- Envisioning the Six Million Dollar Man
- Seeking a Cure for Lou Gehrig's Disease
- Coronary Artery Calcium: An Early Warning System for Cardiovascular Disease
- Getting to the Heart of Obesity's Ill Effects
- Insight into Bone Formation
- It's the Bees Knees: Tissue Engineering for Better ACL Repair
- Antigen Discovery and Validation for a Preventive Vaccine Against Severe Malaria Anemia
- A Novel Approach to Vaccine Development
- Efficacy of Lung Cancer Screening Using Novel Display for Helical Computed Tomography
- Effect of Morphine and Trauma on Acinetobacter (A.) baumannii Infection
- Efficacy of Stereotactic X-Irradiation of Spinal Cord Injury
According to the National Spinal Cord Injury Statistical Center, there are more than 12,000 new cases of spinal cord injury (SCI) occurring in the United States every year. SCI disrupts regular communication between the brain and appendages, affecting motor function and mobility, dramatically changing the affected individual's physical, psychological, and social quality of life. Researcher Dr. Ronald Triolo seeks to improve the quality of life for individuals with paraplegia following SCI through an innovative bracing system that will provide enhanced mobility. The ultimate goal is an articulated thoracic-hip-knee-ankle-foot orthosis that allows users to stand, walk, and climb stairs safely and efficiently with a minimum of effort.
Dr. Triolo received a Fiscal Year 2004 Investigator-Initiated Award to support the development of the new "hybrid neuroprosthesis" for mobility after paralysis from SCI. The "hybrid" combines the best elements of external bracing (orthoses) with electrical stimulation of the paralyzed muscles to yield a new system to augment the function of the damaged nervous system. To date, Dr. Triolo's team has designed new trunk, hip, and knee mechanisms for the orthosis and integrated them into the neuroprosthesis. The bracing components provide mechanical support and stability when the lower extremity joints don't need to move very much, like during standing or when one foot is on the ground during walking or stair climbing, and are flexible when necessary so that the user can take advantage of innate muscle power to propel his or her body forward or upward with electrical stimulation. This neuroprosthesis automatically synchronizes the action of the hip, knee, and ankle joints with electrical stimulation through algorithms that use real-time information from sensors located throughout the brace. Standard motion and metabolic analysis were adapted to evaluate the efficacy of the neuroprosthesis.
The hybrid neuroprosthesis is currently being tested by able-bodied volunteers for safety and design optimization as sequential modifications are made to the brace components. Two volunteers with SCI have participated in initial walking experiments to test the hip component and will participate in future tests of the other components as well as the completed system. Rate of progress on this project has surpassed Dr. Triolo's expectations, in large part because of active and highly productive collaborations with the Rehabilitation Research and Development Service of the US Department of Veterans Affairs, and the potential is high for the neuroprosthesis to improve the quality of life for military veterans and civilians with spinal cord injury-induced paralysis in the foreseeable future.
To CS, Kobetic R, Schnellenberger JR, Audu ML, and Triolo RJ. 2008. Design of a variable constraint hip mechanism for a hybrid neuroprosthesis to restore gait after spinal cord injury. IEEE/ASME Transactions on Mechatronics 13:197-205.
Kern N, Majewski T, Triolo R, Kobetic R, and Quinn R. 2008. A locking compliant device inspired by the anatomy of the spine. ASME, Journal of Mechanical Design (in press).
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's Disease, is an incurable, neurodegenerative disorder that results in paralysis and death. Research to cure ALS is especially relevant to members of the U.S. Military, who are statistically more likely to develop ALS than the general public. The cause of ALS is unclear, but it is known that excessive glutamate receptor activity plays an important role in triggering motor neuron death, which causes the loss of muscle control. Dr. Li Niu of the State University of New York-Albany is exploring the use of RNA aptamers, small single-stranded nucleic acid inhibitors, to control glutamate receptor activity. Decreasing the activity of glutamate receptors may prevent motor neuron death.
