Itt a friss Nature-cikk, szerintem érdekes és tartalmas összefoglalás. Nem biztos, hogy be szabad másolnom ide, de azért mégis bemásolom:
In search of a miracle
Pearson, Helen
Abstract
Paralysed patients are looking to scientists working on spinal-cord regeneration to help them walk again. Is this pressure causing too much faith to be placed in preliminary, inconclusive results? Helen Pearson investigates.
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It was a miracle of almost biblical proportions. In 1998, scientists in Israel revealed that rats whose spinal cords had been severed had walked again after an injection of healing immune cells called macrophages (1). Their hopes buoyed by enthusiastic media coverage, paralysed patients began to dream of taking their own tentative steps.
Five years on, the status of those dreams remains unclear. Proneuron Biotechnologies, a Los Angeles-based company founded on the back of the research of lead investigator Michal Schwartz at the Weizmann Institute of Science in Rehovot, is expected soon to release the results of an initial trial of the procedure on eight patients with spinal injuries. Media reports have indicated that some patients have recovered some feeling and movement, but many researchers do not expect a repeat of the rodent miracle. Indeed, they claim that at least one group has since tried, and failed, to reproduce Schwartz's original animal results.
Schwartz's study is not alone in this regard. Over the past few years, scientists working on spinal-cord repair have revealed encouraging results on several occasions, only to find that other groups have struggled to recreate the same outcome. Three papers published in Neuron (2-4) last month underline the point, reporting contradictory findings in parallel studies of 'knockout' mice lacking proteins that are believed to be among the main inhibitors of nerve growth in the spinal cord. "Reproducibility has been a major problem in spinal-cord injury," says Oswald Steward, director of the Reeve-Irvine Research Center at the University of California, Irvine.
Some think that the problems are simply technical: repairing a rat's string-thin spinal cord is a complicated experiment to copy. Others argue that, in some cases, eager scientists have put an over-optimistic spin on their results. These accusations are hotly disputed, but some researchers privately fear that the expectation of high-profile patient-advocacy groups may be inadvertently creating an atmosphere in which problems are likely to occur. Certainly, some researchers admit to feeling under pressure to perform. "If patients phone you three or four times a year and you can't tell them anything new, that's a pressure," says Isabel Klusman of the University of Zurich in Switzerland.
Delicate balance
Exploring these issues is difficult, as no one wants to be perceived as criticizing patient groups. In particular, researchers say that they owe an immense debt of gratitude to the Hollywood star Christopher Reeve, who was paralysed in a horse-riding accident in 1995. His public determination to recover - and his inspirational support of the science that might help him to - has drawn millions of dollars into research, both directly through the Christopher Reeve Paralysis Foundation and indirectly through government budgets.
This impetus intensified interest in a finding reported in 1980, which provided the first glimmer of hope that a damaged spinal cord might be repaired. Albert Aguayo, now at McGill University in Montreal, Canada, cut rats' spinal cords and showed that they were able to sprout into pieces of tissue grafted from the animals' sciatic nerves (5). This seeded the idea that the lack of regrowth following a spinal injury is partly caused by inhibitory molecules in the spinal cord itself.
Although Reeve's advocacy has undoubtedly brought more funding for research, it has also meant that promising scientific discoveries have been more likely to become front-page news. One study from 1996, for example, received massive coverage. Henrich Cheng at the Karolinska Institute in Stockholm, Sweden, showed that paralysed rats were able to move their legs again after he coaxed spinal nerves to grow across their severed spinal cords. To achieve this, he built 18 tiny bridges of nerves taken from between the ribs and added a growth-promoting protein (6).
For more than six years, no one published a duplication of the results. Eventually, researchers led by Vernon Lin at the Long Beach Veterans Affairs Medical Center in California managed to reproduce Cheng's main findings (7). Lin regards human trials as premature, but Cheng has moved ahead, operating on 40 spinal-injured patients in Taiwan. He expects to publish his results later this year.
Technical trauma
Neuroscientists agree that, in large part, the problems with reproducing studies lie in the technical difficulties. "We're trying to do one of the most difficult things in science," says spinal-cord researcher Wise Young of Rutgers University in Piscataway, New Jersey. Cheng says that he took a year to learn how to build the delicate bridges across a severed spinal cord. "We gave up after six months," says Young.
Another problem is that scientists do not always compare like with like. Each group tends to use its own model of injury - including those that crush the spinal cord, or sever it partially or completely. Crushing more closely mimics a typical human injury, but cannot be compared with severing the cord.
Researchers have also struggled to accurately measure and compare improvements in animals' movement after treatment. In another widely debated study, Almudena Ramón-Cueto, now at the Spanish national research council's Institute of Biomedicine in Valencia, reported that cells taken from an adult rat's olfactory bulb, the first staging post in the neural perception of smell, and transplanted into a severed spinal cord, helped paraplegic animals to walk again (8). Most experts agree that these 'olfactory ensheathing cells', which normally help nerve cells grow projections from the nose to the brain, can help nerves to grow across a site of injury. But subsequent studies have been difficult to compare with those by Ramón-Cueto, partly because the team assessed the animals' recovery by judging their performance in climbing on a wire ramp - a test not used in other labs.
Although technical difficulties may be part of the problem, some experts argue that the field is also plagued by premature enthusiasm. If, after treatment, only one or two nerves grow across a severed cord, this could be seen as a disappointing result. Yet, given the normally barren appearance of such a wound, some researchers might describe the same result as a stunning success. "They're seeing what they want to see," claims Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in La Jolla, California.
