finally contributed to tissue reconstruction.
Recently, we found that Muse cells are a primary source of iPS cells in human fibroblasts (Wakao et al., PNAS, 2011). When human fibroblasts were separated into Muse and non-Muse cells and transduced with Oct3/4, Sox2, Klf4, and c-Myc, iPS cells were generated exclusively from Muse cells, but never from non-Muse cells. Epigenetic alterations were not seen in non-Muse cells and some of the major pluripotency markers were not expressed for the entire period of generation, suggesting that Muse cells whose properties are already similar to that of iPS cells selectively become iPS cells, whereas the remaining cells make no contribution to the generation of iPS cells.
Thus, Muse cells will be beneficial for cell-based therapy and biomedical research.
William Slikker (USA)
Director of the FDA’s National Center for Toxicological Research;Adjunct Professorships in the Departments of Pediatrics, and Pharmacology and Toxicology at the University of Arkansas for Medical Sciences
W. Slikker, Jr., X. Zhang, F. Liu, S. Liu, X. Zou, N.V. Sadovova, R.L. Divine, T.A. Patterson, S.F. Ali, L. Guo, Q. Shi, D. Doerge, J.P. Hanig, M.G. Paule and C. Wang
National Center for Toxicological Research/FDA and Toxicologic Pathology Associates, Jefferson, AR, USA; Center for Drug Evaluation and Research/FDA, Rockville, MD, USA
In several animal models it has been shown that the developing brain is susceptible to anesthetic-induced injury. The window of vulnerability to these neuronal effects of anesthetics is restricted to the period of rapid synaptogenesis, also known as the brain growth spurt. Similar dependencies on dose/duration of exposure and developmental stage are observed in both the non-human primate and rodent models for NMDA receptor-dependent anesthetics (e.g., ketamine). The duration of anesthesia needed to induce cell death as measured by minimal exposure requirements is similar (~ 4-6 hrs) for nonhuman primate and rodent brain cells in culture, and also in vivo in rodent and nonhuman primate models. The susceptible stage or period of development has not been completely described, but in the nonhuman primate it begins somewhere before the last quarter of pregnancy and continues until shortly after birth. Behavioral studies in developing primates have confirmed functional deficits following neonatal ketamine-induced anesthesia as assessed by the NCTR Operant Test Battery. In rats previously exposed to ketamine, microPET imaging data have indicated enhanced 18F Annexin-V retention, a non-invasive marker of apoptosis. It has been postulated that up-regulation of the NR1 subunit of the N-methyl-D-aspartate receptor, a calcium channel regulator, may be an important first step in the pathway to anesthetic-induced neurotoxicity following exposure to NMDA antagonists. Both gene expression studies and NR1 antisense experiments have provided supportive evidence for NMDA receptor involvement in the neurotoxic pathway. Several recent studies have indicated that reduction of oxidative stress may protect the developing animal from anesthetic-induced brain cell death. Evidence for the role of oxidative stress in anesthetic-induced neurotoxicity has been generated in studies that apply oxidative stress blockers, including L-carnitine (mitochondrial protector) and melatonin in vivo and specific antioxidants in vitro including the superoxide dismutase mimetic, M40403 and the NOS inhibitor, 7-nitroindazole. Recent gene expression assessments indicate that genes in the oxidative stress pathway are altered by anesthetic treatment of developing animals. The effect of ISO/N2O on the uptake and retention of [18F]-DFNSH in the brains of different aged rats and the potential protective effect of acetyl-L-carnitine (ALC) on anesthetic-induced neuronal cell death were investigated using microPET imaging. On PND 7, rat pups were exposed to either a mixture of 70% N2O/30% oxygen plus 1% ISO for 8 hours with or without ALC, or to room air only (control). On PNDs 14, 21 and 28, [18F]-DFNSH (18.5 MBq) was injected i.p. and 30 minutes later microPET images were obtained over 90 minutes. In PND 14 rats the uptake of [18F]-DFNSH was significantly increased and the duration of tracer wash-out was prolonged in ISO/N2O-treated rats and ALC block this effect. The data of calcium imaging supports the hypothesis that continuously blocking the NMDA receptors by ketamine can cause compensatory up-regulation of NMDA receptors, which allows the accumulation of toxic levels of intracellular Ca2+ after ketamine withdrawal, subsequently may trigger apoptosis in neurons. Together, the application of omics approaches along with traditional toxicological endpoints indicates that oxidative stress plays a critical role in the susceptibility of the developing brain to anesthetics. Supported by NICHD, NTP/NIEHS and CDER and NCTR/FDA
Director, Department of Pediatrics, Navy General Hospital; Vice President of IANR; Vice Chairman, Stem Cell Engineering Committee, Chinese Medical Association Biomedical Engineering Socie
Zuo Luan, Suqing Qu, Kan Du, Weipeng Liu, Yinxiang Yang, Zhaoyan Wang, Ying Cui1, Qingan Du
Department of Pediatrics, Navy General Hospital Beijing 100037, China
1. Postgraduate student of Soochow University
Objective：To investigate the clinical efficacy of the neural precursor cells transplantation to treat the severe visual impairment – a sequela of neonatal brain injury.
Methods：52 patients with cerebral injury and visual impairments caused by various reasons in our hospital out-patient department from May 2005 to Feb 2009 were selected and randomly divided into 2 groups: the treatment group (n=25, with the average age of 18 months) and the control group (n=27, with the average age of 19.5 months). There were no significant difference in the sex, age, cause of disease, type of cerebral injury and visual impairment degree between two groups. The treatment group received intraventricular transplantation of human neural stem cells and rehabilitation training. The control group received rehabilitation training only.
Results：1 in 5 fundus abnormalities associated with blindness patients got light perception. The visual functions of 15/20 patients with normal fundus were improved 1 level or more. After 2-year follow up, the visual function of 3 paitents improved from level I to level II, 4 from level I to level III, 1 from level I to level IV, 2 from level II to level III, 3 from level II to level IV, 2 from level II to level V. The efficacy appeared on 60 days post transplantation in median and the effective rate is 64% in the treatment group. In the patients showed efficacy in the treatment group, 1 blindness patient got light perception. 5 (31.2%） gotⅠ level improvement, 10 patients （62.5% ）got more than Ⅰ level improvement.