Dr. Niu received a fiscal year 2003 Investigator-Initiated Award to discover glutamate receptor aptamers and to study their utility to inhibit the activity of these receptors. Using novel technologies such as systematic evolution of ligands by exponential enrichment (SELEX) to "breed" candidate aptamers and laser-pulse photolysis to characterize the aptamer-receptor interactions in the microsecond time domain, Dr. Niu and his colleagues have selected several groups of aptamers that display varying affinities to glutamate receptor channels, targeting a key glutamate receptor subunit. These aptamers may aid in the cessation of glutamate-associated neurotoxicity linked to ALS. Dr. Niu characterized the kinetic mechanism for nine different glutamate receptor channels, which will assist in finding additional aptamers specific to varying channel conformations. Dr. Niu is also exploring conformation-specific aptamers that are capable of inhibiting glutamate receptors with high affinities and selectivity by preferentially binding to a conformation of the receptor. This research establishes the foundation for developing new therapeutic candidates and diagnostic probes for the treatment and detection of ALS.
Aptamers M1 and M2 combine to block the glutamate receptor.
Huang Z, Pei WM, Jayaseelan S, Shi H, and Niu L. 2007. RNA aptamers selected against the GluR2 glutamate receptor channel. Biochemistry 46:12648-12655.
Pei WM, Huang Z, and Niu L. 2007. GluR3 flip and flop: Differences in channel-opening kinetics. Biochemistry 46:2027-2036.
Cardiovascular diseases are a major cause of morbidity and mortality in active duty soldiers over the age of 35. These diseases, including coronary artery calcification (CAC), appear readily in senior level personnel within the Army, thus threatening the loss of valuable expertise and experience. Early detection and treatment of cardiovascular disease is vital to the military's continued success. Understanding this need, Dr. Allen Taylor of the Walter Reed Army Medical Center was granted a Fiscal Year 2004 Investigator-Initiated Research Award to work with an innovative device called Electron Beam Computed Tomography (EBCT) to accomplish long-term follow-up on the progression of coronary artery calcification in active duty military personnel between the ages of 40 and 55.
Dr. Taylor and colleagues followed 2000 subjects for this study and accomplished major analytical aims, which include the determination of the relationship of CAC progression to race and metabolic syndrome. Dr. Taylor's findings indicate that although overall CAC was found to be less in African American men than Caucasians, the progression of CAC was comparable. In the study cohort, participants with CAC progression had significantly more metabolic syndrome components than those without clinically significant CAC progression. Currently, over 9000 participant follow-up surveys have been conducted in order to determine incidence of coronary heart disease events over time. Other seminal findings from this study include confirming a clear link between coronary calcium in young men and future risk of heart disease, and the first demonstration that the finding of coronary calcium leads to greater use of aspirin and statin medications. This research will potentially validate the use of EBCT as an early detection method for those at risk for CAC progression.
Taylor AJ, Bindeman J, Feuerstein IM, et al. 2008. Progression of calcified coronary atherosclerosis: Role of traditional risk factors, CRP and non-calcified atherosclerosis. Atherosclerosis197:339-345.
Taylor AJ, Bindeman J, Le T, et al. 2008. The relationship between coronary artery calcium and statin and aspirin use over 6 years. J Am Coll Cardiol 51:1337-1341.
According to the Centers for Disease Control, 66% of American adults are either overweight or obese. It has been established that obesity is comorbid with many other health complications including diabetes, hypertension, and accelerated coronary atherosclerosis. The National Heart, Lung, and Blood Institute describes coronary artery disease (CAD) as a dangerous condition in which plaque (fat, cholesterol, calcium, and other components) builds up within the coronary arteries creating a blockage that leads to reduced blood flow.
Dr. Ira Tabas received a fiscal year 2005 Investigator-Initiated Award to study the molecular mechanisms involved in obesity-associated CAD and to develop treatment strategies. The research aims to explore the cellular and molecular mechanisms by which angiotensin II (AngII), a hormone that is activated in obesity, triggers apoptosis in plaque-associated macrophages. Macrophage apoptosis is associated with plaque rupture and possible myocardial infarction ("heart attack").
Dr. Tabas has successfully elucidated key signaling pathways involved with endoplasmic reticulum (ER) stress-induced apoptosis that are also targeted by AngII. Furthering his inquiry into the mechanism of AngII, Dr. Tabas is studying the ability of AngII to operate as an apoptotic agent when combined with sub-threshold ER stress as well as the possibility that AngII may act as a substitute for subtle ER stresses, thus triggering macrophage cell death in the presence of additional apoptotic signalling pathways. This research sets the stage for the discovery of therapeutic solutions to the link between obesity and CAD in the military and general public.