Researchers whose results have proved difficult to repeat reject any suggestion that they may have been guilty of excessive enthusiasm. "There was no over-interpretation," says Schwartz, "I'm standing behind every word I said." Nir Nimrodi, chief executive of Proneuron, says that the company has replicated and expanded on Schwartz's animal studies, but has not yet published the results, for reasons of intellectual property. Cheng, meanwhile, says that the data from his experiments and the surgical experience of his team gave him the confidence to transfer the technique from the rat model to patients.
Susan Howley, director of research at the Christopher Reeve Paralysis Foundation, based in Springfield, New Jersey, argues that good scientists should not be unduly influenced by patients' desire for good news. Ultimately, she stresses, patients are the losers if preliminary results over overplayed. "They are on a yo-yo," Howley says - buoyed up by one positive result, only to be crushed by the failure of subsequent studies to repeat it.
How can this roller-coaster experience be avoided? One positive sign is an initiative established last year by the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. The $8-million, five-year Facilities of Research Excellence in Spinal Cord Injury programme will devote a proportion of its budget to determining which animal studies are worth pursuing into the clinic. Independent investigators will be encouraged to work with the labs that first report promising findings to ensure that techniques are comparable. "We need to know what is working and under what conditions," says programme director Arlene Chiu. The initiative will also help to develop more quantitative and objective scales to measure animal recovery.
Other experts take solace from the authors of the three papers published last month in Neuron, all of which focused on proteins made by a gene called nogo. One of the proteins, called Nogo-A, is present in the myelin sheaths that wrap up nerves in the spinal cord, and is thought to help prevent nerves from growing back into an injured site. The three groups, led by Stephen Strittmatter of Yale University in New Haven, Connecticut, Martin Schwab of the University of Zurich and Marc Tessier-Lavigne at Stanford University in California, genetically engineered mice to lack Nogo-A. Strittmatter's group found massive regeneration and improved gait after a spinal-cord cut (2), Schwab found some regeneration (3), and Tessier-Lavigne found none (4). The reason for the varied results is unclear, but one possibility is that minor differences in the way that the genes were inactivated affected other proteins that block or boost nerve growth.
Rather than racing each other to publish their results separately, allowing patients' hopes to be raised and then dashed, the researchers agreed to work in consultation. Tessier-Lavigne and Strittmatter realized they were doing similar experiments when they met at a 2001 conference, and later approached Schwab. Tessier-Lavigne even sent some animals and a postdoctoral researcher to Strittmatter's lab to try to ensure that they were making the same type of injury.
Mary Bunge, of the Miami Project to Cure Paralysis at the University of Miami School of Medicine in Florida, argues that similar collaborative approaches must be more widely adopted in order to solve the problems of reproducibility plaguing the field. "It's very important that we all get together and talk about it," she says.
1. Rapalino, O. et al. Nature Med. 4, 814-821 (1998).
2. Kim, J.-E et al. Neuron 38, 187-199 (2003).
3. Simonen, M. et al. Neuron 38, 201-211 (2003).
4. Zheng, B. et al. Neuron 38, 213-224 (2003).
5. Richardson, P. M. et al. Nature 284, 264-265 (1980).
6. Cheng, H., Cao, Y. & Olson, L. Science 273, 510-513 (1996).
7. Lee, Y. S. et al. Neurotrauma 19, 1203-1216 (2002).
8. Ramón-Cueto, A. et al. Neuron 25, 425-435 (2000).
Here is something that may be of interest to you. It gives a pretty
detailed overview of issues related to clinical translation in spinal
injury. This is about the most up to date layman's information
available.
Translating Promising Strategies for Spinal Cord Injury Therapy
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Translating Promising Strategies for Spinal Cord Injury Therapy
February 3-4, 2003
Bethesda, Maryland
Introduction
Background
Discussion
Recommendations/Conclusions
Participants
Introduction
There are over a dozen spinal cord injury (SCI) / paralysis research groups in the U.S. and Canada, as well as strong concentrations of SCI investigators at other institutions. These are university based multidisciplinary research programs that focus on basic, clinical and/or translational research. Their efforts are aimed at improving treatments for paralysis caused by SCI through the application of basic science findings to clinical use, and some are formulating ideas for clinical trials. Despite numerous scientific meetings in the field, there has not been a concerted effort to identify areas of convergence of research interests and opportunities for interactions, collaborations and direct comparisons of results between the groups. The goal of this discussion-based workshop was to bring together leaders of major North American research groups that focus on SCI research, to exchange information about the scope and aims of their programs, and to increase communication and cooperation between them.
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Background
NINDS funding for SCI research has ranged from basic science studies of spinal cord function and regeneration in model systems, to clinical trials to evaluate pharmacological treatments, and rehabilitative approaches to improving outcome. In 1993, NINDS convened a workshop to evaluate "Intraspinal Transplantation and Clinical Application." Issues included our incomplete understanding of human SCI, logistics of clinical transplantation trials, and a need for better preclinical data and outcome measures (Journal of Neurotrauma, 1994, vol. 11(4):369-377). In the intervening years, safety trials of fetal spinal cord grafts have been performed, standardized models of rodent SCI and locomotor function have been established, and clinical trials in fields such as Parkinson's Disease and traumatic brain injury have set important precedents.