In the control group, 4 patients with fundus abnormalities showed no improvement in the visual function. The visual function of 9 cases in the other 23 cases improved at least 1 level. After 2-year follow up, there was no patient whose visual function improved from blindness to level I, 2 from level I to level II, 1 from level I to level III, 4 form level II to level III, 1 from level II to level IV, 1 from level II to level V. The total effective rate is 33.33%. In the patients showed efficacy in the control group,, 6 patients (66.67% )improved Ⅰ level, 3( 33.33%) improved more thanⅠ levels. The efficacy appeared on 365 days in median. Part of the patients underwent the functional Magnetic Resonance Imaging ( fMRI ) showed positive activation signals in occipital lobe, visual pathway and apical lobe After transplantation,
Conclusion：Neural precursor cells transplantation is effective for the patients with severe visual impairment – a sequela of neonatal brain injury. NPCs transplantation showed significantly earlier improvement, higher improvement rate and degree in visual function compared with the traditional rehabilitation training.
Key words：Brain injury; visual impairment; neural precursor cells; transplantation; children
Yahia Yousif, Khaled Batterjee
Research Institute of Batterjee Medical College for science and Technology，Saudi Arabia
Background Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders their incidence reaching epidemic proportions, afflicting approximately 1 in 150 children and increasing dramatically allover the world. It reflects a whole-body process often involving gastrointestinal pathologies, immune dysregulation, mitochondrial dysfunction, gut infections, detoxification pathways and nutrient levels. Increased oxidative stress is reported and has both etiologic and clinical significance. Environmental pollutants especially aluminium and mercury, some food additives and excitotoxins, sensitivity of food components could play a major role. Cerebral hypoperfusion, especially of the temporal lobes, and hypoxia are very common findings in children with autism affecting up to 75% of patients. Cerebral vasculitis and inflammatory-related findings could contribute to the cerebral hypoperfusion. Several clinical studies documented improvements using mono-therapy programs such as supplements, diets, hyperbaric oxygen (HBOT) and stem cell therapy but few clinical trials showed the effects of compatible multi-therapy programs.
Objective：To establish integrated therapeutic program using compatible overlapping therapy methods to manage (ASD).
Method：In this pilot clinical trial 10 diagnosed moderate to severe autistic male children (2-11 years) were admitted to the trial. The integrated therapy program consists of three main overlapping stages:
(A) Daily intake of special Intensive Nutritional Mixture (INM) for three months and continue till the end of the trial. (INM) was prepared in our center using natural food ingredients and tested for two years among autistic children before the trial begin. 10 days Antifungal course (nystatin or fluconazole) was applied for all patients.
(B) Hyperbaric Oxygen course using monoplace chamber and standard protocol of 40 sessions, 1.3 ATA, 24% Oxygen, 75 min/daily. The course was repeated three times after two weeks intervals before proceeding to the third stage.
(C) Administration of Stem Cells: about 5 Mio allogeneic CD34+ umbilical cord cells and mesenchymal cells were daily infused intravenous in 4 day's protocol.
Other therapies, supplements and drugs used by individual patients before the trial were continued without changes.
Evaluation the effectiveness of stages and the total program: The Autism Treatment Evaluation Checklist (ATEC) was used to evaluate the trial. Both Parents and physician submitted a weekly report up day 0 of the trial.
Result：The primary results demonstrated promising findings up till now: Stage (A) showed significant and sustained mild to good improvements in 9/10 of patients. The best scores were reported for following categories of (ATEC): Language/ Communication: Follow commands, respond to order. Sociability: Eye contact, sharing, greeting, affection. Sensory/ Cognitive awareness: Responds, interest, attention. Health/ behavior: wet pants, constipation, hyperactivity, unhappiness, crying, limited diet. Stage (B): Improvements were much more significant scoring good to excellent improvements in all patients up the first week of treatment especially the categories as above. No deteriorations or side effects were reported during these two stages. Stage (C): only few patients complete this stage till now but they showed much more improvements expanding to other items of categories of (ATEC).
Conclusion：Understanding of the biochemical and ecological context of the autism epidemic moves us away from the medical paradigm toward a system approach that focuses on overlapping compatible integrated therapeutic program. Non invasive complementary therapeutic tools like (INM) and (HBOT) in combination with antifungal drugs, CD34+ and mesenchymal umbilical stem cells were noted to induce sustained significant improvements of (ASD) patients could be through synergistic effects in neurological and vascular brain structures, although the number of patients are far too low to draw a definite conclusions. We propose to conduct the study based on the experiences of our group in this field, as well as numerous mono-therapy studies and generated anecdotal evidences of nutritional therapy, (HBOT) and stem cell therapy. We believe that through development of a potent clinical study with appropriate endpoints, much will be learned about the multifaceted pathophysiology of (ASD) and other neurological or vascular disorders which could have pathological similarities with (ASD) such as vascular dementia, CP, stroke, trauma, Attention Deficit/ Hyperactivity Disorder (ADD/AHDH) and the integrated way of their management.