Summary of recent data on how ER stress triggers apoptosis.
Lim WS, Timmins JM, Seimon TA, Sadler A, Kolodgie FD, Virmani R, and Tabas I. 2008. STAT1 is critical for apoptosis in macrophages subjected to endoplasmic reticulum stress in vitro and in advanced atherosclerotic lesions in vivo. Circulation 117(7):940-951.
Thorp E, Kuriakose G, Shah YM, Gonzalez FJ, and Tabas I. 2007. Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of nondiabetic low-density lipoprotein receptor-null mice. Circulation 116(19):2182-2190.
The composition of bone includes a network of collagen fibers and mineral salts, a combination that gives them great density and strength, comparable in some cases with that of reinforced concrete. Within these seemingly solid structures are bone cells, blood vessels, and nerves. Bone construction, performed by osteoblasts, and bone loss, performed by osteoclasts, are occurring throughout life; however, the rate of each process may vary with the stage of life. Tremendous bone formation occurs during childhood and adolescence with comparatively little overall bone loss, whereas adults may lose bone mass at a greater rate than it is formed. Excessive loss of bone mineral leads to osteoporosis, a condition that is characterized by increased risk of bone fracture, which may cause mobility problems, curvature of the spine, and even death.
It is known that hematopoietic stem cells in the bone marrow may differentiate into osteoblasts. With funding from a Fiscal Year 2003 Peer Reviewed Medical Research Program Investigator-Initiated Award, Dr. Alan R. Davis and his colleagues at Baylor College of Medicine have made significant progress investigating the role of primitive hematopoietic stem cells, known as side population (SP) stem cells, during normal bone growth and remodeling. Their investigation of SP cell gene expression profiles identified a small subset of antioxidant genes that were upregulated with age, perhaps as a result of oxygen exposure over time. Such continued exposure eventually may lead to diminished SP cell capabilities. Their results demonstrated that chondrocytes, cells involved in the formation of cartilage, developed under hypoxic conditions while new blood vessels formed under normoxic conditions. Taken together, these and other data suggest that a hypoxic microenvironment may be a necessary element for some aspects of the bone formation process. In vivo studies completed by Dr. Davis' research team suggest that the developmental capacity of SP cells extends to osteogenic differentiation, through an intermediate stage, with the subsequent ability of producing bone. These important findings have led to the conclusion that osteoporosis might be managed through SP cell transplantation.
In addition, this research group studied adult stem cells in a mouse model of stimulated bone repair after fracture, and they have identified the existence of an adult version of an embryonic stem cell. These cells were found to be present in the nerve sheath. These results contribute to an initial understanding of the relationship between the central nervous system and bone formation in cases of severe orthopedic trauma.
Pluripotent stem cells in the sheath of peripheral nerves of adult mice. Osteoblasts are derived from peripheral nerves, as shown in left panel, yet can also lay down new bone, as shown in right panel. Photos courtesy of Dr. Alan R. Davis.
Olmsted-Davis EA, Gannon FH, Ozen M, et al. 2007. Hypoxic adipocytes pattern early heterotopic bone formation. The American Journal of Pathology 170(2):620-632.
Shafer J, Davis AR, Gannon FH, et al. 2007. Oxygen tension directs chondrogenic differentiation of myelo-monocytic progenitors during endochondral bone formation. Tissue Engineering 13:2011-2019.
Bikram M, Fouletier-Dilling C, Hipp JA, et al. 2007. Endochondral bone formation from hydrogel carriers loaded with BMP2-transduced cells. Annals of Biomedical Engineering 35(5):796-807.
Fouletier-Dilling C, Gannon F, Olmsted-Davis EA, et al. 2007. Efficient and rapid osteoinduction in an immune competent host. Human Gene Therapy 18(8):733-745.
Gugala Z, Davis AR, Fouletier-Dilling C, et al. 2007. Adenovirus BMP2-induced osteogenesis in combination with various collagen carriers. Biomaterials 28(30):4469-4479.
Orthopedic injuries represent a significant challenge to both military and civilian medical capabilities. Reconstruction of the anterior cruciate ligament (ACL) of the knee is currently one of the most common orthopedic procedures. Although various graft alternatives have been used with some success to repair torn ACLs, an ideal graft would reproduce the ACL's complex anatomy and biomechanical properties, have a strong, secure fixation, and exhibit rapid biological incorporation. Dr. Christopher T. Wagner and his colleagues proposed a novel approach for development of a hybrid ACL graft that combines the properties of a natural acellular tissue matrix (ATM) with the strength of a biocompatible, bioabsorbable polymeric construct.