Also in recent years, an expanding community of SCI researchers has reported promising progress in developing interventions that limit secondary injury and enhance regeneration, functionally significant sprouting, and recovery of function. Yet, few of these new approaches are being successfully translated into therapies for SCI patients. As the lead federal agency in funding SCI research, the NINDS is ideally positioned to initiate a discussion among SCI research groups focused on the translation of basic research to clinical studies. Discussion topics were suggested by SCI researchers and by members of the International Campaign for Cures of SCI Paralysis, a group of voluntary agencies supporting SCI research in the United States, Canada, the United Kingdom and Australia.
Translation, regenerative medicine and multidisciplinary research teams are all topics of high priority for NIH, and NINDS in particular. In 2002, NINDS initiated several new program announcements in translational research. Thus, it is especially timely to bring together groups in SCI research to discuss current efforts toward translation. The goal of the workshop was to enlist these groups in targeting and accelerating research areas ready for translation. The groups were asked to discuss how, as a field, they can scientifically support the development of clinical studies. Attendance and participation by NIH Program and Review officers, and representatives from FDA, VA and NIDRR added value to the discussions for both the government and the research community.
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Discussion
Overview of SCI Centers and Consortia
The first aim of this workshop was to assess and disseminate information on the breadth of the participating multidisciplinary SCI research groups. Prior to the meeting, faculty lists and interests were compiled, indicating basic-neuroprotection, basic-regeneration and clinical-rehabilitation interests at each Center. The workshop was opened by a review and brief introduction by each Center director, describing the infrastructure and resources of their group. Some SCI research groups are well established, with specialized, focused or broad research programs and experience with clinical trials. Others are relatively young, newly reorganized and/or actively growing. In all, twenty-two U.S. and Canadian Centers or consortia, representing over 250 faculty members, were described, along with some State and private funding programs.
Some Centers have associations with the Veterans Administration, NIDRR-Model SCI Centers, and some represent regionally based consortia. Many of the Centers receive State, corporate and private funding in addition to NIH grant and contract support. All of the groups that receive funding as Facilities of Research Excellence in SCI were present, as were representatives of two European consortia that are developing novel outcome measures for human SCI trials (International Spinal Research Trust and a European Clinical Trials network).
A key component of these Centers is their multidisciplinary faculties. Many foster the interaction of basic and translational scientists with clinicians in neurosurgery, neurology and rehabilitation medicine. The Centers offer some training in translation, though they agree there is a need for additional training opportunities in clinical trials development, conduct and interpretation. Other resources include core facilities, registries of SCI persons, and collections of human SCI tissue available at a few Centers. The stated goal of most groups is to apply basic science findings to developing strategies for clinical studies in SCI. Issues under consideration include which level of injury to target, how much regeneration is possible or needed, what outcome measures will detect changes due to the treatment, and what would most improve quality of life after SCI. The need for delayed interventions and studies that define the nature and reparability of chronic injuries was a recurring theme here and throughout the meeting.
In addition to the Centers represented, SCI funding by California, New Jersey and New York was described. These are a subset of the states that now fund SCI and TBI research through either peer-review or designated support mechanisms. In addition to initiating a competitive grants program, N.Y. State has contracted with the Institute of Medicine to assess the current state of SCI research over the next two years.
Development of SCI Clinical Trials
The discussion of clinical trials included brief mention of several ongoing clinical studies and highlighted the long history of SCI trials, lessons from drug company studies and those in related fields such as TBI. It was clear, however, that many SCI researchers lack knowledge or access to details about this history, and its importance in developing future trials. General issues discussed included patient selection and availability of sufficient study participants, the apparent lack of rigor or equipoise in some clinical applications of novel therapies, and issues of informed consent and understanding of the nature of clinical trials on the part of the patients.
Despite, or because of the enthusiasm often expressed in press coverage of SCI research and the promise of new therapeutic strategies in animal studies, it was considered important to assess these results with great care. This includes the need to directly associate evidence of regeneration with behavioral changes, and to consider that very complex models tested in rodents will not easily translate into clinical applications. The question of what and how much preclinical evidence is needed to warrant a trial in humans led to questions of regulation of trials, and how the decision to initiate a trial is made. The need for researchers in the field to address these questions was raised throughout the workshop. While "advice" on these topics from a group of leaders in the field was seen as valuable, development of further roadblocks or regulations was not supported. It was agreed, however, that training in trials design, mentorship from those experienced with trials and analysis of trial data, and possibly a registry of clinical trial experiences would accelerate the field in a productive direction.
The decision of when to initiate a trial is made by researchers and their sponsors, often with encouragement from patient groups. Trials using investigational drugs, biologics and devices are subject to FDA regulation, and human subject protection is reviewed by local IRBs in accordance with applicable federal regulations. FDA/CBER representatives clarified their role by pointing out that they assess the safety, not efficacy of the treatment or the rationale for going to a trial. FDA representatives strongly encourage researchers to confer with them early in the planning process, as does the NINDS Clinical Trials group, which also advises on pre-phase III studies (pilot studies and planning grants). FDA/CDRH pointed out some differences between device, cell and drug regulations of which applicants should be aware.
Acute, Neuroprotection
The experience of the NASCIS trials of methylprednisolone and other neuroprotection drug candidates was discussed in relation to recent controversies over use of high-dose steroids as a standard-of-care. There is little consensus on standard of acute care in SCI, as illustrated by recently published Guidelines by the American Association of / Congress of Neurological Surgeons (Neurosurgery, supplement to March 2002, volume 50, no. 3). In addition to a lack of evidence-based practice guidelines, medico-legal issues will affect treatment and trial design.