Key Words：Autism, ASD, hyperbaric oxygen, stem cell therapy, nutritional therapy, antifungal, nystatin, fluconazole, attention deficit disorder, hyperactive disorder, ADD/AHDH, diabetic neuropathy, CP, stroke, vascular dementia
Alok Sharma (India)
Neurosurgeon ,Professor & Head,Department of Neurosurgery ,the LTMG Hospital & LTM Medical College, Mumbai
Director, NeuroGen Brain & Spine Institute in Chembur Consultant Neurosurgeon ,the Fortis Hospital, Mulund
Muscular Dystrophy is a genetic disorder with no definite cure available. A study was carried out on one hundred and fifty patients suffering from Muscular Dystrophy .Out of one hundred and fifty patients, 125 were DMD (Duchenne Muscular Dystrophy)type , 20 were LGMD(Limb Girdle Muscular Dystrophy ) and 5 of them were BMD (Becker’s Muscular Dystrophy)variant. They were administered autologous bone marrow derived mononuclear cells intrathecally and intra muscularly at the motor points of the antigravity weak muscles. Assessment after transplantation showed neurological improvements in trunk muscle strength, limb strength on Manual Muscle Testing (MMT), with Gait improvements and a shift on assessment scales such as FIM ; Brooke and Vignos scale. Further, Imaging and Electrophysiological studies also showed significant changes in selective cases. On an average follow up of 12 months ± 1 month, overall 87% muscular dystrophy cases showed subjective and functional improvements , with 3 of them also showing changes of muscle regeneration on MRI and 9 showed improved muscle electrical activity on EMG. On comparison of the previous EMG’s with a year later follow up study , it was confirmed that the interference pattern in the muscles, that were injected with mononuclear cells , had improved thereby confirming increase in muscle strength and activity. 53% patients showed increase in trunk muscle strength , 48% showed increase upper limb strength , 59 % showed increased lower limb strength and about 10 % showed improved Gait. Also the clinical finding were consistent with the electro diagnostic results , thereby confirming halt in the progression of the disorder and also bringing about improvement in clinical condition of the patients. No significant adverse events were noted. The results show that this treatment is safe, efficacious and also improves the quality of life of patients suffering from Muscular Dystrophy.
Keywords: Autologous, Bone Marrow, Mononuclear cells, Muscular Dystrophy, Motor Points, Quality of life.
Honarary President of IANR for life.
Professor of Neural Regeneration,University College London Director of the Spinal Repair Unit,the Institute of Neurology, Queen Square.
Geoffrey Raisman,University College London
It is a great honour and a great pleasure to welcome this distinguished gathering.
What thoughts can I – as a scientist –offer to congratulate and to encourage this international assemblage of pioneers here in Xian?
As a scientist, I seek to consider two questions:
Why do we think of transplanting cells? And:
Why is any more science needed?
Underlying our optimism is the concept that the nerve cells and nerve fibres of the adult brain and spinal cord are alive. And that they retain throughout life the capacity and the potential for new growth, and to establish new connections and the functions that go with them.
We could call it the “Theory of Continual Neuronal Growth.”
This is possible because all the genes we use to direct the development of the nervous system are still there in the adult. Can they not be active in the adult too?
We could call this theory the “The Potential of Continual Genetic Recapitulation.”
The nervous system functions because the nerve fibres make specific patterns of connections. It follows that re-establishment of lost connections is the most logical basis for restoration of lost functions.
If we consider the “Theory of Continual Neuronal Growth” and “The Potential of Continual Genetic Recapitulation” then the problem for repair of the brain and spinal cord is the re-establishment of pathways that can lead damaged nerve fibres to regenerate to their original targets.
I call this “The Pathway Hypothesis.”
Why use olfactory ensheathing cells for repair?
Because the olfactory system is the only part of the central nervous system which can regenerate its connections. Therefore its pathway cells can re-lay a damaged pathway, and open the door into the CNS. By transplanting them to other regions we can – at least in rat models – provide cells which can restore pathways, induce regeneration, and restore function in areas which do not show regeneration after injury.
And always remember there may be other potential pathway cells, as yet undiscovered.
Our team has two goals:
Firstly, to identify a source of reparative cells in man.
Secondly, to devise materials and instrumentation to introduce them into human spinal cord injuries.
------ Our field holds great promise. Therefore we need extra special caution.
Spinal cord injury is one of the most devastating, life-impoverishing conditions that man can experience. The patients are desperate. The sentence is irrevocable, and life-long. Their relatives, friends and loved ones are desperate. We have to be a thousand-fold careful not to mislead them, not – however unconsciously – to exploit their suffering for our benefits.
We do not understand the nature of spinal cord injury. We certainly do not understand a cure. But they will look to every word we say and read into it a solution to their unhappiness.
None of the general public, very few of the press, and few of the medical profession know that almost half of paralysed patients will walk again without any intervention in the spinal cord. They are astounded that rats recover again. To them these facts are peddled as evidence of some pretended cure. Quite a few years ago a colleague calculated that there were even then more than a hundred different ways of curing spinal cord injury in rats. The press regularly reports new breakthroughs. So why are people still in wheelchairs?
Where patients show improvement – either spontaneous or after intensive physio- and rehabilitation therapy – which are of immense benefit to quality of life - we must separate these benefits from the interventions we are trying out.
Operating on the spinal cord is a relatively new and infrequent approach to repair. In general, only minor
benefits are recorded. What are these benefits due to? Untethering? Re-vascularisation? Re-myelination? Growth factors secreted by transplanted cells?
And plasticity. This is a hardly understood phenomenon. When I introduced the term in 1969 I simply meant the formation of new connections after injury. But this was an automatic process. We now know that new connections form both above and below spinal cord injuries. But why? What determines them? What decides what new patterns are formed? Can we control them? Can they, like normal connections in development, be trained? Are they beneficial? Or do they cause problems? May they cause spasticity? Pain? Abnormal sensations? Bladder detrusor dyssyngergia? Autonomic dysreflexia?
Plasticity is a pointer to the “Theory of Continual Neuronal Growth” and “The Potential of Continual Genetic Recapitulation.”
But if we are to benefit from plasticity, we need to know what causes it, how it is controlled, how we can use it. And I believe that the answer lies not in neurons but in the pathway cells, in olfactory ensheathing cells and in astrocytes.
------The great mantra of our day is stem cells. Stem cells have a meaning for governments – they will bring prosperity. For companies a patent-protected cell in a bottle will generate fortunes on the stock exchange. They will sell endless articles for the press, endless programmes for the media. New scientific societies are formed. New careers develop. A true bonanza.
But what are stem cells? Do we need no explanations of these miracles? Can one human embryo give cells which will do all these things? Can we avoid the immune barrier? Will the cells, which are supposed to have endless potential for division be stopped before they form a tumour? Will the cells that can turn into the 200 odd different types of adult cells turn only into the ones we want? And if they did, will they find their way to the injury or tissue to be repaired and be accepted and incorporate themselves anatomically and functionally into it?