Dr. Wagner and his scientific team were sponsored to conduct this research by a Fiscal Year 2005 Investigator-Initiated Research Award. Three potential polymeric core structures were initially evaluated, and a woven tubular core made up of filaments that each carry part of the mechanical load was chosen to be combined with porcine ATM to create a hybrid graft. Biomechanical and physico-chemical properties of the hybrid graft were compared to the properties of native porcine ACL-tissue, and in vitro analyses of the mechanical characteristics such as the ability to carry physiologically relevant loads demonstrated that the hybrid graft performed favorably. In conjunction with Dr. David Butler and Dr. Jason Shearn at the University of Cincinnati, a robotic model was developed to support testing the hybrid graft and its ability to restore pre-reconstruction kinematics and loading over complete gait cycles. In vivo studies using a porcine model of ACL reconstruction surgery showed that the hybrid graft remained functional for the duration of the 12-month study. During the first 8 months, the graft ATM revitalized through a process of cellularization and vascularization and supported collagen turnover and alignment as the polymer was absorbed. At 12 months, histologic data showed that collagen and cellularity densities were comparable to native ACL. The hybrid graft supported 88% of the average native ACL mechanical load capacity and stiffness. These results are significantly better than published results of mechanical performance for bone-patella tendon-bone or soft tissue grafts currently in use.
Dr. Wagner and his team will conduct additional biomechanical studies on the hybird graft, conduct preclinical animal testing, and submit data to the U.S. Food and Drug Administration to support clinical investigations in humans.
Malaria, a disease caused by infection with Plasmodium falciparum, is a significant infectious disease threat to US troops worldwide, who must often serve in malaria-prone areas. An effective malaria vaccine should prevent infection for six months or limit disease progression among individuals who do become infected. Challenges facing the development of an effective malaria vaccine include the number of Plasmodium species and their genetic diversity, the complexity of the parasite’s life cycle, an incomplete understanding of the parasite's biology, and the inability to identify immune correlates of protection. Dr. Patrick Duffy, of the Seattle Biomedical Research Institute, received a fiscal year 2004 Investigator-Initiated Research Award through the Department of Defense Peer Reviewed Medical Research Program to support his investigations of the immune response to malaria infection and how to prevent severe anemia, a common and deadly effect of malaria infection. He and his colleagues proposed to characterize cell surface antigens, proteins produced by the parasite and expressed on the surface of the infected cells that cause severe anemia and are targeted by naturally acquired protective immunity. The research team plans to take a genome-based approach to identify three to five leading candidates for inclusion in a multi-component malaria vaccine.
The researchers investigated the differential genetic expression of potential antigen candidates encoded by (1) var genes that produce P. falciparum erythrocyte membrane protein 1 (PfEMP-1), associated with disease states and parasite representation on the surface of infected erythrocyte cells, and (2) non-var genes that produce proteins with protein-export, PEXEL/VTS, and transmembrane motifs. Gene expression studies were conducted using a DNA microarray platform and RNA probes created from a set of infected patient samples collected in Muheza, Tanzania. Preliminary results identified six var genes and nine non-var genes that were upregulated upon infection by parasites in anemic but not in non-anemic patients, and the team is in the process of confirming these results. Overall, these studies are setting the stage for identifying leading candidate antigens and testing them in preclinical and clinical evaluations.
Photo courtesy of the Seattle Biomedical Research Institute
Ntoumi F , Kwiatkowski DP, Diakité M, Mutabingwa TK, and Duffy PE. 2007. New interventions for malaria: Mining the human and parasite genomes. The American Journal of Tropical Medicine and Hygiene 77:270-275.
Duffy PE and Fried M. 2006. Red blood cells that do and red blood cells that don’t: How to resist a persistent parasite. Trends in Parasitology 22:99-101.
Tularemia is a relatively obscure disease with an incidence of less than 200 cases per year in the US; with prompt medical treatment, few cases are fatal. But the causative bacterium Francisella tularensis has an infectious dose of less than 50 organisms, and when transmitted by aerosols, it can cause a severe pneumonic form of tularemia that is highly fatal. This makes F. tularensis a prime candidate for weaponization, which has increased interest in developing a safe and effective vaccine to protect against exposure.
