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Donald W Marion

Publications and source records attributed to Donald W Marion.

At least 19 recordsLinked to original sources
PubMed2003

Caspase-8 expression and proteolysis in human brain after severe head injury.

Programmed cell death involves a complex and interrelated cascade of cysteine proteases termed caspases that are synthesized as inactive zymogens, which are proteolytically processed to active enzymes. Caspase-8 is an initiator caspase that becomes activated when Fas death receptor-Fas ligand (FasL) coupling on the cell surface leads to coalescence of a "death complex" perpetuating the programmed cell death cascade. In this study, brain tissue samples removed from adult patients during the surgical management of severe intracranial hypertension after traumatic brain injury (TBI; n=17) were compared with postmortem control brain tissue samples (n=6). Caspase-8 mRNA was measured by semiquantitative reverse transcription and polymerase chain reaction, and caspase-8 protein was examined by Western blot and immunocytochemistry. Fas and FasL were also examined using Western blot. Caspase-8 mRNA and protein were increased in TBI patients vs. controls, and caspase-8 protein was predominately expressed in neurons. Proteolysis of caspase-8 to 20-kDa fragments was seen only in TBI patients. Fas was also increased after TBI vs. control and was associated with relative levels of caspase-8, supporting formation of a death complex. These data identify additional steps in the programmed cell death cascade involving Fas death receptors and caspase-8 after TBI in humans.

Age Factors↗
PubMed2003

Alterations in inducible 72-kDa heat shock protein and the chaperone cofactor BAG-1 in human brain after head injury.

The stress response in injured brain is well characterized after experimental ischemic and traumatic brain injury (TBI); however, the induction and regulation of the stress response in humans after TBI remains largely undefined. Accordingly, we examined injured brain tissue from adult patients (n = 8) that underwent emergent surgical decompression after TBI, for alterations in the inducible 72-kDa heat shock protein (Hsp70), the constitutive 73-kDa heat shock protein (Hsc70), and isoforms of the chaperone cofactor BAG-1. Control samples (n = 6) were obtained postmortem from patients dying of causes unrelated to CNS trauma. Western blot analysis showed that Hsp70, but not Hsc70, was increased in patients after TBI versus controls. Both Hsp70 and Hsc70 coimmunoprecipitated with the cofactor BAG-1. The 33 and 46, but not the 50-kDa BAG-1 isoforms were increased in patients after TBI versus controls. The ratio of the 46/33-kDa isoforms was increased in TBI versus controls, suggesting negative modulation of Hsp70/Hsc70 protein refolding activity in injured brain. These data implicate induction of the stress response and its modulation by the chaperone cofactor and Bcl-2 family member BAG-1, after TBI in humans.

Adolescent↗
PubMed2003

Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats.

OBJECTIVES: To determine whether transient, moderate hypothermia is beneficial after traumatic brain injury in fentanyl-anesthetized rats. DESIGN: Prospective, randomized study. SETTING: University-based animal research facility. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: All rats were intubated, mechanically ventilated, and anesthetized with fentanyl (10 microg/kg intravenous bolus and then 50 microg.kg(-1).hr(-1) infusion). Controlled cortical impact was performed to the left parietal cortex, followed immediately by 1 hr of either normothermia (brain temperature 37 +/- 0.5 degrees C) or hypothermia (brain temperature 32 +/- 0.5 degrees C). Hypothermic rats were rewarmed gradually over 1 hr. Fentanyl anesthesia and mechanical ventilation were continued in both groups until the end of rewarming (2 hrs after traumatic brain injury). MEASUREMENTS AND MAIN RESULTS: Histologic assessment performed 72 hrs after traumatic brain injury was the primary outcome variable. Secondary outcome variables were physiologic variables monitored during the first 2 hrs after traumatic brain injury and plasma catecholamine and serum fentanyl concentrations measured at the end of both hypothermia and rewarming (1 and 2 hrs after traumatic brain injury). Contusion volume was larger in hypothermic vs. normothermic rats (44.3 +/- 4.2 vs. 28.6 +/- 4.0 mm, p <.05), but hippocampal neuronal survival did not differ between groups. Physiologic variables did not differ between groups. Plasma dopamine and norepinephrine concentrations were increased at the end of hypothermia in hypothermic (vs. normothermic) rats (p <.05), indicating that hypothermia augmented the systemic stress response. Similarly, serum fentanyl concentrations were higher in hypothermic (vs. normothermic) rats at the end of both hypothermia and rewarming (p <.05), demonstrating that hypothermia reduced the clearance and/or metabolism of fentanyl. CONCLUSIONS: Moderate hypothermia was detrimental after experimental traumatic brain injury in fentanyl-anesthetized rats. Since treatment with hypothermia has provided reliable benefit in experimental traumatic brain injury with inhalational anesthetics, these results indicate that the choice of anesthesia/analgesia after traumatic brain injury may dramatically influence response to other therapeutic interventions, such as hypothermia. Given that narcotics commonly are administered to patients after severe traumatic brain injury, this study may have clinical implications.