Many issues of trial design were raised for which there were no ready answers. A key issue is how big an effect size to expect and what outcome measures can detect this in large-scale trials. In relatively "safe" areas, such as thoracic injuries, even measures that are sensitive enough to detect reliable changes in function attributable to an intervention will not likely yield a functional improvement to patients, or improve their quality of life. Setting the bar too high for trials is also not productive. SCI trial designs will be complicated by naturally occurring recovery in some patients and our limited ability to predict such recovery reliably. Yet placebo controlled trials of complex invasive therapies were considered unlikely to be attempted.
The question of how much benefit justifies a trial depends in large part on the potential risk of the therapy to the patients. It was suggested that acute neuroprotective studies might offer relatively more potential benefit than currently available regenerative strategies. Before experimental therapies are tested, it was suggested that some surgical issues (decompression, realignment, stabilization) be addressed in randomized controlled studies. For new therapies, more information is needed about the window of therapeutic opportunity, which depends in part on the mechanism of action of a particular intervention.
Promising strategies for neuroprotection are evolving, including hypothermia, blockers of secondary injury, and cellular therapies. Therapies with differing mechanisms may have different optimal times of application. To ensure the robustness of preclinical findings, these strategies need to be tested in more than one laboratory, model of injury or in larger animal models; the results of these studies, positive or negative should be published. Additional considerations discussed included gender differences, genetic diversity and the use of relatively young rodents versus trials on mature patients. The need for primate studies was conditional, depending on the model, intervention and functional analysis being studied. Improving outcome measures in animal studies would involve use of physiological measures, biomarkers, and indicators of cell survival where appropriate. In addition, longer studies to assess the persistence of any functional advantage to a protective therapy were called for.
Chronic, Regeneration
A number of strategies to promote regeneration have been identified, including growth factors, stem cells, Schwann cells and olfactory ensheathing cells, myelin neutralization, extracellular matrix inhibition, and guidance channels. Some also promote remyelination. The timeframe for application of a therapy will depend on its effects on the spinal cord; some strategies could be advantageous in both acute and chronic injuries. A common component of effective therapies, including activity-based therapies, may be altering function by stimulating endogenous plasticity. The question of how much of the mechanism needs to be clearly defined before a strategy is tested clinically was a topic of some discussion.
While trials should be designed to apply a therapy at a time that is appropriate to its mechanism of action, calling for more mechanistic studies can also lead to a perpetual "we need to know more" research mode. One advantage of proving a therapy successful in a number of models in the preclinical stage is to assess its robustness, despite a lack of clear understanding of its mechanism of action. In this respect, rehabilitation studies are an example of studies that can be safe and productive, and inform future trials in defining functional outcomes that can be assessed, without full understanding of their physiological consequences.
The issue of understanding what a truly chronic injury is in animal models was raised several times. Relating animal findings to human studies requires better information about continuing damage in the cord, and the potential for plasticity and regeneration. A resource for housing chronically injured animals was suggested to accelerate translational studies.
Assessing the "window of opportunity," for maximal effectiveness of a therapy has not been accomplished preclinically for most, if any, strategies. The NASCIS neuroprotection trials defined the useful therapeutic window during the clinical trials. It is also not known when there may be no hope for effect, or what the optimal duration of most treatments are. Relying on anatomical changes seen in animal studies is not sufficient, as behavioral recovery can be measured over many weeks, while lesion size may be expanding in experimental models. Attention to these questions with further research is needed.
Translation
Regardless of the intervention being targeted, common issues arose relating to translation and preclinical testing. These include assessment of potential adverse effects, and developing a hierarchy of interventions to be translated, based in part on risk. In Phase I trials that assess safety of cellular grafts, it was pointed out that measuring adverse events is not enough; proof that the cells survived is needed to truly assess safety, and therefore better imaging or biomarkers are needed. Because the criteria needed to initiate any given trial are so dependent on the specifics of the chosen patient population, intervention, and follow-up measures, many of the workshop participants felt that it was essential to seek agreement based on considerations of animal models, replications, safety and mechanism of action. It was agreed that a fair evaluation of evidence would require access (preferably in reviewed publications) to both positive and negative findings relating to the strategies being tested. Development of an informatics structure to make such findings available was suggested.
Many topics of clinical relevance were discussed for which no simple guidelines are available from animal studies: testing for side effects such as pain, determination of appropriate patient inclusion and exclusion criteria, best outcome measures, consideration of normal functional recovery, length of trial, coordination of multi-center sites to ensure compliance, marketing of eventual treatment, definition of trial success. Clinical experience shows that the accuracy of prognosis after SCI increases over the first hours and days after the injury. Neuroprotection trials may be initiated before a clear prognosis can be established, and so may require blinded, controlled trials for assessment, whereas trials in complete subjects initiated several days or a week after injury may strongly suggest efficacy without placebo controls.
