Measurement of Intraspinal Pressure After Spinal Cord Injury: Technical Note from the Injured Spinal Cord Pressure Evaluation Study.

Intracranial pressure (ICP) is routinely measured in patients with severe traumatic brain injury (TBI). We describe a novel technique that allowed us to monitor intraspinal pressure (ISP) at the injury site in 14 patients who had severe acute traumatic spinal cord injury (TSCI), analogous to monitoring ICP after brain injury. A Codman probe was inserted subdurally to measure the pressure of the injured spinal cord compressed against the surrounding dura. Our key finding is that it is feasible and safe to monitor ISP for up to a week in patients after TSCI, starting within 72 h of the injury. With practice, probe insertion and calibration take less than 10 min. The ISP signal characteristics after TSCI were similar to the ICP signal characteristics recorded after TBI. Importantly, there were no associated complications. Future studies are required to determine whether reducing ISP improves neurological outcome after severe TSCI.

Waveform Analysis of Intraspinal Pressure After Traumatic Spinal Cord Injury: An Observational Study (O-64).

Following a traumatic brain injury (TBI), intracranial pressure (ICP) increases, often resulting in secondary brain insults. After a spinal cord injury, here the cord may be swollen, leading to a local increase in intraspinal pressure (ISP). We hypothesised that waveform analysis methodology similar to that used for ICP after TBI may be applicable for the monitoring of patients with spinal cord injury.An initial cohort of 10 patients with spinal cord injury, as presented by the first author at a meeting in Cambridge in May 2012, were included in this observational study. The whole group (18 patients) was recently presented in the context of clinically oriented findings (Werndle et al., Crit Care Med, 42(3):646-655, 2014, PMID: 24231762). Mean pressure, pulse and respiratory waveform were analysed along slow vasogenic waves.Slow, respiratory and pulse components of ISP were characterised in the time and frequency domains. Mean ISP was 22.5 ± 5.1, mean pulse amplitude 1.57 ± 0.97, mean respiratory amplitude 0.65 ± 0.45 and mean magnitude of slow waves (a 20-s to 3-min period) was 3.97 ± 3.1 (all in millimetres of mercury). With increasing mean ISP, the pulse amplitude increased in all cases. This suggests that the ISP signal is of a similar character to ICP recorded after TBI. Therefore, the methods of ICP analysis can be helpful in ISP analysis.

Opportunities and dangers for neurosurgery in the current NHS.

The NHS is entering a third decade of administrative turbulence and cost pressures and many view the new NHS structure and systems as complex and confusing. Health and social care budgets are being merged in some geographical areas and large efficiency savings are needed by 2020. There are risks that lie ahead for neurosurgery and our patients if the specialty becomes further fragmented and opportunities for positive change are missed. One of the new care models proposed in the NHS five year plan is specialist care provided across multiple hospital sites by a single overarching specialist trust, mirroring ophthalmology where the Moorfields trust provides specialist eye services in over 20 locations in London and the South East. This model lends itself to adoption by neurosurgery and has the potential to increase standards, efficiency, training and research.

Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study*.

OBJECTIVES: To develop a technique for continuously monitoring intraspinal pressure at the injury site (intraspinal pressure) after traumatic spinal cord injury. DESIGN: A pressure probe was placed subdurally at the injury site in 18 patients who had isolated severe traumatic spinal cord injury (American Spinal Injuries Association grades A-C). Intraspinal pressure monitoring started within 72 hours of the injury and continued for up to a week. In four patients, additional probes were inserted to simultaneously monitor subdural pressure below the injury and extradural pressure. Blood pressure was recorded from a radial artery catheter kept at the same horizontal level as the injured segment of the spinal cord. We determined the effect of various maneuvers on spinal cord perfusion pressure and spinal cord function and assessed using a limb motor score and motor-evoked potentials. SETTING: Neurosurgery and neuro-ICU covering a 3 million population in London. SUBJECTS: Patients with severe traumatic spinal cord injury. Control subjects without spinal cord injury (to monitor spinal cerebrospinal fluid signal and motor evoked potentials). INTERVENTIONS: Insertion of subdural spinal pressure probe. MEASUREMENTS AND MAIN RESULTS: There were no procedure-related complications. Intraspinal pressure at the injury site was higher than subdural pressure below the injury or extradural pressure. Average intraspinal pressure from the 18 patients with traumatic spinal cord injury was significantly higher than average intraspinal pressure from 12 subjects without traumatic spinal cord injury. Change in arterial PCO2, change in sevoflurane dose, and mannitol administration had no significant effect on intraspinal pressure or spinal cord perfusion pressure. Increase in inotrope dose significantly increased spinal cord perfusion pressure. Bony realignment and laminectomy did not effectively lower intraspinal pressure. Laminectomy was potentially detrimental by exposing the swollen spinal cord to compression forces applied to the skin. By intervening to increase spinal cord perfusion pressure, we could increase the amplitude of motor-evoked potentials recorded from below or just above the injury level in nine of nine patients with traumatic spinal cord injury. In two of two patients with American Spinal Injuries Association grade C traumatic spinal cord injury, higher spinal cord perfusion pressure correlated with increased limb motor score. CONCLUSIONS: Our findings provide proof-of-principle that subdural intraspinal pressure at the injury site can be measured safely after traumatic spinal cord injury.

Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain.

OBJECTIVE: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model. METHODS: NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected. RESULTS: We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions. INTERPRETATION: Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.

Diffusion tensor imaging discriminates between glioblastoma and cerebral metastases in vivo.

In a prospective study, patients with a radiologically proven brain tumour underwent diffusion tensor imaging (DTI) prior to definitive diagnosis and treatment. Twenty-eight patients with a histologically proven glioblastoma or metastasis were included in the study. Following the definition of regions of interest, DTI metrics [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for the tumour volume and the surrounding region of peritumoral oedema. These metrics were then subjected to logistic regression to investigate their ability to discriminate between glioblastomas and cerebral metastases. A cross-validation was performed to investigate the ability of the model to predict tumour. The logistic regression analysis correctly distinguished glioblastoma in 15 of 16 cases (93.8%) and metastasis in 11 of 12 cases (91.7%). Cross-validation resulted in the model correctly predicting 14 of 16 (87.5%) glioblastomas and 10 of 12 (83.3%) metastases studied. MD was significantly higher (p = 0.02) and FA was significantly lower (p = 0.04) within the oedema surrounding metastases than within the oedema around glioblastomas. MD was significantly higher (p = 0.02) within the tumour volume of the glioblastomas. Our results demonstrate that, when DTI metrics from the tumour volume and surrounding peritumoral oedema are studied in combination, glioblastoma can be reliably discriminated from cerebral metastases.

Dangers of bone graft substitutes: lessons from using GeneX.

BACKGROUND: Bone graft substitutes are widely used in spinal surgery. Here, serious complications associated with the bone graft substitute GeneX are presented. GeneX contains tri-calcium phosphate and calcium sulphate. METHODS: GeneX was used in three patients who had spinal decompression and fusion. Mice were also injected with GeneX, demineralised bone matrix (DBX) or saline subcutaneously. After 24 h the extent of tissue damage and inflammation in tissue sections was quantified. To understand the licensing process for bone graft substitutes, the U.S. Food and Drug Administration (FDA) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) websites were accessed. RESULTS: All patients developed sterile pus in soft tissues adjacent to the GeneX followed by skin breakdown in two and pharyngeal perforation in one. In mice, GeneX produced moderate or severe skin damage compared with no or mild skin damage after DBX (p<0.05) or saline (p<0.05) injection. GeneX caused more inflammation in mouse dermis (1704±193 leucocytes/mm2, mean ± SE) than DBX (537 ± 266, p<0.01) or saline (136 ± 19, p<0.01). The FDA and MHRA classify bone graft substitutes as medical devices. In contrast with drugs, medical devices do not need to undergo clinical safety tests before obtaining FDA 510(k) clearance for use in patients. CONCLUSION: GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs.

Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.

Ex-vivo HRMAS of adult brain tumours: metabolite quantification and assignment of tumour biomarkers.

BACKGROUND: High-resolution magic angle spinning (HRMAS) NMR spectroscopy allows detailed metabolic analysis of whole biopsy samples for investigating tumour biology and tumour classification. Accurate biochemical assignment of small molecule metabolites that are "NMR visible" will improve our interpretation of HRMAS data and the translation of NMR tumour biomarkers to in-vivo studies. RESULTS: 1D and 2D 1H HRMAS NMR was used to determine that 29 small molecule metabolites, along with 8 macromolecule signals, account for the majority of the HRMAS spectrum of the main types of brain tumour (astrocytoma grade II, grade III gliomas, glioblastomas, metastases, meningiomas and also lymphomas). Differences in concentration of 20 of these metabolites were statistically significant between these brain tumour types. During the course of an extended 2D data acquisition the HRMAS technique itself affects sample analysis: glycine, glutathione and glycerophosphocholine all showed small concentration changes; analysis of the sample after HRMAS indicated structural damage that may affect subsequent histopathological analysis. CONCLUSIONS: A number of small molecule metabolites have been identified as potential biomarkers of tumour type that may enable development of more selective in-vivo 1H NMR acquisition methods for diagnosis and prognosis of brain tumours.

