Arterial spin-labeling and MR spectroscopy in the differentiation of gliomas.

BACKGROUND AND PURPOSE: Noninvasive grading of gliomas remains a challenge despite its important role in the prognosis and management of patients with intracranial neoplasms. In this study, we evaluated the ability of cerebral blood flow (CBF)-guided voxel-by-voxel analysis of multivoxel proton MR spectroscopic imaging ((1)H-MRSI) to differentiate low-grade from high-grade gliomas. MATERIALS AND METHODS: A total of 35 patients with primary gliomas (22 high grade and 13 low grade) underwent continuous arterial spin-labeling perfusion-weighted imaging (PWI) and (1)H-MRSI. Different regions of the gliomas were categorized as "hypoperfused," "isoperfused," and "hyperperfused" on the basis of the average CBF obtained from contralateral healthy white matter. (1)H-MRSI indices were computed from these regions and compared between low- and high-grade gliomas. Using a similar approach, we applied a subgroup analysis to differentiate low- from high-grade oligodendrogliomas because they show different physiologic and genetic characteristics. RESULTS: Cho(glioma (G)/white matter (WM)), Glx(G/WM), and Lip+Lac(G)/Cr(WM) were significantly higher in the "hyperperfused" regions of high-grade gliomas compared with low-grade gliomas. Cho(G/WM) and Lip+Lac(G)/Cr(WM) were also significantly higher in the "hyperperfused" regions of high-grade oligodendrogliomas. However, metabolite ratios from the "hypoperfused" or "isoperfused" regions did not exhibit any significant differences between high-grade and low-grade gliomas. CONCLUSION: The results suggest that (1)H-MRSI indices from the "hyperperfused" regions of gliomas, on the basis of PWI, may be helpful in distinguishing high-grade from low-grade gliomas including oligodendrogliomas.

Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia.

Traumatic brain injury (TBI) can be associated with memory impairment, cognitive deficits, or seizures, all of which can reflect altered hippocampal function. Whereas previous studies have focused on the involvement of neuronal loss in post-traumatic hippocampus, there has been relatively little understanding of changes in ionic homeostasis, failure of which can result in neuronal hyperexcitability and abnormal synchronization. Because glia play a crucial role in the homeostasis of the brain microenvironment, we investigated the effects of TBI on rat hippocampal glia. Using a fluid percussion injury (FPI) model and patch-clamp recordings from hippocampal slices, we have found impaired glial physiology 2 d after FPI. Electrophysiologically, we observed reduction in transient outward and inward K(+) currents. To assess the functional consequences of these glial changes, field potentials and extracellular K(+) activity were recorded in area CA3 during antidromic stimulation. An abnormal extracellular K(+) accumulation was observed in the post-traumatic hippocampal slices, accompanied by the appearance of CA3 afterdischarges. After pharmacological blockade of excitatory synapses and of K(+) inward currents, uninjured slices showed the same altered K(+) accumulation in the absence of abnormal neuronal activity. We suggest that TBI causes loss of K(+) conductance in hippocampal glia that results in the failure of glial K(+) homeostasis, which in turn promotes abnormal neuronal function. These findings provide a new potential mechanistic link between traumatic brain injury and subsequent development of disorders such as memory loss, cognitive decline, seizures, and epilepsy.

Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation.

Cognitive deficits persist in patients who survive traumatic brain injury (TBI). Lateral fluid percussion brain injury in the mouse, a model of human TBI, results in hippocampal-dependent cognitive impairment, similar to retrograde amnesia often associated with TBI. To identify potential substrates of the cognitive impairment, we evaluated regional neuronal loss, regional hippocampal excitability and inhibitory synaptic transmission. Design-based stereology demonstrated an approximate 40% loss of neurons through all subregions of the hippocampus following injury compared with sham. Input/output curves recorded in slices of injured brain demonstrated increased net synaptic efficacy in the dentate gyrus in concert with decreased net synaptic efficacy and excitatory postsynaptic potential-spike relationship in area CA1 compared with sham slices. Pharmacological agents modulating inhibitory transmission partially restored regional injury-induced alterations in net synaptic efficacy. Both evoked and spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in surviving dentate granule neurons were smaller and less frequent in injured brains than in uninjured brains. Conversely, both evoked and spontaneous mIPSCs recorded in surviving area CA1 pyramidal neurons were larger in injured brains than in uninjured brains. Together, these alterations suggest that regional hippocampal function is altered in the injured brain. This study demonstrates for the first time that brain injury selectively disrupts hippocampal function by causing uniform neuronal loss, inhibitory synaptic dysfunction, and regional, but opposing, shifts in circuit excitability. These changes may contribute to the cognitive impairments that result from brain injury.