------Discovery begins with the statement that we don’t know. The statement that we do know prevents advance. Let us accept that we do not know how to cure spinal cord injury. We have a few clues, minor.
What is needed?
First, I believe that the science base can give clues, directions among the many alternative possibilities. Those who oppose animal experimentation on ethical grounds, or those who think money spent on science is wasted, should realise that the alternative is to experiment on people. It’s a choice.
Second, from the few patients who are being treated world wide, we should collect clinical evidence. Each trial is a mine of information, but that information has to be extracted from the mine. A full, longitudinal neurological evaluation, before and after by independent observers would be immensely valuable. Intensive pre-interventive physiotherapy should exclude that any further benefits can be obtained before our planned intervention.
And Thirdly, maybe it is time to evaluate the almost universal practice of vertebral carpentry. The remaining nerve fibres are microscopically small, but the messages they carry decide the patient’s future life. Their location is invisible to the surgeon. They are finer and more delicate than the finest threads of silk. The manipulations needed to re-align and screw and cage vertebrae are physically forceful. Screwing vertebrae saves money and beds. It gets the patient up and mobile quickly. Spinal injured patients are subject to postural hypotension. Does an early the upright posture imperil the tenuous blood supply of the few remaining spinal cord fibres? Those few remaining fibres are vital to any benefit the patient has. Can these interventions do as much to harm them as to protect them?
------The present is the threshold of the future.
We have overcome the idea that nothing can be done.
But we still do not know what is to be done.
Don’t let’s lose credibility by responding to patient, press, government, or career pressures. Or the lure of wealth.
We alone are responsible for what we do.
Let’s do it wisely.
And for the good of our fellow human beings.
We have set our sails, and we travel into an unknown ocean. We carry with us a cargo which is as fragile as it is precious -
That cargo is Hope.
Hari S Sharma, Aruna Sharma
Laboratory of Cerebrovascular Research, Dept. of Surgical Science, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University
Pathophysiology of the Central nervous system (CNS) injury is complex and involves damage to neuronal, glial and endothelial cells leading to brain dysfunction [1-3]. Studies carried out in our laboratory since 1977 shows that disruption of the blood-brain barrier (BBB) to proteins play crucial roles in precipitating brain edema formation and cell damage [3-6]. Thus, restoration of the BBB with drugs, antibodies, stem cells or other therapeutic agents are needed to induce neuroprotection or neurorepair in the CNS following noxious insults. Recently, it appears that nano delivery of stem cells, antibodies or therapeutic agents leads to enhancement of neuroprotection and cell repair [1-4]. Using animal models of CNS injury including traumatic, ischemic, hyperthermic, or following psychostimulants abuse we have demonstrated breakdown of the BBB and brain edema formation that is instrumental for brain damage [4-6]. Using antibodies to serotonin, tumor necrosis factor-alpha (TNF-a) and dynorphin A (Dyn-A) either alone or in combination leads to remarkable neuroprotection in spinal cord injury (SCI). Furthermore, nanowired delivery of these antibodies leads to long-term neuroprotection in SCI. Our experiments also showed that hyperthermia or brain injuries when inflicted in animals with hypertension or diabetes, the pathophysiology of brain damage is exacerbated. In such situations, nanowired delivery of mesenchymal stem cells is able to induce profound neuroprotection whereas other drugs or therapeutic agents did not induce remarkable brain protection. In hyperthermia, cerebrolysin, a mixture of various neurotrophic factors and peptide fragments showed enhanced neuroprotection when administered using nanodrug delivery. On the other hand, normal compound alonewas limited in inducing neuroprotection in hyperthermia. These observations suggests that nanodelivery of stem cells, antibodies and other therapeutic agents could results in superior neuroprotectionfollowing CNS injury leading to neurorestoration in a more effective way. The functional significance of these findings in relation to neurorestoratology will be discussed.
He retired from the position of Chief Neurologist of the Russian Navy as colonel of the Medical Naval Service and continued his clinical and research work in private hospital “NeuroVita”. He pursues treatment of neurological disorders through stem cells for 25 years. In 2005-2009 he headed the Department of Cell Reparative Medicine of the Russian State Medical University.
National Institute of Regenerative Medicine,
NeuroVita Clinic of Restorative Interventional Neurology and Therapy ,Moscow, Russia.
The idea that decoding the structure of genetic defect of pathological neural cells (NCs) in major neural disorders (NDs) will lead to their efficient treatment has long prevailed in classical neurology. Successfully accomplished The Human Genome Project demonstrated that decoding genome of a somatic cell (SomC) did not approximate understanding of pathogenesis and treatment of incurable human diseases (cancer, diabetes, SCI). Consequently, the sciences involved into restoration of neural tissue (NT) place their hopes on the development of post-genomic technologies, such as proteomics, metabolomics, secretomics of NCs etc. In 2010 a new global project, the Human Proteome Project was initiated, to map the protein based molecular architecture of human body and answer fundamental questions of developmental biology and molecular medicine.
Presumably, it is methodologically incorrect to view cell proteome as cataloguing proteins in specific chromosomes, even though associated with specific NDs. First, such “accounting” approach to protein evaluation is hardly justified for lack of knowledge, as by now science has only gathered evidence on about 2000 high copy number and medium copy number proteins and almost nothing about low copy number and very low copy proteins. Second, all proteins of cell proteome present on the one hand a high-speed information protein network, while on the other a global information database the elements of which have complicated information relationship. This information database forms karyotype and phenotype of a SomC and its proteome presents a fundamental characteristic of the information flow issued by protein pathways that interconnect extracellular environment with cell gene transcription control. This information can be either the cause or the effect of ND processes. The relations of genome and proteome are still unclear. Only 1.5% of genome in the somatic cell nucleus is responsible for the formation of a whole cellular protein network, the rest parts of genome present a regulatory software to provide protein synthesis and a so-called junk DNA the role of which is not determined yet. Thus, cell proteome is to be studied as information relationship between information structure of a cell and its microenvironment.