Comparing the realities of clinical testing to expectations from animal studies highlighted issues of functional outcome assessment. The usefulness and sensitivity of existing outcome measures to assess regeneration strategies was questioned. While these strategies may not restore "useful" function, early studies will need to assess any improvement. Motor and sensory function assessed by the ASIA scale does not take pain, autonomic or sexual function into account, and may not be sensitive enough to detect even several spinal levels of regeneration in thoracic injuries. The basic scientists were reminded that acute SCI patients are not stable, and risks of surgeries can be high. Long-term studies, that require rehabilitation and continued follow-up may not be practical for patients, especially when long distance travel is involved. The financial implications of such studies were also discussed
There is general agreement among basic scientists that some combination of strategies will be needed to restore function. Developing these combinations clinically will present challenges, and incremental tests of therapies will need to aim at detecting incremental benefits. Many rehabilitation therapies being discussed are not, themselves, evidence-based standards of care, and so multiple experimental therapies would, by necessity, be tested simultaneously. It is not clear whether patients that have participated in one trial should be excluded from other trials, but this is an additional "risk" to the patient that must be considered. It was pointed out that every patient experiences a "combination" therapy, and examples from other fields, such as cancer therapy should be sought. FDA representatives pointed out that in combination therapies, each component must be shown to be effective and required, whereas approved devices (e.g., drug pumps) are approved for their function, not specific applications.
One of the largest hurdles may lie in overcoming patient expectations. Patients must be made aware that there is always "something to lose" as well as gain. Obtaining informed consent in trauma cases is a difficult issue (especially in very acute interventions), but precedents have been set in brain injury and other SCI trials. Subjective reports are subject to large placebo effects in SCI patients, and objective outcome measures are needed. Basic scientists need to be better educated about available tools for behavioral analysis as well, and their limitations. It was agreed that improved outcome measures for both animal and human studies need to be addressed, and some new measures are being developed. Finally, given the initiation of several Phase I trials in recent years, it is not clear what outcome is being sought to justify planning for further clinical studies. Without the possibility in clinical studies of assessing evidence of cell survival, clear assignment of clinical prognosis, markers of cell or drug activity, or even clearly defined mechanisms of action, many participants remained skeptical of taking any of the existing strategies to trial.
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Recommendations/Conclusions
Discussion throughout the meeting was active, and important concerns emerged. While agreement was not reached on solutions for many of these concerns, the discussion was viewed as useful and productive for further consideration at the Centers. Participants expressed enthusiasm for continuing the discussion next year. While specific therapies were not identified or prioritized within the context of this meeting, working groups were initiated to work in the coming year on several documents, including a summary paper from this meeting, a historical look at SCI trials and lessons learned from them, and a position paper providing advice on translation in SCI. The following issues were identified as important to accelerating translation:
Improving outcome measures (animal and human) sensitive to regeneration/plasticity
Training of SCI trial specialists, or information about and access to available training
Definition/study of chronic injury, relationship between animal and human injuries
Need for chronic animal resource to accelerate initiation of studies, study of human tissue samples after SCI
Replication of promising studies, publication of results positive or negative
FORE-SCI contract is initiating acute and chronic replication studies
Trials in larger animals in some interventions
Continued discussion across disciplines, international groups
Participants valued present workshop/style and endorse meeting again next year
Increased awareness/training of trial design and history among basic/translational labs;
Decision: to draft a paper reviewing SCI trials experience, past to present; participants will follow up
Need for an advisory group within the field for anticipating trials, planning translation
Decision: participants will follow up
The NINDS would like to acknowledge additional support for this workshop provided by the Christopher Reeve Paralysis Foundation.
Megkerdeztem a Bresciai egyetemet. Brunelli professzor mar nyugdijas es fogalmuk sincs hol van....
Valami renegad sebesz lehet...:)
Mindenesetre bator:)
Name BRUNELLI Giorgio
Title Professore associato di ortopedia e traumatologia
Type academic staff
Office phone +39-30-3995401-202-393981
Dept phone +39-30-3384093-3995308
Fax +30-30-393832
Department UP Patologia chirurgica - II Ortopedia
Address c/o II^ ortopedia traumatologia, Spedali Civili
E-Mail no email
Tőle meg lehet kérdezni.
Egyébként ez egy perifériális ideg áthidaló megoldás lehet amiről szintén olvastam. Ez magét a gerincsérülést nem gyógyítja meg de ha deréktájt tört a gerinc akkor a láb idegeit felvezetik a törött rész felé.
Ez nyaki sérülésnél sajnos nem segít.
A baj az hogy már ezért a műtétért is lehordta az orvostársadalom, hogy hogy mer ilyet csinálni. pedig az ilyen bátor emberek viszik előre a fejlődést.
Azt a gliális heget lebontó enzimet is be kellett volna már rég adni valakinek (aki természetesen minden következményét vállalja , azt is ha netán rosszabbodik az állapota). de akik ilyenre ilyen feltételekkel vállalkoznának, azoknak sem engedik.
En az ilyen cikkekkel mindig szkeptikus vagyok. Tudod, lehet, hogy a Kiskegyedben megjelenik, hogy megtalaltak az AIDS gyogyszeret, ozt megsem...
Ha tudomanyos (peer reviewed) lapban lenne akkor oke. Ha pedig nincs lekozolve akkor az is jelzeserteku.
Kerdeseim a cikkel kapcsolatban:
1. Mekkora volt az eredeti serules?
Ez nagyon fontos dolog, mert ha nem szakad meg teljesen a gerincvelo akkor spontan is lehet jelentos javulas, mely idoben elegge elhuzodo lehet.