Acute cytoskeletal alterations and cell death induced by experimental brain injury are attenuated by magnesium treatment and exacerbated by magnesium deficiency.

Traumatic brain injury results in a profound decline in intracellular magnesium ion levels that may jeopardize critical cellular functions. We examined the consequences of preinjury magnesium deficiency and post-traumatic magnesium treatment on injury-induced cytoskeletal damage and cell death at 24 h after injury. Adult male rats were fed either a normal (n = 24) or magnesium-deficient diet (n = 16) for 2 wk prior to anesthesia and lateral fluid percussion brain injury (n = 31) or sham injury (n = 9). Normally fed animals were then randomized to receive magnesium chloride (125 micromol, i.v., n = 10) or vehicle solution (n = 11) at 10 min postinjury. Magnesium treatment reduced cortical cell loss (p < 0.05), cortical alterations in microtubule-associated protein-2 (MAP-2) (p < 0.05), and both cortical and hippocampal calpain-mediated spectrin breakdown (p < 0.05 for each region) when compared to vehicle treatment. Conversely, magnesium deficiency prior to brain injury led to a greater area of cortical cell loss (p < 0.05 compared to vehicle treatment). Moreover, brain injury to magnesium-deficient rats resulted in cytoskeletal alterations within the cortex and hippocampus that were not observed in vehicle- or magnesium-treated animals. These data suggest that cortical cell death and cytoskeletal disruptions in cortical and hippocampal neurons may be sensitive to magnesium status after experimental brain injury, and may be mediated in part through modulation of calpains.

The use of antibodies targeted against the neurofilament subunits for the detection of diffuse axonal injury in humans.

Axonal injury is a common feature of human traumatic brain injury. Typically, damaged axons cannot be recognized unless a patient survives the injury by at least 10-12 hours (h). Limitations associated with the use of the traditional silver methods have been linked with this inability to recognize early posttraumatic reactive axonal change. Recently, we reported that antibodies targeting the neurofilament subunits proved useful in recognizing early traumatically induced axonal change in traumatically brain-injured animals. Accordingly, in the present communication, we employed antibodies to detect at the light microscopic level the 68 kD Nf-L and 170-200 kD Nf-H neurofilament subunits in head-injured patients who survived the traumatic event for periods ranging from 6 h to 59 days. Antibodies targeting all of the above-described subunits revealed a progression of reactive axonal change. Antibodies to the 68 kD subunit proved most useful, as they were not complicated by concomitant immunoreactivity in surrounding nuclei and/or dendritic and somatic elements. These immunocytochemical strategies revealed, at 6 h postinjury, focally swollen axons which appeared intact. By 12 h, this focal swelling had progressed to disconnection, with the immunoreactive swelling undergoing further expansion over 1 week postinjury. These findings demonstrate the utility of the previously described immunocytochemical strategies for detecting reactive axonal change in brain-injured humans, particularly in the early posttraumatic course. More importantly, these methods also demonstrate in humans that reactive axonal change is not necessarily caused by traumatically induced tearing.

A review and rationale for the use of genetically engineered animals in the study of traumatic brain injury.

The mechanisms underlying secondary cell death after traumatic brain injury (TBI) are poorly understood. Animal models of TBI recapitulate many clinical and pathologic aspects of human head injury, and the development of genetically engineered animals has offered the opportunity to investigate the specific molecular and cellular mechanisms associated with cell dysfunction and death after TBI, allowing for the evaluation of specific cause-effect relations and mechanistic hypotheses. This article represents a compendium of the current literature using genetically engineered mice in studies designed to better understand the posttraumatic inflammatory response, the mechanisms underlying DNA damage, repair, and cell death, and the link between TBI and neurodegenerative diseases.