From the point of view of information approach the genome is the most stable structure to support a karyotype and species of a healthy cell (HC) of nervous tissue (NT). Transcriptome is a more flexible cell structure, and the most flexible is proteome which still depends on microenvironment, active methylation processes, histone modification and iRNA transformation. Proteome of a HC of NT is quite stable and strictly correlates with the phase of a cell cycle (CC), differentiation stage, cell effector functions (EF). In different tumors of central nervous system (CNS) aneuploidy and chromosome mutations of tumor cells (TCs) make genome the most unstable structural element leading to transitory disorders of transcriptome that change cell karyotype used to diagnose TC phenotype. Yet proteome of a TC is a rather stable information structure that characterizes tumor karyotype, phenotype and EF (proliferation, angiogenesis, migration etc). In degenerative diseases point chromosome mutations of NCs lead to CC disorder and trigger specific EFs (autophagy, apoptosis, atrophy) conditioned by accumulation of various pathogenic proteins in cell cytoplasm (b-amyloid in Alzheimer’s disease, Levi bodies in Parkinson’s disease and various dementias, etc) and excitotoxic effect on neurons.
Microarray analysis (MAA) of transcriptome and mass-spectrometry (MS) of proteome of various cells demonstrated that correlation of protein profiles of the components of cellular protein network is observed only in HCs and is hardly present in pathological cells. Normalized signal intensity (NSI) of cell transcriptome and proteome proteins revealed several patterns: 1. NSI structure and parameters of transcriptome and proteome proteins of differentiated NCs, SCs and cells of specific (even pathological) line differ only quantitatively and matrix of distinction includes from 30 to 40 of the same proteins with varying NSI. 2. From 70 to 95% out of 907 studied proteins of proteomic profile (PP) in CNS cancer stem cells differ from the proteins of healthy SCs, and similarity matrix makes only 48 proteins (5.4%). Depending on malignancy this indication of distinction matrix varies from 45 to 96.3%. In other words, proteome network of cancer SCs displays information protein incompatibility with proteome network of healthy SCs. Attempting to preserve its species identity and relieve itself from foreign proteins, cancer SCs get rid of them in a primitive way by mitosis. However, critical percentage (over 50%) of non-species proteins does not allow for preservation of the species through cell division thus conditioning uncontrolled mitoses in cancer SCs. In degenerative disease (Parkinson’s disease) matrix of distinction does not exceed 30%, while the MAA results have no correlations at all.
Based on PP of NT cells, we offered a novel approach to develop personalized cell preparations (PCP) for neurorestoratology. To obtain PCP for NT restoration of a specific patient healthy hematopoietic, mesenchymal or neural SCs labeled with specific antibodies (SAB) with magnetic beads are isolated from bone marrow sample, or leukoconcentrate of peripheral blood or resuspended olfactory sheath of the patient’s nose, respectively. Similarly, cancer SCs or atrophic NCs, also labeled with magnetic beads SAB are isolated from the tumor sample or specialized pathological NCs. MAA of miRNA is done and the result is processed with standard software Affimetrix Gene Chip. Tryptic peptides of healthy and cancer SCs are analyzed on a flow cytometer combined with MS. Obtained MS results are standardized with software Proteome Discoverer 1/0 (Thermo).
The MAA and MS data are brought to NSI. To exclude the noise of dynamic changes in cell protein network on healthy SC NSI PP, the values of NSI of proteins received in MAA and values of NSI or proteins of cell cytoskeleton are subtracted from the database of MS healthy SC proteins. Then the NSI PP of examined cell systems is compared and the difference between the NSI of specific healthy SCs proteins and the NSI of specific cancer SCs (matrix of distinction) is detected. The results of maximal difference between NSI of healthy and cancer SCs detected one or several (but no more than 4) key proteins of healthy SC PP. According to the detected key proteins one or several regulatory proteins or a chemical compound is chosen from the database, that have a potential for inductive effect on key protein changing NSI PP of the latter in a personalized fashion consistent with cancer SCs PP. Provisionally selected healthy autologous and/or allogeneic HLA-haploidentic multipotent SCs and/or progenitors are cultured with one or several regulatory proteins or chemical agents to obtain required PCP.
One of the principles of modification (reprogramming) of NSI PP of healthy SC proteins is the principle of approximation or identity of key proteins, when the selected regulatory protein(s) or chemical agent(s) modify the profile of healthy SCs approaching its values to those of cancer SCs key proteins, that is upregulating or downregulating it to the values of key proteins NSI in cancer SCs or slightly higher than in cancer CSs. Other principle of reprogramming NSI protein proteome profile of healthy SCs is the principle of inversion or suppression of key proteins, when regulatory protein(s) or chemical agent(s) modify the healthy SC PP by maximal downregulation (or blocking) of key proteins in a healthy SC which are maximally upregulated in cancer SCs, that is, reduce it to the value (or slightly lower) of key proteins NSI in cancer SCs. To enhance anticancerous action combinations are also possible. Healthy SCs are induced by addition of appropriate regulatory protein(s) or chemical agent(s) during culturing and further washing. The PCP is administered intravenously, intracerebrally or intramedullarly.
The development of PCP on the basis of transcriptome and proteome profiling of healthy SCs and pathological cells of the patient can become a universal method for personalized therapy of nervous disorders in the near future.
Dafin F. Muresanu (Romania)
Professor of Romanian CFR Medical University；Head of Department of Neurology of afflicated hospital；Associate Dean of "Iuliu Hatieganu" University；members of the Romanian Academy of Medical Sciences
Dafin F. Muresanu
Chairman Department of Neurosciences
University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj -Napoca, Romania
There is increasing evidence that cerebrovascular dysfunction plays a role in vascular causes of cognitive impairment (VCI) and also in Alzheimer’s disease (AD). Coexistence of ischemic and neurodegenerative pathology was found to have a profound impact on the expression of the dementia, suggesting reciprocal interactions.
This presentation will highlight some important molecular mechanisms involved in the complexity of vascular changes underlying pathological developments in Alzheimer’s disease and vascular dementia. New data regarding the role of endogenous neurogenesis in this disorders will be presented.
Both A-beta and vascular risk factors target the structure and function of cerebrovascular cells, glia, and neurons (neurovascular unit), resulting in neurovascular dysfunction. As a general feature, coexisting cerebrovascular disease or incident ischemic lesions may shorten the preclinical stage of AD and accelerate disease progression.