With the support of an FY02 Investigator-Initiated Research Award, Dr. Horwitz has taken an unusual and effective approach to developing an F. tularensis vaccine by focusing on proteins secreted by the bacterium as vaccine components. F. tularensis has a thick surface coating that obscures its surface proteins, and it grows inside host cells, so Dr. Horwitz hypothesized that the bacterial surface proteins, which are the usual targets in vaccine development, would not stimulate the type of immune response needed to combat this organism. To fight this intracellular bacterium, host lymphocytes would need to recognize bacterial proteins that are released inside the host cell, processed into small pieces, and transported to the surface of the host cell for display. Hence, proteins secreted by F. tularensis within host cells should be the focus of vaccine development, as they should be available for processing and presentation by the immune system and able to stimulate a protective immune response. Dr. Horwitz and colleagues purified the most abundant proteins secreted by F. tularensis, cloned them, and used a different, benign bacterial strain that presents antigens to the immune system via the same antigen presentation pathway as F. tularensis to deliver the antigens. When immunized intradermally with this recombinant vaccine and exposed to aerosolized virulent F. tularensis, 100% of mice survived a lethal dose, and 75% of mice survived a 10-fold lethal dose. The effectiveness and safety of this vaccine exceeded that of the only currently available tularemia vaccine, which kills 3% to 5% of immunized mice and confers lethal dose protective immunity to only 80% of the survivors. This result is a breakthrough in the development of a safe and effective tularemia vaccine. Dr. Horwitz and colleagues are continuing to explore different combinations of immunogenic proteins, the use of adenovirus as a vector, and vaccination schemes involving boosts with either purified recombinant proteins or heterologous vectors expressing the proteins in order to create a vaccine ready for human trials.
Human macrophage ingesting F. tularensis. Photo courtesy of American Society for Microbiology and the Marcus A. Horwitz Laboratory reproduced from Clemens et al. 2005. Infect. Immun. 73:5892-5902.
Clemens DL and Horwitz MA. 2007. Uptake and intracellular fate of Francisella tularensis in human macrophages. Annals of the New York Academy of Sciences 1105:160-186.
Lee B-Y, Horwitz MA, and Clemens DL. 2006. Identification, Recombinant Expression, Immunolocalization in Macrophages, and T-Cell Responsiveness of the Major Extracellular Proteins of Francisella tularensis. Infection and Immunity 74: 4002-4013.
Lung cancer is a leading cause of cancer-related death in the United States. Several large screening studies have shown that early detection and treatment can reduce mortality rate in most types of lung cancer cases. A primary tool used for lung cancer screening is the low-dose computed tomography (CT) scanner, which generates a set of image slices covering the entire lung area. The conventional method for reading lung CT images requires the radiologist to interpret data slice by slice. This procedure is becoming more complex due to the production of more slices per scan through improved technology. Dr. Xiao Hui Wang and colleagues at the University of Pittsburgh proposed to solve this dilemma by developing a 3D display for helical CT using stereoscopic projection, based on a mechanism similar to that found in human vision. A stereo display of a stack of thin CT slices may be able to clarify 3D structures, while avoiding the loss of resolution and ambiguities due to tissue superposition.
Dr. Wang, recipient of a fiscal year 2004 Department of Defense Peer Reviewed Medical Research Program Investigator-Initiated Award, has built a novel stereo display workstation for chest CT images and conducted a pilot observer performance study. The main objectives of the study were to measure relative accuracy and reading efficiency for detection and classification of lung nodules between three display modes, including the newly developed stereoscopic 3D, commonly used slice-by-slice, and maximum-intensity projection. An evaluation of data collected by a group of radiologists showed superior performance of the 3D stereo display with less interpretation time and fewer false positive findings.
Dr. Wang and her team are in the process of conducting an evaluation of their novel technology in a larger retrospective study. If successful, this project will significantly improve the efficacy of lung cancer screening and may inspire the application of these techniques to other types of virtual data management.
Wang XH and Good WF. 2008. Real-time stereographic rendering and display of medical images with programmable GPUs. Computerized Medical Imaging and Graphics 32:118-123.