Bilateral growth-related protein expression suggests a transient increase in regenerative potential following brain trauma.

The potential of mature central nervous system (CNS) neurons to regenerate after injury represents a fundamental issue in neurobiology. The regional expression of proteins associated with axonal elongation, such as microtubule-associated protein 1B (MAP1B), its phosphorylated isoform (MAP1B-P), growth-associated protein 43 (GAP-43), and polysialylated neural cell-adhesion molecule (PSA-NCAM), was examined using immunohistochemistry from 24 hours to 2 months following lateral fluid percussion brain injury of moderate severity (2.4-2.6 atmospheres) in anesthetized rats. Uninjured (control) rats were subjected to anesthesia and surgery without injury or were subjected to anesthesia alone. Within the site of maximal injury, only increases in MAP1B and MAP1B-P were observed. Increased immunoreactivity was observed bilaterally for all growth-related proteins that were evaluated. By 24 hours postinjury, MAP1B and MAP1B-P increased within the cortex (P < 0.01) and the hippocampus (P < 0.001), whereas MAP1B-P also was elevated in the thalamus (P < 0.05). Within the dentate gyrus, increased immunoreactivity was observed for all proteins examined. By 48 hours postinjury, GAP-43 was elevated bilaterally within the inner molecular layers of the dentate gyrus (P < 0.005) and within the stratum lacunosum moleculare (P < 0.01), the stratum radiatum (P < 0. 005), and the stratum oriens (P < 0.05) of the hippocampus. Increased numbers of PSA-NCAM-labeled neurons were observed in the granule cell layers of the dentate gyrus from 48 hours through 2 weeks postinjury (P < 0.0005). The bilateral nature of increased expression of growth-related proteins differs from unilateral patterns of neuronal degeneration previously characterized for the lateral fluid-percussion model of brain injury. Taken together, these results suggest the existence of a temporary posttraumatic state in which the CNS may have increased regenerative potential. Enhancement of such a response may be one therapeutic strategy in treating CNS injury.

Mild traumatic brain injury induces apoptotic cell death in the cortex that is preceded by decreases in cellular Bcl-2 immunoreactivity.

Although mild traumatic brain injury is associated with behavioral dysfunction and histopathological alterations, few studies have assessed the temporal pattern of regional apoptosis following mild brain injury. Anesthetized rats were subjected to mild lateral fluid-percussion brain injury (1.1-1.3 atm), and brains were evaluated for the presence of in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling, TUNEL) and morphologic characteristics of apoptotic cell death (nuclear and cytoplasmic condensation, presence of apoptotic bodies). Significant numbers of apoptotic TUNEL(+) cells were observed in the injured parietal cortex and underlying white matter up to 72 h post-injury (P<0.05 compared to sham-injured-injured), with maximal numbers present at 24 h. Apoptosis was confirmed by the presence of 180-200 bp nuclear DNA fragments in tissue homogenates. The appearance of apoptotic TUNEL(+) cells in the injured cortex was preceded by a marked decrease in immunoreactivity for the anti-cell death protein, Bcl-2, as early as 2 h post-injury. This decrease in cellular Bcl-2 staining was not accompanied by a concomitant loss of staining for the pro-cell death Bax protein, suggesting that post-traumatic neuronal death in the cortex may be dependent on altered cellular ratios of Bcl-2:Bax. In the hippocampus, no significant increase in apoptotic TUNEL(+) cells was observed compared to sham-injured-injured animals. However, selective neuronal loss was evident in the CA3 region at 24 h post-injury, that was preceded by an overt loss of neuronal Bcl-2 immunoreactivity at 6 h. No changes in either cellular Bcl-2 or Bax expression were observed in the thalamus or white matter at any time post-injury. Taken together from these data, we suggest that apoptosis contributes to cell death in both gray and white matter, and that decreases in cellular Bcl-2 may, in part, be associated with both apoptotic and non-apoptotic cell death following mild brain trauma.

