Skip to main content
Top
Published in: BMC Medical Imaging 1/2009

Open Access 01-12-2009 | Research article

Evaluating regional blood spinal cord barrier dysfunction following spinal cord injury using longitudinal dynamic contrast-enhanced MRI

Authors: Ilkan Tatar, Peter Cheng-te Chou, Mohamed Mokhtar Desouki, Hanaa El Sayed, Mehmet Bilgen

Published in: BMC Medical Imaging | Issue 1/2009

Login to get access

Abstract

Background

In vivo preclinical imaging of spinal cord injury (SCI) in rodent models provides clinically relevant information in translational research. This paper uses multimodal magnetic resonance imaging (MRI) to investigate neurovascular pathology and changes in blood spinal cord barrier (BSCB) permeability following SCI in a mouse model of SCI.

Methods

C57BL/6 female mice (n = 5) were subjected to contusive injury at the thoracic T11 level and scanned on post injury days 1 and 3 using anatomical, dynamic contrast-enhanced (DCE-MRI) and diffusion tensor imaging (DTI). The injured cords were evaluated postmortem with histopathological stains specific to neurovascular changes. A computational model was implemented to map local changes in barrier function from the contrast enhancement. The area and volume of spinal cord tissue with dysfunctional barrier were determined using semi-automatic segmentation.

Results

Quantitative maps derived from the acquired DCE-MRI data depicted the degree of BSCB permeability variations in injured spinal cords. At the injury sites, the damaged barriers occupied about 70% of the total cross section and 48% of the total volume on day 1, but the corresponding measurements were reduced to 55% and 25%, respectively on day 3. These changes implied spatio-temporal remodeling of microvasculature and its architecture in injured SC. Diffusion computations included longitudinal and transverse diffusivities and fractional anisotropy index. Comparison of permeability and diffusion measurements indicated regions of injured cords with dysfunctional barriers had structural changes in the form of greater axonal loss and demyelination, as supported by histopathologic assessments.