Water movements in the brain: role of aquaporins.

About 80% of the brain is water. This review discusses the importance of the three brain water-channel proteins (AQP1, AQP4, AQP9) in brain physiology. AQP1 is expressed in the choroid plexus and participates in forming cerebrospinal fluid. AQP4, found in astrocyte foot processes, glia limitans and ependyma, facilitates water movement into and out of the brain, accelerates astrocyte migration and alters neuronal activity. Recently, AQP4 autoantibodies were discovered in patients with neuromyelitis optica, a demyelinating disease, and are now being used to diagnose this condition. AQP9 is present in some glia and neurons, but its function is unclear. Finally, we discuss how the discovery of AQP activators and inhibitors will be the next major step in this field.

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.

Correlations between in vivo (1)H MRS and ex vivo (1)H HRMAS metabolite measurements in adult human gliomas.

PURPOSE: To assess how accurately ex vivo high-resolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy ((1)H MRS) from small biopsy tissues relate to in vivo (1)H MRS (from larger tumor volumes) in human astrocytomas. MATERIALS AND METHODS: In vivo (PRESS, TE = 30 msec) and ex vivo (presaturation) (1)H spectra of 17 human astrocytomas (4 grade II, 1 grade III and 12 glioblastomas) were quantified using LCModel. Concentrations of 11 metabolites and 2 lipid/macromolecules were retrospectively compared, with histogram analysis of the in vivo MRI data used to evaluate tumor heterogeneity. RESULTS: For homogeneous-appearing tumors, significant correlations were found between in vivo and ex vivo (1)H MRS concentrations of those metabolites known to be metabolically stable in postmortem tissues (eg, creatine, myo-inositol, total cholines, and the approximately 1.3 and 0.9 ppm lipids). Anaerobic glycolysis during biopsy surgical removal depletes the tissue of glucose, increasing alanine and lactate, and resulted in no correlation between these in vivo and ex vivo metabolite concentrations. CONCLUSION: Within defined limitations, ex vivo astrocytoma biopsy HRMAS (1)H spectra have similar metabolic profiles to that obtained in vivo and therefore detailed ex vivo characterization of glioma biopsies can directly relate to the original tumor.

Combined use of neuroradiology and 1H-MR spectroscopy may provide an intervention limiting diagnosis of glioblastoma multiforme.

PURPOSE: To evaluate the accuracy of (1)H-MR spectroscopy ((1)H-MRS) as an intervention limiting diagnostic tool for glioblastoma multiforme. GBM is the most common and aggressive primary brain tumor, with mean survival under a year. Oncological practice currently requires histopathological diagnosis before radiotherapy. MATERIALS AND METHODS: Eighty-nine patients had clinical computed tomography (CT) and MR imaging and 1.5T SV SE (1)H-MRS with PRESS localization for neuroradiological diagnosis and tumor classification with spectroscopic and automated pattern recognition analysis (TE 30 ms, TR 2000 ms, spectral width 2500 Hz and 2048 data points, 128-256 signal averages were acquired, depending on voxel size (8 cm(3) to 4 cm(3)). Eighteen patients from a cohort of 89 underwent stereotactic biopsy. RESULTS: The 18 stereotactic biopsies revealed 14 GBM, 2 grade II astrocytomas, 1 lymphoma, and 1 anaplastic astrocytoma. All 14 biopsied GBMs were diagnosed as GBM by a protocol combining an individual radiologist and an automated spectral pattern recognition program. CONCLUSION: In patients undergoing stereotactic biopsy combined neuroradiological and spectroscopic evaluation diagnoses GBM with accuracy that could replace the need for biopsy. We do not advocate the replacement of biopsy in all patients; instead our data suggest a specific intervention limiting role for the use of (1)H-MRS in brain tumor diagnosis.

Implementation of the European Working Time Directive in neurosurgery reduces continuity of care and training opportunities.