Epidural hemorrhage: is it abuse?

OBJECTIVE: To determine whether children presenting with epidural hemorrhage (EDH) are as likely to have been abused as are children presenting with subdural hemorrhage (SDH). DESIGN: Retrospective chart review. SETTING: Level I regional trauma center and a regional children's hospital. PATIENTS: All children at both institutions 3 years old or younger with a diagnosis of EDH or SDH identified by a search of the computerized trauma registry and hospital medical records from 1985 through 1991. MEASUREMENT AND RESULTS: Complete records were found for 93 of 94 eligible subjects. The diagnosis of accidental or inflicted injury was ascertained from the patient's hospital medical record or the records of Child Protective Services. Of all subjects (n = 93), 52% (48/93) were male and the median age was 15 months. Abuse was diagnosed in 47% (28/59) of children with SDH and 6% (2/34) of those with EDH. Other significant injuries were found in 47% of children with SDH and 18% of children with EDH. There was no statistically significant difference between the two groups with respect to the likelihood of identifying a skull fracture, the need for surgical evacuation of the hemorrhage, or mortality. CONCLUSIONS: Our data are consistent with current biomechanical concepts of intracranial injury. EDHs results from brief linear contact forces that commonly occur in unintentional falls. SDHs are caused by global high-energy rotational acceleration/deceleration forces that are commonly generated in episodes of abuse. Compared with SDH, EDH rarely results from abuse.

Brain SPECT and the effect of cerebral angioplasty in delayed ischemia due to vasospasm.

Cerebral vasospasm is a major determinant of outcome after subarachnoid hemorrhage (SAH). Brain SPECT with 99mTc-HMPAO was obtained before and after cerebral angioplasty in 10 patients with delayed ischemia due to vasospasm. Eight patients had clinically evident neurologic improvement after the procedure. Visual interpretation and an internal-reference (cerebellum), manual, semi-quantitative region of interest (ROI) analysis revealed improvement of regional cerebral blood flow (rCBF) in 9 out of 10. There were disagreements between the visual and ROI analysis in the two that did not improve clinically. For all 10, the average increase per anterior circulation vessel dilated (n = 17) was 8.8% by comparison of the corticocerebellar ratios. For the eight that improved, the average increase was 10.5%. Brain SPECT is valuable for evaluating delayed cerebral ischemia caused by vasospasm after SAH and is useful to document the changes in rCBF induced by angioplasty. It is possible that SPECT may be useful to detect critical reductions in perfusion before clinical deficits develop, thereby offering the potential to identify candidates for early treatment with angioplasty.

Regional patterns of blood-brain barrier breakdown following central and lateral fluid percussion injury in rodents.

In order to determine how fluid percussion injury (FPI) effect is distributed throughout the brain, and to assess the extent to which individual brain nuclei and regions are affected, the pattern of blood-brain barrier (BBB) breakdown was determined in groups with different injury cannula locations. Injury cannulas were placed either at midline, or 2 or 4 mm to the side. One hour following FPI, animals were given horseradish peroxidase (HRP) and the brains were stained using the TMB method. The distribution of HRP leakage varied considerably depending upon the location of the injury cannula, however, there were also common sites of leakage among these groups. Locally the cortex and hippocampus under and adjacent to the injury cannula were heavily affected, with a clear asymmetric effect in the lateral cannula groups. Common sites of leakage included the dorsal thalamus, septal area, pontine tegmentum, periaqueductal gray, substantia nigra, and narrow zones adjacent to ventricular or cisternal surfaces. The hippocampus tended to be involved at greater distances than the cerebral cortex. The cervicomedullary junction proved to be especially vulnerable to FPI with extensive HRP leakage, and petechial hemorrhage ranging from minor to fatal coalescent hemorrhage. A very narrow threshold separated these outcomes. Neurologic impairment of the animals correlated most directly with the extent of cervico-medullary junction injury. Thus FPI produces a mix of local and diffuse effects on the BBB. Injury at the cervicomedullary junction is a prominent effect and is the limiting factor in trying to establish more severe diffuse injury.