Wang XH, Durick JE, Lu A, Herbert DL, Golla SK, Foley K, Piracha CS, Shinde DD, Shindel BE, Fuhrman CR, Britton CA, Strollo DC, Shang SS, Lacomis JM, and Good WF. 2007. Characterization of radiologists' search strategies for lung nodule detection: Slice-based versus volumetric displays. Journal of Digital Imaging ISSN 0897-1889, page(s):1-11.
A. baumannii infections leading to sepsis have been occurring with increased incidence in battlefield casualties involving wounds. Outside of military settings, A. baumannii infections are usually nosocomial, causing sepsis only in immunosuppressed patients. Dr. Toby Eisenstein and her scientific group, recipients of a Fiscal Year 2005 Peer Reviewed Medical Research Program Award, seek to understand why soldiers with healthy immune systems become critically ill from this pathogen. The research team has proposed a unique hypothesis that morphine, which is often given to injured soldiers on the battlefield, acts as a co-factor in sensitizing to sepsis infection. The team has initiated their study by developing a murine model of systemic infection utilizing five clinically isolated strains of A. baumannii. Preliminary studies in mice have demonstrated that an effective infection can be established using the intranasal and the intratracheal routes of inoculation. Necropsy studies correlated the subsequent rapid death of the inoculated animals to bacterial involvement.
The initial pilot study tested the effect of morphine versus placebo on an Acinetobacter- challenged infection in mice. In this study, morphine sensitized to the infection. Additionally, more extensive testing confirmed that morphine is responsible for increased sensitivity to A. baumannii infection as the opioid antagonist, naltrexone, blocked the increased mortality in morphine-treated animals. Trauma by itself was not sufficient to sensitize to infection, and in vitro studies confirmed that morphine by itself does not promote A. baumannii bacterial growth. Further research is ongoing to verify this exciting preliminary data and to determine the mechanisms by which morphine alters susceptibility to infection.
If further studies support that morphine is a co-factor in battlefield-acquired sepsis and sepsis in post-operative patients, it could profoundly affect the current strategies for pain treatment, both in immunocompromised hosts and those with trauma sustained on the battlefield.
The spinal cord often responds to injury with profound loss of neural tissue and functional capacity. In the United States alone, approximately 12,000 new cases of spinal cord injury (SCI) appear every year, while 240,000 chronic cases continue to plague the population. War veterans comprise approximately 22% of this group due to the hazardous nature of combat-related activities. The only available therapy, methylprednisolone, has been shown to have efficacy for SCI. However, some of the limitations of this drug are modest recovery, time dependency for initial administration, and the development of possible myopathy and infection. Thus, there is a great need for clinically tested and potentially superior SCI countermeasures.
Dr. Richard Zeman and his scientific team, encouraged by their preliminary results on the therapeutic use of conventional X-irradiation, have decided to further develop this unique approach. Sponsored by a Fiscal Year 2004 Peer Reviewed Medical Research Program Investigator-Initiated Research Award, Dr. Zeman's team has proposed to evaluate the efficacy of the SCI stereotactic X-irradiation both as stand alone treatment and in combination with methylprednisolone. The expected benefit of using the stereotactic versus conventional X-irradiation approach is in the delivery of a radiation beam directly to the target with high precision, avoiding unnecessary injury to the surrounding tissues and uninjured portions of the spinal cord. Furthermore, the precise delivery of this novel therapy will allow pin-point accuracy in determining the optimal dimensions of the target site volume with respect to the contusion epicenter. Initial rodent studies have demonstrated that stereotactic radiosurgery (1) improved locomotor and histological outcomes after SCI, (2) was equally effective when used in combination with methylprednisolone, and (3) had greater therapeutic value than methylprednisolone alone. Interestingly, irradiation of the adjacent spinal cord segments, either rostrally or caudally, to the contusion epicenter sites of the spinal cord produced equivalent increases in locomotor recovery. Future studies will help further define the anatomical location of the minimum therapeutic target delivery, the time-dependent effects of the novel therapy, clinical trials on efficacy of stereotactic X-irradiation of SCI, and the role of angiogenesis and tissue perfusion in improved post-therapeutic recovery.
Zeman RJ, Wen X, Ouyang N, Rocchio R, Shih L, Alfieri A, Moorthy C, and Etlinger JD. 2006. Stereotactic radiosurgery improves locomotor and histological outcomes after spinal cord injury in rats. J Spinal Cord Med 29(4):465.