Conclusion

The results from this study collectively demonstrated the feasibility of quantitatively mapping regional BSCB dysfunction in injured cord in mouse and obtaining complementary information about its structural integrity using in vivo DCE-MRI and DTI protocols. This capability is expected to play an important role in characterizing the neurovascular changes and reorganization following SCI in longitudinal preclinical experiments, but with potential clinical implications.
Appendix
Available only for authorised users
Literature
1.
go back to reference Tator CH, Koyanagi I: Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg. 1997, 86: 483-492. 10.3171/jns.1997.86.3.0483.CrossRefPubMed Tator CH, Koyanagi I: Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg. 1997, 86: 483-492. 10.3171/jns.1997.86.3.0483.CrossRefPubMed
2.
go back to reference Whetstone WD, Hsu JY, Eisenberg M, Werb Z, Noble-Haeusslein LJ: Blood-spinal cord barrier after spinal cord injury: relation to revascularization and wound healing. J Neurosci Res. 2003, 74: 227-239. 10.1002/jnr.10759.CrossRefPubMedPubMedCentral Whetstone WD, Hsu JY, Eisenberg M, Werb Z, Noble-Haeusslein LJ: Blood-spinal cord barrier after spinal cord injury: relation to revascularization and wound healing. J Neurosci Res. 2003, 74: 227-239. 10.1002/jnr.10759.CrossRefPubMedPubMedCentral
3.
go back to reference Maikos JT, Shreiber DI: Immediate damage to the blood-spinal cord barrier due to mechanical trauma. J Neurotrauma. 2007, 24: 492-507. 10.1089/neu.2006.0149.CrossRefPubMed Maikos JT, Shreiber DI: Immediate damage to the blood-spinal cord barrier due to mechanical trauma. J Neurotrauma. 2007, 24: 492-507. 10.1089/neu.2006.0149.CrossRefPubMed
4.
go back to reference Bilgen M, Narayana PA: A pharmacokinetic model for quantitative evaluation of spinal cord injury with dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Med. 2001, 46: 1099-1106. 10.1002/mrm.1305.CrossRefPubMed Bilgen M, Narayana PA: A pharmacokinetic model for quantitative evaluation of spinal cord injury with dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Med. 2001, 46: 1099-1106. 10.1002/mrm.1305.CrossRefPubMed
5.
go back to reference Bilgen M, Abbe R, Narayana PA: Dynamic contrast-enhanced MRI of experimental spinal cord injury: in vivo serial studies. Magn Reson Med. 2001, 45: 614-622. 10.1002/mrm.1083.CrossRefPubMed Bilgen M, Abbe R, Narayana PA: Dynamic contrast-enhanced MRI of experimental spinal cord injury: in vivo serial studies. Magn Reson Med. 2001, 45: 614-622. 10.1002/mrm.1083.CrossRefPubMed
6.
go back to reference Bilgen M, Dogan B, Narayana P: In vivo assessment of blood-spinal cord barrier permeability: serial dynamic contrast enhanced MRI of spinal cord injury. Magn Reson Imaging. 2002, 20: 337-10.1016/S0730-725X(02)00504-0.CrossRefPubMed Bilgen M, Dogan B, Narayana P: In vivo assessment of blood-spinal cord barrier permeability: serial dynamic contrast enhanced MRI of spinal cord injury. Magn Reson Imaging. 2002, 20: 337-10.1016/S0730-725X(02)00504-0.CrossRefPubMed
7.
go back to reference Guertin PA: Paraplegic mice are leading to new advances in spinal cord injury research. Spinal Cord. 2005, 43: 459-461. 10.1038/sj.sc.3101701.CrossRefPubMed Guertin PA: Paraplegic mice are leading to new advances in spinal cord injury research. Spinal Cord. 2005, 43: 459-461. 10.1038/sj.sc.3101701.CrossRefPubMed
8.
go back to reference Rosenzweig ES, McDonald JW: Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair. Curr Opin Neurol. 2004, 17: 121-131. 10.1097/00019052-200404000-00007.CrossRefPubMed Rosenzweig ES, McDonald JW: Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair. Curr Opin Neurol. 2004, 17: 121-131. 10.1097/00019052-200404000-00007.CrossRefPubMed