Adaptation of the fluid percussion injury model to the mouse.

Fluid percussion injury (FPI) is a well-characterized experimental model of traumatic brain injury (TBI) in the rat. Many pathophysiologic consequences and mechanisms of recovery after TBI rely on neurochemical pathways that can be examined in genetically altered mice. Therefore, FPI applied to mice may be a useful experimental tool to investigate TBI at the molecular level. In the present study, we establish FPI as a viable model of TBI in the mouse by characterizing acute neurological, histopathological, and behavioral changes. Right-sided parasagittal FPI or sham treatment was administered in male C57BL/6 mice. Acute neurological evaluation revealed righting reflexes in the injured animals (p < 0.001). Deficits in spatial learning and memory were observed in the Morris water maze (MWM) 5 and 6 days after injury. A novel MWM data analysis protocol is described. The injured group (n = 18) demonstrated impaired performance in the MWM during acquisition (p < 0.05) and probe trials (p < 0.025) compared to sham animals (n = 16). At 7 days postinjury, glial fibrillary acidic protein immunohistochemistry revealed intense cortical, callosal, and hippocampal gliosis. The modified Gallyas silver degeneration stain consistently labeled cell bodies and terminals throughout the ipsilateral cortex, axons in the gray matter-white matter interface above the corpus callosum and within the corpus callosum bilaterally, and terminals and fibers in the thalamus bilaterally. Additionally, the mouse FPI model described is immediately employable in labs already using the FPI rat model with no modifications to a pre-existing FPI apparatus.

Fluid percussion injury causes loss of forebrain choline acetyltransferase and nerve growth factor receptor immunoreactive cells in the rat.

Memory dysfunction is a common sequela of human traumatic brain injury (TBI). Cholinergic forebrain neurons are recognized for their role in memory. We tested the hypothesis that forebrain cholinergic neurons are vulnerable to fluid percussion injury (FPI), a model of human TBI. Rodents were subjected to a moderate parasagittal FPI, sham injury, or fimbria/fornix axotomy and then killed 10 days after the procedure. Additional animals underwent FPI or sham injury and were killed 7, 14, and 28 days after the procedure. Neurons in the medial septal nucleus and vertical limb of the nucleus of the diagonal band of Broca were identified and quantitated using choline acetyltransferase (ChAT) and low affinity nerve growth factor receptor (NGF-R) immunohistochemistry. Our results showed a significant decrease in ChAT (17% +/- 5%) and NGF-R (24% +/- 8%) immunoreactive cells in FPI animals killed after 10 days when compared to sham-injured animals. Animals undergoing fimbria/fornix axotomy showed a greater reduction in ChAT (53% +/- 13%) and NGF-R (55% +/- 5%) immunoreactive cells 10 days postaxotomy. The number of ChAT and NGF-R immunoreactive neurons was reduced at all time points. However, statistical significance was present 10 and 14 days postinjury for ChAT immunoreactive neurons and 10 days only for NGF-R immunoreactive neurons. These studies have shown that FPI produces transient loss of ChAT and NGF-R immunoreactive neurons.

Ultrastructural studies of diffuse axonal injury in humans.

Diffuse axonal injury (DAI) is observed commonly in traumatically brain injured humans. However, traditional histologic methods have proven of limited use in identifying reactive axonal change early (< 12 h) in the posttraumatic course. Recently, we have reported, in both humans and animals, that antibodies targeting neurofilament subunits are useful in the light microscopic recognition of early reactive change. In the present study, we extend our previous efforts in humans by analyzing the progression of traumatic brain injury (TBI)-induced axonal change at the ultrastructural level. This effort was initiated to follow the subcellular progression of reactive axonal change in humans and to determine whether this progression parallels that described in animals. Two commercially prepared antibodies were used to recognize reactive axonal change in patients surviving from 6 to 88 h. The NR4 antibody was used to target the light neurofilament subunit (NF-L), and the SMI32 antibody was used to target the heavy neurofilament subunit (NF-H). Plastic-embedded tissue sections were screened for evidence of reactive axonal change, and once identified, this reactive change was analyzed at the ultrastructural level. At 6 h survival, focally enlarged, immunoreactive axons with axolemmal infolding or disordered neurofilaments were seen within fields of axons exhibiting no apparent abnormality. By 12 h, some axons exhibited continued neurofilamentous misalignment, pronounced immunoreactivity, vacuolization, and, occasionally, disconnection. At later stages, specifically 30 and 60 h survival, further accumulation of neurofilaments and organelles had led to the further expansion of the axis cylinder, and clearly disconnected reactive swellings were recognized. These contained a dense core of disordered immunoreactive neurofilaments partially encompassed by a cap of less densely aggregated organelles. At 88 h, the reactive axons were larger and elongated, consistent with the continued delivery of organelles by axoplasmic transport. At the later time points, considerable heterogeneity was observed, with focally enlarged disconnected axons being observed in relation to axons showing less advanced reactive change. Our findings suggest that neurofilamentous disruption is a pivotal event in axonal injury.