BACKGROUND: Implementation of the European Working Time Directive (EWTD) raises questions about reduced surgical training opportunities and lost continuity of patient care. We studied the effect that the EWTD has had in these areas for residents in the neurosurgical unit at St. George's Hospital, London, UK. METHODS: Case notes for 50 emergency and 50 elective operative admissions were randomly selected before and after implementation of an EWTD compliant resident roster (total, 200 episodes). Each was objectively scored for continuity of care from the operating surgeon. Rosters from 3 months before and after implementation were compared to assess training opportunities available. RESULTS: A significant reduction was observed in continuity of emergency care following introduction of the EWTD compliant roster (P < 0.009). The same proportion of residents consented and operated on elective cases; however, a significant reduction in continuity of postoperative care was observed (P < 0.0001). Resident training opportunities were substantially affected with reduced involvement in outpatient (72% vs. 60%) and operating sessions (79% vs. 63%) with their nominated consultant. CONCLUSIONS: The EWTD has had a marked adverse impact on continuity of care for neurosurgical patients at St. George's Hospital. Residents' training opportunities were reduced.

The clinical value of early postoperative MRI after lumbar spine surgery.

INTRODUCTION: MRI scanning has historically been considered difficult to interpret in the early period following lumbar spine surgery, and hence of limited value. We investigate the hypothesis that MRI scanning within 6 weeks of lumbar spine surgery cannot accurately diagnose neural compression in symptomatic patients, and define the utility of postoperative MRI in this context. METHODS: A series of 32 consecutive patients had early postoperative MRI following lumbar discectomy or laminectomy for continued, worsening or new symptoms of neural compression. The neuroradiologists' reports were evaluated for the reported presence of neural compression and confidence level (low, medium, high). These MRI findings were then compared to the patients' subsequent course and findings of any surgery performed. RESULTS: Twenty of 29 scans (69%) were confidently predictive of the correct treatment pathway (reoperation with positive finding or conservative treatment with a good outcome) whereas 3/3 (100%) patients who had conservative management despite the MRI confidently suggesting compression had poor outcome. The MRI is highly likely to influence management: 11/14 (79%) patients with scans suggesting neural compression had revision surgery and 18/18 (100%) patients with no neural compression on MRI were managed conservatively. CONCLUSIONS: Our data suggest that early MRI scanning after lumbar laminectomy or discectomy accurately detects neural compression at the surgery site in patients with continued or worsening symptoms.

Patient safety and image transfer between referring hospitals and neuroscience centres: could we do better?

INTRODUCTION: District general hospital scanners have historically been linked to regional neuroscience units for specialist opinions on scans and to make decisions on transfer of patients requiring neurosurgical management. The implementation of digital picture archiving and communication systems (PACS) in all hospitals in the UK has disrupted these dedicated links and technical and information governance issues have delayed reprovision of electronic transfer of images for rapid expert decision making in this group of patients. We studied improvement in image transfer to acute neurosurgery units over a 4-year period. METHODS: Four-year sequential review of national provision of image transfer facilities into neurosurgery units; observational study of delays associated with image transfer modalities in one representative tertiary referral centre. RESULTS: During the 4 years of study, all hospitals nationally have implemented digital PACS systems for image viewing. Remote image viewing facilities have gradually changed with dedicated image links being replaced by remote PACS access. However, a minority of referrals (12%) still require images to be physically transferred between hospitals using couriers for CD-ROMs. The detailed study within our own unit shows that this adds a mean delay of 5.8 h to decision making. CONCLUSIONS: Image transfer in neuroscience has been neglected following the shift to PACS servers. The recommendations of the 2004 Neuroscience Critical Care Report are unmet and patient safety is being threatened by a continued failure to implement a coordinated solution to this problem.

Semiautomatic tractography: motor pathway segmentation in patients with intracranial vascular malformations. Clinical article.