9.
go back to reference Steward O, Schauwecker PE, Guth L, Zhang Z, Fujiki M, Inman D, Wrathall J, Kempermann G, Gage FH, Saatman KE, et al: Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models. Exp Neurol. 1999, 157: 19-42. 10.1006/exnr.1999.7040.CrossRefPubMed Steward O, Schauwecker PE, Guth L, Zhang Z, Fujiki M, Inman D, Wrathall J, Kempermann G, Gage FH, Saatman KE, et al: Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models. Exp Neurol. 1999, 157: 19-42. 10.1006/exnr.1999.7040.CrossRefPubMed
10.
go back to reference Kigerl KA, McGaughy VM, Popovich PG: Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J Comp Neurol. 2006, 494: 578-594. 10.1002/cne.20827.CrossRefPubMedPubMedCentral Kigerl KA, McGaughy VM, Popovich PG: Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J Comp Neurol. 2006, 494: 578-594. 10.1002/cne.20827.CrossRefPubMedPubMedCentral
11.
go back to reference Pannu R, Christie DK, Barbosa E, Singh I, Singh AK: Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem. 2007, 101: 182-200. 10.1111/j.1471-4159.2006.04354.x.CrossRefPubMed Pannu R, Christie DK, Barbosa E, Singh I, Singh AK: Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem. 2007, 101: 182-200. 10.1111/j.1471-4159.2006.04354.x.CrossRefPubMed
12.
go back to reference Pearse DD, Chatzipanteli K, Marcillo AE, Bunge MB, Dietrich WD: Comparison of iNOS inhibition by antisense and pharmacological inhibitors after spinal cord injury. J Neuropathol Exp Neurol. 2003, 62: 1096-1107.CrossRefPubMed Pearse DD, Chatzipanteli K, Marcillo AE, Bunge MB, Dietrich WD: Comparison of iNOS inhibition by antisense and pharmacological inhibitors after spinal cord injury. J Neuropathol Exp Neurol. 2003, 62: 1096-1107.CrossRefPubMed
13.
go back to reference Elshafiey I, Bilgen M, He R, Narayana PA: In vivo diffusion tensor imaging of rat spinal cord at 7 T. Magn Reson Imaging. 2002, 20: 243-247. 10.1016/S0730-725X(02)00493-9.CrossRefPubMed Elshafiey I, Bilgen M, He R, Narayana PA: In vivo diffusion tensor imaging of rat spinal cord at 7 T. Magn Reson Imaging. 2002, 20: 243-247. 10.1016/S0730-725X(02)00493-9.CrossRefPubMed
14.
go back to reference Kim JH, Loy DN, Liang HF, Trinkaus K, Schmidt RE, Song SK: Noninvasive diffusion tensor imaging of evolving white matter pathology in a mouse model of acute spinal cord injury. Magn Reson Med. 2007, 58: 253-260. 10.1002/mrm.21316.CrossRefPubMed Kim JH, Loy DN, Liang HF, Trinkaus K, Schmidt RE, Song SK: Noninvasive diffusion tensor imaging of evolving white matter pathology in a mouse model of acute spinal cord injury. Magn Reson Med. 2007, 58: 253-260. 10.1002/mrm.21316.CrossRefPubMed
15.
go back to reference Aimone JB, Leasure JL, Perreau VM, Thallmair M: Spatial and temporal gene expression profiling of the contused rat spinal cord. Exp Neurol. 2004, 189: 204-221. 10.1016/j.expneurol.2004.05.042.CrossRefPubMed Aimone JB, Leasure JL, Perreau VM, Thallmair M: Spatial and temporal gene expression profiling of the contused rat spinal cord. Exp Neurol. 2004, 189: 204-221. 10.1016/j.expneurol.2004.05.042.CrossRefPubMed
16.
go back to reference Ousman SS, David S: MIP-1alpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci. 2001, 21: 4649-4656.PubMed Ousman SS, David S: MIP-1alpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci. 2001, 21: 4649-4656.PubMed
17.