Rapid infusion system for neurosurgical treatment of massive intraoperative hemorrhage.

Using an illustrative case of severe closed head injury that resulted in a posterior fossa epidural hematoma (EDH) and supratentorial epidural/subdural hematomas (SDH), the massive blood losses associated with operative repair of the torn sigmoid sinus and the significant fluid losses associated with refractory diabetes insipidus were treated by the intraoperative use of the Rapid Infusion System (RIS, Haemonetics). The RIS can rapidly infuse warm blood, crystalloid, or colloid at rates up to 1.5 L/min, thereby limiting the commonly associated hypotension, hypothermia, and coagulopathies. During the suboccipital craniectomy for evacuation of the EDH and repair of the sigmoid sinus, the patient required 18 units of blood replacement secondary to a large tear in the sigmoid sinus. During a separate craniotomy for evacuation of the SDH, the patient also developed diabetes insipidus, which increased the operative fluid replacement to 39 L. Despite these massive blood and fluid losses, the RIS limited the hypotension to less than 2 min and prevented hypothermia and the frequently associated coagulopathies. When used in a neurosurgical setting associated with massive blood and/or fluid losses, the RIS accomplishes three important objectives: (1) rapid infusion of intravenous fluids for maintaining perfusion pressure, (2) rapid warming of fluids despite high intravenous infusion rates of cold crystalloids, thereby preventing intraoperative hypothermia, and (3) continuous monitoring of infusion rates and totals.

P-selectin blockade following fluid-percussion injury: behavioral and immunochemical sequelae.

Traumatic brain injury (TBI) can cause polymorphonuclear leukocyte (PMN) migration into brain parenchyma, mediating various cytodestructive mechanisms. We examined the effect of blocking leukocyte/endothelial cell adhesion molecules (CAMs) on the anatomic and behavioral sequelae in lateral fluid-percussion injury in rats. Monoclonal antibodies (MAb) directed against a functional (PB1.3) or nonfunctional (PNB1.6) epitope on endothelial P-selectin were used as treatments. Subjects were tested in the Morris water maze (MWM) at 7 and 14 days postinjury then immunohistochemistry was performed using antibodies that recognize ChAT, GFAP and OX-42. A second set of animals underwent myeloperoxidase (MPO) assay in the brain parenchyma and a third set was used to examine neutrophil migration using the MAb RP-3. Time in quadrant, but not escape latency or proximity improved with PB1.3 (p < 0.05). Similarly, PB1.3 reduced MPO levels after injury (p < 0.05), in the ipsilateral cortex. No significant difference occurred in neutrophil counts in cortex, corpus callosum, hippocampus, and thalamus between injured only rats and injured rats treated with PB1.3. Quantitative analysis of cholinergic cells in the medial septum showed a protective effect by PB1.3. Densitometry readings of GFAP and OX-42 immunolabeling revealed no discernible differences between the treated and untreated injured rats. Qualitatively, there was no difference in microglia or astrocyte response to treatment. Treatment with P-selectin blockade in brain-injured rats may reduce PMN migration into brain, help preserve cholinergic immunolabeling of medial septal nucleus neurons, and may alleviate mnemonic deficits.