2. Masreszt ha jol veszem ki akkor az ep gerincvelohoz kapcsolta a n. ischiadicust es igy teremtett osszekottetest, tehat a karosodast nem befolyasolja a beavatkozas (ettol fuggetlenul erdekes a dolog).
cikk:
Dr.: Surgery Allowed Woman To Walk
August 30, 2002
LOS ANGELES (AP) -- An experimental nerve-graft surgery allowed a paraplegic woman whose spinal cord was severed in an automobile accident to reacquire limited use of her legs, an Italian doctor reported this week at a conference in California.
In a 14-hour surgery performed in July 2000, Dr. Giorgio Brunelli, of the Universita' di Brescia, Italy, removed a portion of the 28-year-old's sciatic nerve and used it as a graft to connect the undamaged portion of her spine to muscles in her buttocks and thighs. He said the graft allowed the regrowth of nerves connected to the central nervous system into the muscle tissue.
The unidentified patient first showed movement in her legs in September and since has begun walking with assistance, Brunelli said. The woman had used a wheelchair for five years prior to the surgery.
"It is rudimentary walking - she needs a walker - but she can move," Brunelli said in an interview Thursday.
Some doctors are skeptical about the procedure, said Dr. Wise Young of Rutgers University, who has followed Brunelli's research.
Young said the permanent severing of the sciatic nerve guarantees a patient loses use of the leg muscle - something that may cause problems if better treatments are eventually found.
"If the procedure fails, this is a very major loss. This concept (that) patients have nothing to lose is terribly wrong," Young said. "One shouldn't assume we will have no therapies for spinal cord injury forever - and this is a 28-year-old woman."
Other spinal cord injury research being pursued includes the use of implantable devices that provide electrical stimulation to promote nerve regrowth.
Another spinal cord expert criticized the surgery, never before performed in humans, as ethically questionable.
"Unless you do a very controlled clinical trial, many times you get fooled," said M. Dalton Dietrich of The Miami Project to Cure Paralysis. "We shouldn't be jumping the gun ... there is a major ethical question about doing these types of procedures in people until there is compelling evidence this is the answer to the problem."
Brunelli wrangled with a medical ethics board in Italy for several years before he received approval to perform the operation. Brunelli said he has experimented on more than 1,000 rats and 40 primates since 1980.
Brunelli stressed that the surgery is experimental, but said he plans to operate on a second patient, a man injured in a November automobile accident, next month.
"I will not give any illusions to patients," he said.
Brunelli presented his results, including a video that shows the woman walking, on Wednesday at the San Diego meeting of the International Society of Orthopedic Surgery and Traumatology.
Copyright 2002 The Associated Press. All rights reserved.
Training
Post Doctoral fellow at U.S. Air Force School of Aerospace Medicine, Brooks Air Force Base, TX
Ph.D. Michigan State University, East Lansing MI
M.S. University of Houston, Houston TX
B.A. University of Texas, Austin TX
Major Teaching Responsibilities
GMS 7706C "Medical Neuroscience" Participant
BMS410 "Medical Science First Semester", Co-director and Participant
Joint appointment
University of Florida Department of Neurological Surgery
Research Interests
A primary focus of Dr. Anderson's research program on spinal cord injury (SCI) has been on understanding the mechanisms responsible for tissue damage and then testing appropriate pharmacological agents to reduce the effects of acute SCI. Past studies contributed to the development of the synthetic glucocoorticoid, methylprednisolone, as the first and current pharmacological treatment for acute SCI in humans. Studies on the acute injury are continuing in collaboration with Harry Nick, Ph.D. (Department of Neuroscience). The purpose of these ongoing studies is to evaluate the expression of a series of genes during acute SCI in a well-established rat model. The genes under investigation have roles which are both protective and damaging during acute inflammatory events. The importance of these genes in exacerbating or attenuating the post-traumatic inflammatory response will also be evaluated in mice where these genes for these proteins have been removed from the mouse genome (i.e.,"gene knockouts"). The ultimate goal of these studies is to use therapeutic regimens such as gene therapy to upregulate those genes which have been determined to be beneficial during SCI and downregulate those genes that promote further damage.
In addition to studies on the acute injury, a second component of Dr. Anderson's program focuses on repair of the chronically injured spinal cord. Specifically, the goal is to assess the capacity of intraspinal transplants of embryonic central nervous system (CNS) tissue to anatomically reconstruct the injured spinal cord and enhance recovery of hindlimb locomotor function. In previous studies that were performed in collaboration with Paul Reier, Ph.D. (Departments of Neurological Surgery and Neuroscience) it was demonstrated that fetal spinal cord (FSC) tissue grafted up to 30 weeks post-compression injury in adult cats survived and grew. In most cases, the transplant filled the lesion cavity with good integration between the host and graft tissue. These studies also demonstrated a measurable improvement in post-graft hindlimb function in approximately 40% of the cats which appeared to depend on at least two factors, the time interval between injury and grafting and whether or not the lesion site was surgically cleaned (debrided) at the time of grafting. These findings suggested that there may be a "therapeutic window" following injury during which grafts of FSC tissue must be introduced in order to maximally enhance recovery of generalized locomotion and that debridement of the lesion site can cause further damage to the host spinal cord. These findings provided part of the foundation for a recently initiated a clinical pilot study that is designed to test the feasibility and safety of FSC tissue transplants in patients with progressive syringomyelia. This clinical trial is under the direction of Edward Wirth, M.D., Ph.D. (Department of Neuroscience) and is in collaboration with a variety of individuals from the Departments of Neurological Surgery (Richard Fessler, M.D. and Paul Reier), Neuroscience (Floyd Thompson, Ph.D. and Charles Vierck, Ph.D.), Neurology (Basim Uthman, M.D.), and Physical Therapy (Andrea Behrman, Ph.D.). Studies in cats to assess the capacity of FSC transplants to improve different motor functions including interlimb coordination are ongoing under the direction of Dena Howland, Ph.D. (Department of Neuroscience) through an extensive series of rigorous, quantitative behavioral, anatomical, and neurophysiological experiments that are now in progress under the auspices of an NIH- NINDS funded Program Project Grant.