go back to reference Parker D: Pharmacological approaches to functional recovery after spinal injury. Curr Drug Targets CNS Neurol Disord. 2005, 4: 195-210. 10.2174/1568007053544192.CrossRefPubMed Parker D: Pharmacological approaches to functional recovery after spinal injury. Curr Drug Targets CNS Neurol Disord. 2005, 4: 195-210. 10.2174/1568007053544192.CrossRefPubMed
18.
go back to reference Pearse DD, Bunge MB: Designing cell- and gene-based regeneration strategies to repair the injured spinal cord. J Neurotrauma. 2006, 23: 437-452. 10.1089/neu.2006.23.437.CrossRef Pearse DD, Bunge MB: Designing cell- and gene-based regeneration strategies to repair the injured spinal cord. J Neurotrauma. 2006, 23: 437-452. 10.1089/neu.2006.23.437.CrossRef
19.
go back to reference Bilgen M: A new device for experimental modeling of central nervous system injuries. Neurorehabil Neural Repair. 2005, 19: 219-226. 10.1177/1545968305278635.CrossRefPubMed Bilgen M: A new device for experimental modeling of central nervous system injuries. Neurorehabil Neural Repair. 2005, 19: 219-226. 10.1177/1545968305278635.CrossRefPubMed
20.
go back to reference Bilgen M: Simple, low-cost multipurpose RF coil for MR microscopy at 9.4 T. Magn Reson Med. 2004, 52: 937-940. 10.1002/mrm.20228.CrossRefPubMed Bilgen M: Simple, low-cost multipurpose RF coil for MR microscopy at 9.4 T. Magn Reson Med. 2004, 52: 937-940. 10.1002/mrm.20228.CrossRefPubMed
21.
go back to reference Bilgen M, Al-Hafez B, Berman NE, Festoff BW: Magnetic resonance imaging of mouse spinal cord. Magn Reson Med. 2005, 54: 1226-1231. 10.1002/mrm.20672.CrossRefPubMed Bilgen M, Al-Hafez B, Berman NE, Festoff BW: Magnetic resonance imaging of mouse spinal cord. Magn Reson Med. 2005, 54: 1226-1231. 10.1002/mrm.20672.CrossRefPubMed
22.
go back to reference Bilgen M: Imaging corticospinal tract connectivity in injured rat spinal cord using manganese-enhanced MRI. BMC Medical Imaging. 2006, 6: 15-10.1186/1471-2342-6-15.CrossRefPubMedPubMedCentral Bilgen M: Imaging corticospinal tract connectivity in injured rat spinal cord using manganese-enhanced MRI. BMC Medical Imaging. 2006, 6: 15-10.1186/1471-2342-6-15.CrossRefPubMedPubMedCentral
23.
go back to reference Bilgen M, Elshafiey I, Narayana PA: Mohr diagram representation of anisotropic diffusion tensor in MRI. Magn Reson Med. 2002, 47: 823-827. 10.1002/mrm.10119.CrossRefPubMed Bilgen M, Elshafiey I, Narayana PA: Mohr diagram representation of anisotropic diffusion tensor in MRI. Magn Reson Med. 2002, 47: 823-827. 10.1002/mrm.10119.CrossRefPubMed
24.
go back to reference Bilgen M, Narayana PA: Mohr diagram interpretation of anisotropic diffusion indices in MRI. Magn Reson Imaging. 2003, 21: 567-572. 10.1016/S0730-725X(03)00071-7.CrossRefPubMed Bilgen M, Narayana PA: Mohr diagram interpretation of anisotropic diffusion indices in MRI. Magn Reson Imaging. 2003, 21: 567-572. 10.1016/S0730-725X(03)00071-7.CrossRefPubMed
25.
go back to reference Wei H, Desouki MM, Lin S, Xiao D, Franklin RB, Feng P: Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues. Mol Cancer. 2008, 7: 7-10.1186/1476-4598-7-7.CrossRefPubMedPubMedCentral Wei H, Desouki MM, Lin S, Xiao D, Franklin RB, Feng P: Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues. Mol Cancer. 2008, 7: 7-10.1186/1476-4598-7-7.CrossRefPubMedPubMedCentral
26.
go back to reference Bilgen M, Rumboldt Z: Neuronal and vascular biomarkers in Syringomyelia: investigations using longitudinal MRI. Biomarkers in Medicine. 2008, 2: 113-124. 10.2217/17520363.2.2.113.CrossRefPubMed Bilgen M, Rumboldt Z: Neuronal and vascular biomarkers in Syringomyelia: investigations using longitudinal MRI. Biomarkers in Medicine. 2008, 2: 113-124. 10.2217/17520363.2.2.113.CrossRefPubMed