OBJECT: The visualization of white matter tracts using tractography has previously been achieved by displaying streamlines that pass between regions of interest (ROIs). These techniques require a significant amount of user interaction, and their results are entirely dependent on the positioning of the ROIs. Furthermore, in patients with intracerebral hemorrhage secondary to intracranial vascular malformation, there is often significant cerebral edema and susceptibility artifact from the hematoma, which degrade the reliability of tractography. In this paper, the authors' objectives were to visualize the motor pathways of patients with hemorrhagic and nonhemorrhagic vascular malformations by using a novel semiautomated technique that functions without the need for multiple ROIs. METHODS: The authors investigated the tractography appearance of the descending motor pathways in 6 patients with intracranial vascular malformations. Of these patients 4 presented with a spontaneous intracranial hemorrhage, 2 of whom were clinically hemiparetic. Diffusion tensor imaging was performed using a 1.5-T clinical MR imaging system, and whole-brain tractography was performed after reconstruction of the data. A fractional anisotropy threshold of 0.05 was used to terminate the tractography. The semiautomatic motor pathway segmentation technique required definition of a single voxel within the corticospinal tract of the medulla from which the descending motor pathways were automatically defined by grouping together all streamlines within the entire image with a geometry similar to that of the single streamline generated from this initial voxel. The results of this segmentation were then visually assessed and compared with the patient's motor function. RESULTS: The authors' semiautomatic algorithm consistently visualized the location of the descending motor pathways in patients with nonhemorrhagic and hemorrhagic vascular malformations. In 1 patient whose complete right hemiplegia (complete paralysis) was caused by a large left frontal hematoma that bisected the descending motor pathways, the authors were unable to reconstruct the motor pathways due to severe tract degeneration. However, in all cases in which motor function was intact or only mildly impaired, the technique clearly delineated the motor pathways, even in the presence of large anatomical displacement by the vascular abnormality or associated hemorrhage. CONCLUSIONS: Semiautomatic tractography allows consistent and rapid demonstration of the descending motor pathways in patients with hemorrhagic and nonhemorrhagic intracranial vascular malformations. The technique allows the use of a comparatively low fractional anisotropy threshold and does not require the definition of multiple ROIs. These techniques may help to improve the clinical feasibility and potentially the reliability of tractography for the evaluation of patients with intracranial vascular malformations as well as other space-occupying lesions of the brain.

Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice.

Aquaporin-4 (AQP4) is a water channel protein expressed in astrocytes throughout the CNS. In brain, AQP4 facilitates water balance and glial scar formation, which are important determinants of outcome after injury. Here, we provide evidence for AQP4-dependent spinal cord swelling following compression injury, resulting in remarkably improved outcome in AQP4-null mice. Two days after transient T6 spinal cord compression injury, wild-type mice developed more severe hindlimb weakness than AQP4-null mice, as assayed by the Basso open-field motor score, inclined plane method and footprint analysis. Basso motor scores were 1.3 +/- 0.5 (wild-type) versus 4.9 +/- 0.6 (AQP4-null) (SE, P < 0.001). Improved motor outcome in AQP4-null mice was independent of mouse strain and persisted at least 4 weeks. AQP4-null mice also had improved sensory outcome at 2 days, as assessed by spinal somatosensory evoked responses, with signal amplitudes approximately 10 microV (uninjured), 1.7 +/- 0.7 microV (wild-type) and 6.4 +/- 1.3 microV (AQP4-null) (P < 0.01). The improved motor and sensory indices in AQP4-null mice corresponded to remarkably less neuronal death and myelin vacuolation, as well as reduced spinal cord swelling and intraparenchymal spinal cord pressure measured at T6 at 2 days after injury. AQP4 immunoreactivity at the injury site was increased in grey and white matter at 48 h. Taken together, our findings indicate that AQP4 provides a major route for excess water entry into the injured spinal cord, which in turn causes spinal cord swelling and elevated spinal cord pressure. Our data suggest AQP4 inhibition or downregulation as novel early neuroprotective manoeuvres in spinal cord injury.

Toward accurate quantification of metabolites, lipids, and macromolecules in HRMAS spectra of human brain tumor biopsies using LCModel.

High-resolution magic angle spinning (HRMAS) (1)H MR spectroscopy of biopsy samples provides detailed biochemical profiles that can be related to the lower-resolution spectra obtained in vivo. Nevertheless, there is still significant overlap of many resonance peaks and contributions from broad lipid and macromolecule resonances that impede accurate quantification. We determined a minimum set of in vitro metabolite and simulated lipid and macromolecule resonances needed for LCModel analysis and quantification of brain tumor biopsy HRMAS spectra. We also demonstrate the quality of the LCModel fit for the four main brain tumor types (astrocytoma grade II, glioblastoma, metastasis, and meningioma). Our data suggest that when fitting resonances of coupled spins systems in high-resolution spectra, interactions between metabolites and the macromolecular environment of the biopsy may cause small peak shifts not found in the solution spectra. However, LCModel is shown to provide a user-independent method of analyzing HRMAS brain tumor spectra.