A final aspect of Dr. Anderson's program that also focuses on repair of the injured spinal cord and recovery of locomotion deals with the evaluation of rehabilitation training strategies aimed at enhancing locomotor recovery after SCI. In collaboration with Dena Howland, studies have been designed and are in progress to establish if recovery of interlimb coordination requires task specific training or can occur following no training and/or non-task specific training in SCI cats. In addition, this study will determine if training efficacy is dependent on injury magnitude and requires some subset of the anatomical pathway responsible for this specific motor function. This study is funded by the Department of Veterans Affairs Merit Review System and is a continuation of Dr. Anderson's long-standing SCI research program in the VA.
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Még egy példa, hogy milyen messzire jutottak már, és milyen szinten kutatják már ezt a témát.
A weblap:
http://www.mbi.ufl.edu/Dept/Faculty/Reier.html
részlet:
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Paul Reier
Professor &
Eminent Scholar
Training
Ph. D. Case Western Reserve University
Major Teaching Responsibilities
GMS 6077 "Neural Degeneration and Regeneration"
Joint appointment
University of Florida Department of Neurological Surgery
Research Interests
Regeneration in the central and peripheral nervous systems with emphasis on neural tissue transplantation and spinal cord injury and repair; cellular biology of neurons and glia in the developing and injured PNS and CNS. Current Research: Experiments are being conducted to determine whether grafts of embryonic CNS tissue can promote structural and functional repair of the injured spinal cord. Our recent studies have shown that intraspinal transplants of fetal spinal cord tissue can undergo extensive differentiation and survive for long post-graft intervals even in lesions resembling those seen in cases of human spinal cord trauma. We are currently using a variety of modern neuroanatomical methods and magnetic resonance imaging techniques to assess the cellular composition of these grafts, their ability to integrate with the host spinal cord, and the axonal interactions established between host and donor tissues in both acute and chronic lesions of the rat and cat spinal cord. The ability of intraspinal grafts to reduce functional deficits associated with spinal cord damage is also being evaluated using behavioral and electrophysiological approaches. In this context, we have recently obtained various lines of evidence for functional integration of host and graft tissue, the basis for which is presently under investigation. Other studies also are in progress that are addressing the issue of transplantation immunology and the induction of immunotolerance in adult recipients. Future directions of this laboratory will involve the introduction of molecular approaches whereby genes that might play important roles in regeneration (e.g., those encoding for growth factors) will be either introduced into cells of the injured nervous system or donor tissue constituents. Experiments also are being performed to define alternative sources of tissue for transplantation. Stem/progenitor cells, which are found in the postnatal and adult brain, are currently under active investigation as one potential other source of embryonic-like neural cells for spinal cord repair.
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Írtam neki, kikérve a véleményét mi várható 5-10 éves távlatban. Nála autentikusabb választ nem kapunk.
Ha megjön a válasz, ideteszem.
úgy tudom most is alkalmaznak már módszereket a sérülés utáni további károsodás elkerülésére, vagy nem?
Pl. immuno szuppresszánsokat meg ezeket:
methylprednisolone, naloxone, 'megadose'
ezeket alkalmazzák nálunk?
pont azokat a folyamatokat tanulmányozzák igen részletesen amiket írtál, már molekuláris szinten, és nagyon sokat megtudtak már.
Persze emberek gerincébe nem fecskendeznek össze vissza mindent, bár lehet hogy 1-2 már most hatásos lenne, csakhát nem lehet tudni előre, további vizsgálatok nélkül.
bar azt irjak a makrofagos modszer a helyreallitast celozza. Hogy mit allit helyre, nem igazan ertem, a masodlagosan es az elsodlegesen karosodott szovet kozott milyen kulonbseg van.
A Medline-ban Schwartz absztraktjait olvasva nekem inkabb az jott le, hogy vedi a tovabbi karosodastol a szovetet.
Az elsodleges karosodas vilagos, van egy hatas, mondjuk egy trauma es elpusztulnak az idegsejtek. Igenam de eszrevettek, hogy sokkal tobb idegsejt hal meg, mint amennyinek kellene a traumatol. Sot ugy fest, hogy nagysagrendi kulonbseg is van, tehat a idegsejtpusztulas zomet nem a direkt karosodas okozza, hanem kicsit kesobb masodlagosan jon letre.
Mi ennek az oka?
Lehet, hogy az elsodlegesen elpusztult idegsejtekbol olyan anyagok szabadulnak fel, amelyek karositjak a tobbi erintetlen idegsejtet (ezek altalaban ingerlo hatasu atvivoanyagok pl. glutamat, aspartat melyek nagy koncentracioban neurotoxicusak).
Lehet, hogy az immunrendszer is ludas, a serult idegsejtek valamilyen immunvalaszt inditanak es az karositja a tobbi sejtet. Na itt avatkozhat be a macrophag rendszer esetlegesen...
ebbnen a makrofagos esetben talan. de mas tesztek is kezdodnek nemsoka.
bar azt irjak a makrofagos modszer a helyreallitast celozza. Hogy mit allit helyre, nem igazan ertem, a masodlagosan es az elsodlegesen karosodott szovet kozott milyen kulonbseg van.