Vascular dementia is a heterogeneous cluster of different syndromes and disorders with cognitive deficit, arising from a cerebrovascular disease as a common feature. Entities do not share aetiologies, mechanisms, clinical features, evolution or treatment. However, there is a tendency to define this entity as a distinct type of dementia with clinical and pathophysiological specificities.
Most common members of this group are: multi-infarct dementia, lacunar state, single strategically-placed infarct, post-stroke cognitive deterioration, Binswanger’s disease, genetic forms (e.g. CADASIL), hypoxic-ischemic-encephalopathy, Alzheimer’s disease with cerebrovascular disease, intracerebral and subarachnoid haemorrhage with cognitive impairment.
Treatment of broad dementia spectrum disorders is a challenging issue. A potential chance, beyond identification and treatment of risk factors, might be the use of pleiotropic and multimodal endogenous like molecules.
Honorary Visiting Consultant, Midlands Centre for Spinal Injuries, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK Advisor, China RehabilitationResearch Centre, Beijing, Project Advisor, Spinal Cord Repair, Institute of Neurosciences, Beijing
Background Cognitive neural impairment occurs in all ages from childhood to the seniles. Their causes vary considerably from cerebral palsy to Alzheimer’s Disease. In stroke and brain injury, the maximum damages have already been done during the accident and become more or less stable after the subacute stage. The management of cognitive impairment in these accidents is by and large rehabilitative. However, in age-related lesions, the impairment is slowly progressive. Hence, its management is not only rehabilitative but also has preventative (both primary and secondary) and therapeutic implications. In these lesions, if cognitive impairments can be detected and dealt with early, further progress may be prevented, slowed down and some of the existing problems reversed. All these effects are based on neural plasticity which declines with age. Whatever the cause of cognitive impairment, they share some common features that are the focus of discussion of this section.
Cognition is occupying more and more centre stage in neuro-science and neuro-rehabilitation for following reasons.
1. Increasingly long life expectancy associated with a high incidence of cognitive impairments has made the study of the problem a matter of some urgency.
2. The role of physical medicine has been well established whilst cognition is yet to be fully recognised and understood. Weight is shifting to cognitive rehabilitation, particulary in researches, without which neural rehabilitation process in not complete.
3. Advanced molecular biology since discovery of DNA structure offers deep insight into almost every molecule, its structure, composition and behaviour.
4. New functional imaging technologies like functional magnetic resonance imaging (fMRI), positron emission tomography (PET), event-related potentials (ERP) and magneto-encephalography (MEG) allow scientists to visualise this difficult aspect of neuroscience and psychology in vivo and in dynamics.
Summary：Cognition impairment has posed as a huge challenge to the society as the population is ageing, particularly in the developed world. Although difficult cases should be left for the specialists like psychologists and neurologists, the general medical profession or even the society in general need to be familiar with basic knowledge and skills in dealing with its mild form. Obviously, this short note is not for acquiring in-depth knowledge but for drawing attention to the problem. For this purpose, reading the recommended books below is advisable. From there, readers can expand their own references. Fishing out relevant references from an ocean of journal articles is very difficult and extremely time-consuming.
Recommended further reading：
1. Raskin SA. Neuroplasticity and rehabilitation. The Guilford Press, New York, London 2011; pp351.
2. Stuss DT, Wincour G, Robertson IH. Cognitive neurorehabilitation. Cambridge University Press 2008; 606.
3. Cabeza R, Kingstone A. Handbook of functional neuroimaging of cognition. The MIT Press, Massachusetts, London 2001; 410.
Giovanni Tosi (Italy)
Pharmaceutical Technology researcher,the University of Modena and Reggio Emilia;Coordinator of "Applied Technology" curricula for PhD school in Health Products;member of Instruments Commission of Dep.Pharm.Sci.,Representative of the Dep.Pharm.Sci
G. Tosi*, B. Ruozi*, D. Belletti*, A. Vilella°, M. Zoli°, A.M. Grabruker§, F. Forni*, M.A. Vandelli*
*Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Italy
°Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy
§Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, US
In the last years, the application of "nanotechnology “to the field of “medicine” surely represented the most innovative strategy to cop_20e with diseases and it could be named as nanomedicine applied to difficult-to-treat diseases.
As known, in this field of research, the most important goal to be reached is an increase in selectivity and specificity of drug action. Several results with stimulating findings in preclinical or clinical phases have been reached by using nanocarriers, delivering agents to targeted pathologies, and among them, it is known that neuro-pathologies represent a stimulating issue. In fact, the pharmaceutical treatment of Central Nervous System (CNS) disorders is the second largest area of therapy, following cardiovascular diseases. Nowadays, non-invasive drug delivery systems for CNS are actively studied. In fact, the development of new delivery systems (nanoparticles and liposomes) started with the discovery that properly surface-engineered colloidal vectors, with a diameter around 200 nm, were shown to be able to cross the Blood-Brain Barrier without apparent damage, and to deliver drugs or genetic materials into the brain. During this talk, an overview will be presented considering the most recent literature results of nanomedicine applied to brain diseases, carried out with all the most popular kinds of nanoparticulate systems, focusing in particular on immune-nanoparticles and peptide-decorated nanosystems able to target the CNS, with in vivo and in vitro evidences investigating the pathway for BBB crossing and CNS localization of engineered nanoparticles. The brain localization and the multi-modal pathways for BBB crossing highlighted the endocytosis as preferential pathway; moveover, in vitro test on hippocampal neurons showed the presence of cell-to-cell transport of nanoparticles.
Gustavo Moviglia (Argentina)
Vice Presiden of professional Committee of IANR；Director of the Centre for the Investigation in Tissue Engineering and Cellular Therapy (in Spanish, CIITT) in Buenos Aires, Argentina
cSCI patients have not an appropriate vascularization of the damaged area, neither the Spinal Cord distal segment that, as consequence of the lack of brain connections, is also atrophied. The activity of pro repair inflammatory activity has disappeared. Conversely, there is a chronic inflammation that has generated an extracellular matrix which prevents repair. Stem Cells are not attracted to the injured area. The brain cortex disrupted the normal synapses network (engram) that organize appropriated muscle movements and spatial recognition of sensation originated in the affected area and down of that site.