27.
go back to reference Inman D, Guth L, Steward O: Genetic influences on secondary degeneration and wound healing following spinal cord injury in various strains of mice. J Comp Neurol. 2002, 451: 225-235. 10.1002/cne.10340.CrossRefPubMed Inman D, Guth L, Steward O: Genetic influences on secondary degeneration and wound healing following spinal cord injury in various strains of mice. J Comp Neurol. 2002, 451: 225-235. 10.1002/cne.10340.CrossRefPubMed
28.
go back to reference Inman DM, Steward O: Physical size does not determine the unique histopathological response seen in the injured mouse spinal cord. J Neurotrauma. 2003, 20: 33-42. 10.1089/08977150360517164.CrossRefPubMed Inman DM, Steward O: Physical size does not determine the unique histopathological response seen in the injured mouse spinal cord. J Neurotrauma. 2003, 20: 33-42. 10.1089/08977150360517164.CrossRefPubMed
29.
go back to reference Wamil AW, Wamil BD, Hellerqvist CG: CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury. Proc Natl Acad Sci USA. 1998, 95: 13188-13193. 10.1073/pnas.95.22.13188.CrossRefPubMedPubMedCentral Wamil AW, Wamil BD, Hellerqvist CG: CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury. Proc Natl Acad Sci USA. 1998, 95: 13188-13193. 10.1073/pnas.95.22.13188.CrossRefPubMedPubMedCentral
30.
go back to reference Bonny JM, Gaviria M, Donnat JP, Jean B, Privat A, Renou JP: Nuclear magnetic resonance microimaging of mouse spinal cord in vivo. Neurobiol Dis. 2004, 15: 474-482. 10.1016/j.nbd.2003.11.026.CrossRefPubMed Bonny JM, Gaviria M, Donnat JP, Jean B, Privat A, Renou JP: Nuclear magnetic resonance microimaging of mouse spinal cord in vivo. Neurobiol Dis. 2004, 15: 474-482. 10.1016/j.nbd.2003.11.026.CrossRefPubMed
31.
go back to reference Stieltjes B, Klussmann S, Bock M, Umathum R, Mangalathu J, Letellier E, Rittgen W, Edler L, Krammer PH, Kauczor HU, et al: Manganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice. Magn Reson Med. 2006, 55: 1124-1131. 10.1002/mrm.20888.CrossRefPubMed Stieltjes B, Klussmann S, Bock M, Umathum R, Mangalathu J, Letellier E, Rittgen W, Edler L, Krammer PH, Kauczor HU, et al: Manganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice. Magn Reson Med. 2006, 55: 1124-1131. 10.1002/mrm.20888.CrossRefPubMed
32.
go back to reference Bilgen M, Al-Hafez B: Comparison of spinal vasculature in mouse and rat: investigations using MR angiography. Neuroanatomy. 2006, 5: 12-18. Bilgen M, Al-Hafez B: Comparison of spinal vasculature in mouse and rat: investigations using MR angiography. Neuroanatomy. 2006, 5: 12-18.
33.
go back to reference Gaviria M, Bonny JM, Haton H, Jean B, Teigell M, Renou JP, Privat A: Time course of acute phase in mouse spinal cord injury monitored by ex vivo quantitative MRI. Neurobiol Dis. 2006, 22: 694-701. 10.1016/j.nbd.2006.01.011.CrossRefPubMed Gaviria M, Bonny JM, Haton H, Jean B, Teigell M, Renou JP, Privat A: Time course of acute phase in mouse spinal cord injury monitored by ex vivo quantitative MRI. Neurobiol Dis. 2006, 22: 694-701. 10.1016/j.nbd.2006.01.011.CrossRefPubMed
34.
go back to reference Kim JH, Trinkaus K, Ozcan A, Budde MD, Song SK: Postmortem delay does not change regional diffusion anisotropy characteristics in mouse spinal cord white matter. NMR Biomed. 2007, 20: 352-359. 10.1002/nbm.1138.CrossRefPubMed Kim JH, Trinkaus K, Ozcan A, Budde MD, Song SK: Postmortem delay does not change regional diffusion anisotropy characteristics in mouse spinal cord white matter. NMR Biomed. 2007, 20: 352-359. 10.1002/nbm.1138.CrossRefPubMed
35.