Az erasmus kórházban belgiumban már embereken tesztelik a makrofág módszert....
amit én nem értek, miért nem alkalmazzák ezzel együtt azt az enzimet ami lebontja a glial scar-t.
Szerintem emogott az is allhat, hogy a gyogyszerceg nagyot akar kaszalni. Most elinditja a studyt es ha kijon valami minimalis eredmeny akkor minden gerincserultnek lehet adni a macrophagos koktelt. Az eljaras nem bonyolult, sok beteg lesz, nagy profit... :-)).
A nagy probléma továbbá az, hogyha sikerülne is a komplett regeneráció, azok akik évek óta nyomorékok, izomilag is elkorcsosultak es az izmok elsorvadnak a mozgáshiány miatt. Tehát agyilag/gerincileg hiába tudna járni izomilag nem tud.
Szerintem a gerinc rszéleges regenerálása 10 éven belül lehetséges lesz új és régi esetekben is. Az izom probléma lesz a fő gond.
Az izom nem olyan gond, mint gondolnad! Gyogytornaval rendben tarthato, ha sikerulne a regeneracio akkor ez nem lenne akadaly.
Ha mostanaban attores lenne ilyen tekintetben akkor minimum 5 ev a gyogyszer kifejlesztese.
Nezd meg mi a helyzet az AIDS-el, pedig ott szerintem sokkal nagyobb a mozgaster a kutatas szempontjabol, megsincs evtizedek ota gyogyito ellenszer.
És érthető miért előbb friss esetek próbálják. Azert a friss eseteken, mert ugy fest a macrophag a masodlagos karosodasra lehet jo es ez a karosodas a serules utan napos nagysagrendben jelentkezik.
Az ossejtes es graftos kiserletek igeretesek, de itt is az a baj, hogy hogyan ered el, hogy oda regeneralodjon az axon ahova regen kapcsolodott.
Ha sikerul is kiserletesen regeneraciot eloidezni, az nem er celba (van novekedes, de leginkabb ossze-vissza) ill. funkcionalisan nem okoz javulast.
amit én nem értek, miért nem alkalmazzák ezzel együtt azt az enzimet ami lebontja a glial scar-t. A macrophagos dolognal a masodlagos karosodas kivedese a cel. A glial scar lebontasa eseten pedig a regeneraciora lenne talan tobb esely. Ez idoben es mechanizmusaban is teljesen kulon folyamat.
amit én nem értek, miért nem alkalmazzák ezzel együtt azt az enzimet ami lebontja a glial scar-t.
az őssejt, swann sejt, graft módszer éppen a régi sérülésekre irányul.
És azt sem tudni előre milyen áttörés lesz a tudományban 1-2-3-4 év múlva ami közvetlenül, vagy közvetve érinti ezt a témát.
A nagy probléma továbbá az, hogyha sikerülne is a komplett regeneráció, azok akik évek óta nyomorékok, izomilag is elkorcsosultak es az izmok elsorvadnak a mozgáshiány miatt. Tehát agyilag/gerincileg hiába tudna járni izomilag nem tud.
Szerintem a gerinc rszéleges regenerálása 10 éven belül lehetséges lesz új és régi esetekben is. Az izom probléma lesz a fő gond.
Itt vannak a bevalasztasi kriteriumok:
Ahogy gondoltam akut esetekrol van szo es gondolom az a cel, hogy a szekunder karosodast csokkentsek a kezelessel. Tehat nem gyogyitja a regi eseteket...
Who Can Participate
Proneuron is recruiting worldwide for patients to participate in a Phase 1 clinical trial of an experimental therapy for Complete Spinal Cord Injury. Patients who have suffered Acute Complete Spinal Cord Injury within the last 2 weeks, may provide their treating physician with the following eligibility information. Suitable patients will need to be transported to the clinical site to undergo the experimental treatment. The patient will be required to remain in the specific site for approximately 3 months for follow-up evaluation and rehabilitation.
Eligibility Criteria
Patients must fully conform to inclusion/exclusion criteria detailed below.
The patient must be less than 14 days when the treatment is administered.
An MRI showing the injury must be sent (preferably by e-mail) to Proneuron before the patient is accepted, or the radiologist could be in direct contact with one of the treating neurosurgeons to discuss details.
To ensure the patient's agreement to participate in the study, he/she will sign the Informed Consent form before he/she is accepted, and again before the procedure is performed.
The patient will return to his/her home country after 3 months.
During the following 9 months, the patient must be available for further assessments (performed in his/her home country by Proneuron's representatives)
Inclusion Criteria
Age between 16 and 65.
Male or non-pregnant non-lactating female.
Individuals who have suffered a definitively diagnosed complete spinal cord injury
A single spinal cord lesion in the segment from C6 to T11.
The location of the injury can be determined by MRI as the region of the bony defect.
The spinal cord injury is due to blunt, non-penetrating trauma.
Can be treated before 14 days have elapsed after the injury.
Informed consent obtained and consent form signed.
Engem inkább az érdekelne, miért olyan hülye az emberi szervezet, hogy hegszövetet növeszt, amivel megakadályozza az idegek összenövését, amikor pedig elvileg az idegek össze tudnának nőni.