The discontinuity of central nerve pathways and the subsequent new engram generated thereafter are Responsibly for：
1. - Perception of analgesic and dysestesic skin areas
2. – Experience of paresis and paralysis, pathologic reflexes and so called spontaneous movements.
3. - Autonomic Nervous Dysfunction in the somatic territories innervated by the lesion site and below (dysautonomy);
Any therapeutic aproach maigth contemplate all thes facts to be structural and functional effective. Different strategies are presented in this lecture.
Adeeb AlZoubi1,2 , David Audley3, Mohammed El-Khateeb4,5, Bellur Prabhakar6, Mark Holterman2,
Ziad AlZoubi7, Emad Jafar7, Mohammad Shahin7, Feras Twal1, Rula Al-Azzeh1, Sameh Al-Bakheet1, Gigi Sia1, Farah Khalifeh1, Bahar Barzangy1, Suzana Dwas1, Mahasen Zalloum1, Samah AlZoubi1, Maen Abbasi1
1 Stem Cells of Arabia, Amman, Jordan
2 Department of Surgery, University of Illinois College of Medicine in Peoria, Peoria, IL, USA
3 International Cellular Medicine Society, Salem, OR, USA
4 Department of Pathology, Faculty of Medicine, University of Jordan, Amman, Jordan
5 National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan
6 Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, USA
7 Department of Neurorestoratology, Jordan Orthopedic and Spine Center, Amman, Jordan
The fast advancing field of stem cell-based therapy is currently affecting vast majority of medical practices worldwide. With the exception of hematological malignancies, to date, there are no clear rules and guidelines which govern the utilization of stem cells in clinical practice. This is mainly due to the fast evolving nature of this new and exciting field of medicine, which limits the ability of governmental agencies from following up with the latest discoveries and advancements in stem cell research. One of the most challenging phases of biomedical research is to translate the available scientific findings from research bench to applicable clinical practice in order to serve the increasing demands of patients. This is most evident in the field of stem cell research, where there is an apparent lack of coherent and standard rules and guidelines that can be applied to regulate stem cell-based therapies in an acceptable international format. Classical biomedical research approach requires extensive, long, and exhaustive research efforts, which may take up to fifteen years before implementation in clinical practices. Additionally, there must be abundance of long term funding in order to carry out all the required steps from basic research to all three phases of clinical trials. This is rather difficult when it comes to stem cell-based therapies since there is little interest of biopharmaceutical industries due to the limited profitability of this type of practice. However, pressuring demands from patients for availability of treatments in shorter periods of time dictate formulating a more realistic approach in a timely manner. This approach must guarantee the delivery of high quality treatments to patients without compromising patient safety and authenticity of results.
A reliable stem cell-based therapy approach should include defining types and sources of stem cells, methods of stem cell collection and handling in the laboratory, and methods of transplantation of prepared cell populations under acceptable medical practice. In order to fulfill these three requirements, the team responsible for executing stem cell-based therapy protocols should guarantee the preparation and delivery of acceptable cellular products by authorized personnel in a licensed facility by utilizing well known and published procedures.
We, at Stem Cells of Arabia (SCA) in Amman, Jordan, and in collaboration with the International Cellular Medicine Society (ICMS), College of Medicine at the University of Illinois, Faculty of Medicine at the University of Jordan, National Center for Diabetes, Endocrinology and Genetics in Jordan, and Jordan Orthopedic and Spine Center, have formulated a new system for governance of high quality cell-based therapies. This system governs the utilization of autologous adult stem cells as source of cells, preparation of these cells using internationally accredited methods, and transplantation of prepared cells into the patient by acceptable and accredited medical procedures. To accomplish these objectives, our system consists of three accreditation parts: (1) accreditation of standard operating procedures (SOPs) (by the Institutional Review Board (IRB) of ICMS) that define patient enrolment and follow up, source and type of stem cells, methods of collection, manipulation, and transplantation of prepared cells into the patient, (2) accreditation of personnel involved in performing the above SOPs, which includes laboratory personnel (scientists, researchers, stem cell processing specialists, and quality control officers), physicians, nurses and other medical assistants involved in the procedure, and (3) accreditation of the facility where the SOPs are to be carried out, which must be a licensed institution by the appropriate governmental facility in the country where the procedure is to be carried out.
We believe this system can be applied internationally and in accordance with local rules and guidelines in the country where the procedures are to be performed. Although the current accreditation system is limited to the use of un-manipulated autologous stem cells in a safe manner, the system can be modified and extended to include other types of stem cells in different settings or formats.
Seyed Hassan Emami–Razavi*1; BabakArjmand1,2; HamidrezaAghayan1,2;
HooshangSaberi1; Abbas Norouzi-Javidan1
1、Brain and Spinal Injury Repair Research Center / Tehran University of Medical Sciences
2、Endocrinology and Metabolism Research Center / Tehran University of Medical Sciences
Objectives：In recent years, like many other countries in the world, modern cell therapy has been started in Iran. Furthermore, Iran has a leadership role in stem cell research and therapy among the middle eastern Muslim countries. Autologous Schwann cell transplantation for spinal cord injury, Mesenchymal stem cell transplantation for multiple sclerosis, cirrhosis, diabetes and myocardial regeneration, and hematopoietic fetal stem cell transplantation for diabetes, cirrhosis and multiple sclerosis are prominent examples of current clinical trials. These trials are generally regulated by scientific and ethical committees of medical universities but two of them have been registered in ministry of health (as national projects). Legal framework for cell and tissue research and therapy is based on the ‘‘Deceased or Brain dead patient organ transplantation’’ act (passed in 2000). There was no specific regulatory oversight for cell and tissue research and therapy by the national health authority till two years ago, that a new legislation was established to supervise the manufacturing of cell and tissue products as a basic and minimal safety standard for cell therapy centers while, cell manufacturing centers have established their own quality policies that have been referred to basic and general quality standards (cGMP, cGTP, and GLP) without any correlation to others.