Effects of chronic, post-injury Cyclosporin A administration on motor and sensorimotor function following severe, experimental traumatic brain injury.

PURPOSE: Cyclosporin A (CsA) is widely used in clinical situations to attenuate graft rejection following organ and central nervous system transplantation. Previous studies demonstrated that CsA administration is neuroprotective in models of traumatic brain injury (TBI). However, no studies, to date, have evaluated the influence of post-injury CsA administration on behavioral recovery after TBI. METHODS: Rats (n = 33) were anesthetized and subjected to severe, lateral fluid percussion brain injury. Fifteen minutes thereafter, animals were randomized to receive the first of 28 daily injections of either CsA (10 mg/kg, ip) or saline. Sham-operated animals (n = 14) were anesthetized and surgically prepared without injury and treated daily either with CsA or saline. Motor and sensorimotor functions were assessed at one day before and two days after injury, and weekly thereafter up to 4 wks post-injury. Cognition was assessed at 1 and 4 wks post-injury using a Morris Water Maze test. RESULTS: Injured animals showed significant impairments in motor, sensorimotor and cognitive function over the 4-week post-injury period. Injured animals treated with CsA showed a significant improvement in motor function assessed using a composite neuroscore (at day 28) and in sensorimotor function assessed using a sticky paper test (at days 2, 14, and 28) (p < 0.05, when compared to vehicle treated, injured animals). No beneficial effects on cognitive function were observed following CSA administration. CONCLUSION: These data suggest that daily post-injury treatment with CsA improves certain aspects of motor and sensorimotor function following experimental TBI.

Evidence disputing the importance of excitotoxicity in hippocampal neuron death after experimental traumatic brain injury.

The hippocampus is selectively vulnerable to experimental traumatic brain injury (TBI). Beneficial effects of glutamate receptor antagonists and increased extracellular levels of glutamate have suggested that glutamate-mediated excitotoxicity may be responsible for this selective damage. In order to clarify this important issue, we applied a severe parasagittal fluid percussion injury (FPI) to strains of mice shown to be susceptible and resistant to kainic acid (KA)-induced excitotoxic hippocampal damage. Dystrophic neurons were present by 10 min after FPI in the hippocampi of both strains. Damaged hippocampal neurons were absent at 4 days and 7 days. Additionally, there was no significant difference (p = 1.00) in CA3 neuron survival between KA-susceptible and -resistant mice at 4 days. In conclusion, excitotoxicity does not significantly contribute to hippocampal neuron loss after FPI and, in contrast to classic studies of excitotoxicity in vivo, the pattern of hippocampal cell death after TBI is extremely acute.

Improvement in the organ donation rate at a large urban trauma center.

OBJECTIVE: To implement and then determine the efficacy of a "hospital development" (HD) plan designed to increase organ donation rates at an urban trauma center. DESIGN/SETTING: Retrospective reviews of all deaths at an urban, level I trauma center for 1991 to 1994. SUBJECTS: Potential organ donors were identified by standardized criteria, and the reasons why potential donors did not become actual organ donors ("nonproductive donors") were categorized. Actual donors were defined as individuals in whom one transplantable organ was recovered. Results also were expressed as percentages of potential donors for each year. Changes in actual donor numbers and in nonproductive donor categories were compared for the "pre-HD" (1991-1992) and "post-HD" (1993-1994) periods. INTERVENTION: The HD plan had six components: identification of key contact individuals, development and modification of relevant hospital policies, improvement in procurement agency visibility in hospital units, education of hospital staff regarding organ donation, institution of early on-site donor evaluations, and provision of feedback to hospital staff about the disposition of potential organ donors. RESULTS: Institution of the HD plan was associated with a highly significantly increase in actual donors for the post-HD period as compared with the pre-HD period (P < .001), and pre-HD and post-HD donor rates were 26.1% and 49.5%, respectively. This increase was due primarily to a marked improvement in hospital staff identification and referral of potential donors (P < .001). CONCLUSIONS: A coordinated plan incorporating continuing staff education, organ donation policy refinement, and increased visibility and availability of organ procurement agency personnel can substantially increase organ donation at an urban trauma center.