go back to reference Huang ZL, He YY, Bilgen M: In vivo tracing of corticospinal tract in mouse using manganese-enhanced contrast. J Neurol Sci [Turk]. 2007, 24: 38-44. Huang ZL, He YY, Bilgen M: In vivo tracing of corticospinal tract in mouse using manganese-enhanced contrast. J Neurol Sci [Turk]. 2007, 24: 38-44.
36.
go back to reference Loy DN, Kim JH, Xie M, Schmidt RE, Trinkaus K, Song SK: Diffusion tensor imaging predicts hyperacute spinal cord injury severity. J Neurotrauma. 2007, 24: 979-990. 10.1089/neu.2006.0253.CrossRefPubMed Loy DN, Kim JH, Xie M, Schmidt RE, Trinkaus K, Song SK: Diffusion tensor imaging predicts hyperacute spinal cord injury severity. J Neurotrauma. 2007, 24: 979-990. 10.1089/neu.2006.0253.CrossRefPubMed
37.
go back to reference Bilgen M: Magnetic resonance microscopy of spinal cord injury in mouse using a miniaturized implantable RF coil. J Neurosci Methods. 2007, 159: 93-97. 10.1016/j.jneumeth.2006.06.024.CrossRefPubMed Bilgen M: Magnetic resonance microscopy of spinal cord injury in mouse using a miniaturized implantable RF coil. J Neurosci Methods. 2007, 159: 93-97. 10.1016/j.jneumeth.2006.06.024.CrossRefPubMed
38.
go back to reference Bilgen M, Al-Hafez B, Alrefae T, He YY, Smirnova IV, Aldur MM, Festoff BW: Longitudinal magnetic resonance imaging of spinal cord injury in mouse: changes in signal patterns associated with the inflammatory response. Magn Reson Imaging. 2007, 25: 657-664. 10.1016/j.mri.2006.10.009.CrossRefPubMed Bilgen M, Al-Hafez B, Alrefae T, He YY, Smirnova IV, Aldur MM, Festoff BW: Longitudinal magnetic resonance imaging of spinal cord injury in mouse: changes in signal patterns associated with the inflammatory response. Magn Reson Imaging. 2007, 25: 657-664. 10.1016/j.mri.2006.10.009.CrossRefPubMed
39.
go back to reference Clark CA, Werring DJ, Miller DH: Diffusion imaging of the spinal cord in vivo: estimation of the principal diffusivities and application to multiple sclerosis. Magn Reson Med. 2000, 43: 133-138. 10.1002/(SICI)1522-2594(200001)43:1<133::AID-MRM16>3.0.CO;2-X.CrossRefPubMed Clark CA, Werring DJ, Miller DH: Diffusion imaging of the spinal cord in vivo: estimation of the principal diffusivities and application to multiple sclerosis. Magn Reson Med. 2000, 43: 133-138. 10.1002/(SICI)1522-2594(200001)43:1<133::AID-MRM16>3.0.CO;2-X.CrossRefPubMed
40.
go back to reference Bilgen M, Al-Hafez B, He YY, Brooks WM: Magnetic resonance angiography of rat spinal cord at 9.4 T: a feasibility study. Magn Reson Med. 2005, 53: 1459-1461. 10.1002/mrm.20471.CrossRefPubMed Bilgen M, Al-Hafez B, He YY, Brooks WM: Magnetic resonance angiography of rat spinal cord at 9.4 T: a feasibility study. Magn Reson Med. 2005, 53: 1459-1461. 10.1002/mrm.20471.CrossRefPubMed
41.
go back to reference Callot V, Duhamel G, Cozzone PJ: In vivo mouse spinal cord imaging using echo-planar imaging at 11.75 T. Magma. 2007, 20: 169-173. 10.1007/s10334-007-0079-x.CrossRefPubMedPubMedCentral Callot V, Duhamel G, Cozzone PJ: In vivo mouse spinal cord imaging using echo-planar imaging at 11.75 T. Magma. 2007, 20: 169-173. 10.1007/s10334-007-0079-x.CrossRefPubMedPubMedCentral
Metadata
Title
Evaluating regional blood spinal cord barrier dysfunction following spinal cord injury using longitudinal dynamic contrast-enhanced MRI
Authors
Ilkan Tatar
Peter Cheng-te Chou
Mohamed Mokhtar Desouki
Hanaa El Sayed
Mehmet Bilgen
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medical Imaging / Issue 1/2009
Electronic ISSN: 1471-2342
DOI
https://doi.org/10.1186/1471-2342-9-10

Other articles of this Issue 1/2009

BMC Medical Imaging 1/2009 Go to the issue