Coding and traceability：The importance of effective coding, documentation, and traceability in safety and quality assurance of tissue and cell products is not negligible. Despite the lack of national authorization of coding, each cell manufacturing center has understood the importance of coding and traceability in tracking adverse events and reactions related to biologic products. According to these concerns some of them have defined a method in their SOPs for tracking all reported events from the donor to the recipient, and vice versa just inside their organization.
Conclusions：In order to achieve the higher level of safety the authors recommend that a more specialized national standard for cell therapy should be established by the government. We also believe that implementation of some general quality managementsystem based on the ISO 9001 and ISO13485 can improve safety of cell based products. Additionally, we need to make a unique system to harmonize coding and traceability in the country and also in the region.
Keywords：Cell therapy . Coding . Traceability
XI Haitao1,2 , CHEN Lin1,3 , HUANG Hongyun 1,3 *, ZHANG Feng1,2 , LIU Yancheng 1,3, CHEN Di 1
1、Beijing Hongtianji Neuroscience Academy, Beijing 100143
2、Neurological Center,,Jingdong Zhongmei Hospital, Hebei Province 101601
3、Center of Neurorestoratology, Beijing Rehabilitation Center, Beijing 100144
*Corresponding author: E-mail:email@example.com
Objective：To investigate the long-term effects for patients with the sequeal of stroke through multiple kinds of cell transplantation.
Methods：Ten patients with sequeal of stroke were treated by multiple kinds of cell transplantation from November 2003 to April 2011. Among them, there were 6 males and 4 females and 6 cases with cerebral infarction, 4 cases with brain hemorrhage. Age from 42 to 87 years, average of 55.00±14.38 year old. The course of disease was ranged from 0.5 to 20 years, average of 5.80±5.71 years. According to Second Generation of Neurorestorotherapy, umbilical cord stromal cells, Schwann cells, neural progenitor cells, olfactory ensheathing cells were given through intravenous, intrathecal, parenchyma transplantation. The neurological function was assessed by clinic neurologic impairment scale and and Barthel Index before treatment and 0.5 to 2 year ( 1.45±0.60 years) follow-up.
Result：Ten patients achieved neurological function amelioration to different degrees during follow-up, which including speech, muscle strength,muscular tension, balance, pain and breathing. Barthel Index score increased from preoperative 59.50±28.52 points to postoperative 64.00±29.70 points (p=0.041). Clinic neurologic impairment scale score decreased from preoperative 13.60±8.44 points to postoperative 12.30±8.55 points (P=0.039).
Conclusion：Multiple kinds of cell therapy for patients with sequeal of stroke is safe and feasible, which can improve their neurological functions and quality of life in some degree.
Key words：Sequeal of stroke; Multiple kinds of cells; Transplantation; Second Generation of Neurorestorotherapy
郗海涛12 陈琳13 黄红云13 * 张峰12 刘彦铖13 陈娣1
结果：随访结果显示10例病人均有不同程度语言、肌力、肌张力、平衡、疼痛、呼吸等神经功能改善。Barthe 评分由59.50±28.52 增加到64.00±29.70（p=0.041），临床神经功能评分由13.60±8.44降至12.30±8.55（p=0.039）。术后和随访未发现长期发热、头痛、头晕、恶心及呕吐等并发症。
关键词：脑卒中后遗症 多种细胞 移植 神经修复第二代治疗
Shinn-Zong(John) Lin (Taiwan,China)
President of Beigang Hospital of China Medical University；Professor of Neurosurgery of China Medical University
Shinn-Zong Lin1,2, 3, Demeral Liu1, Woei-Cherng Shyu1, 3
1Neuropsychiatry Center, China Medical University Hospital, Taichung, Taiwan
2Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
3 Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
Introduction：Our animal study in chronic stroke rats showed that intracranial implantation of peripheral blood stem cells (PBSC) mobilized by granulocyte colony stimulating factor (GCSF) improved the anatomical regeneration of corticospinal tracts and motor function. Previous phase I trial in 6 old stroke patients by using antologous PBSC also revealed an improvement in functional outcome.
Methods：This randomized, controlled phase II trials was conducted in 30 chronic stroke patients who suffered from stroke for 6 months up to 5 years with a stable neurological deficit. CD34+ PBSC about 3-8×106 were implanted stereotactically into the damaged corticosipnal tract under local anesthesia in the treatment group. The primary end points were improvement in NIHSS, European Stroke Scare (ESS), ESS motor subscale (EMS) and Modified Rankin Scale (mRS). The secondary end points were fiber numbers asymmetry (FNA) in corticospinal tract (CST) and motor evoked potential (MEP).
Results：There were no serious adverse events found in all 30 patients in the 12 months follow-up period. Significant improvements (p<0.05) were noted in NISS, ESS, EMS and mRS in treatment group as compared to control. FNAs were increased in every treated patient, but not in the control ones. MEP response reappeared in 9 of the 15 treated patients, but none in the control group.
Conclusion：Autologous PBSC intracranial implantation in chronic stroke patients is safe and feasible.
Barry J. Hoffer (USA)
Adjunct Professor, Case Western Reserve University, Neurosurgery and Genetics
Barry J. Hoffer
Although initially thought to be important primarily in neural development, a number of trophic proteins have been found to possess neuroprotective and neuroregenerative activity in the adult central system, particularly for midbrain dopamine neurons (MDN). There is a considerable recent literature on trophic properties of TGF-ß superfamily proteins for MDN’s, including glial cell-derived neurotrophic factor (GDNF), neurturin, and bone morphogenetic proteins (BMPs). This talk will review studies with the factors listed above, as well as describe more recent studies with two newly described trophic proteins, MANF and CDNF. Data will be presented from various animal models of PD, both toxin and genetic, suggesting that these trophic proteins may eventually lead to novel PD therapeutics in man. In addition, some data on small molecules with neuroprotective properties (AP4A, retinoic acid and vitamin D3) will also be presented. The following table summarizes similarities and differences between neurotrophic factors GDNF, NRTN, CDNF and MANF from a potential clinical perspective.