Anesthesia, Intravenous↗
PubMed2003

Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury.

OBJECTIVE: To test the hypothesis that etomidate treatment improves functional, cognitive, and histologic outcome after experimental traumatic brain injury. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Traumatic brain injury was produced by controlled cortical impact injury (4 m/sec, 2.6 mm of tissue deformation). Etomidate (2 mg/kg) was administered intravenously immediately before injury (n = 13) or 5 mins after injury (n = 12). Additional rats received saline treatment 5 mins after injury (n = 12) or served as sham controls (n = 10). MEASUREMENTS AND MAIN RESULTS: Rats were evaluated on beam balance and beam walk tasks on postoperative days 1-5 and then trained in the Morris water maze on postoperative days 14-18. On day 28, the rats were killed, and hippocampal CA1 and CA3 neuron counts and cortical lesion volume were measured in histologic brain sections. Preinjury etomidate attenuated beam balance deficits, water maze deficits, hippocampal CA3 neuronal loss, and cortical tissue loss but did not attenuate beam walk deficits or hippocampal CA1 neuronal loss. Postinjury etomidate attenuated water maze deficits, but it did not affect any other outcome measure. CONCLUSIONS: Administration of etomidate both before and after injury attenuates secondary injury resulting from traumatic brain injury, but the effect is more pronounced with pretreatment. The ineffectiveness of postinjury etomidate on motor and histologic tasks suggests a brief therapeutic treatment window in rats. However, the treatment window in humans is unknown. Lastly, postinjury etomidate did not exacerbate neurologic or histologic outcome.

Animals↗
PubMed2003

Physical medicine and rehabilitation consultation: relationships with acute functional outcome, length of stay, and discharge planning after traumatic brain injury.

OBJECTIVE: Patients hospitalized with traumatic brain injury comprise a large portion of the population treated at trauma centers, and physiatry consultants evaluate many traumatic brain injury patients in this setting. The purpose of this study was to delineate relationships between physical medicine and rehabilitation consultation in this population and acute functional outcome, length of stay, and discharge planning. DESIGN: Data were obtained for 1866 adult patients hospitalized with nonfatal traumatic brain injury. Functional outcome was determined using a modification of the FIM trade mark. Descriptive and regression analyses were used to determine the relationship of physical medicine and rehabilitation consultation to acute discharge FIM score, length of stay, and discharge disposition. RESULTS: Patients receiving physical medicine and rehabilitation consultation had more severe injuries, lower acute discharge FIM scores, and longer length of stay. However, multivariate analysis showed that earlier (<48 hr after admission) physical medicine and rehabilitation consultation resulted in significantly better FIM scores with transfers (odds ratio, 2.61; 95% confidence interval, 1.06-6.40) and locomotion (odds ratio, 3.54; 95% confidence interval, 1.34-9.32) and a significantly shorter acute length of stay (P = 0.001). CONCLUSIONS: Early physical medicine and rehabilitation consultation may positively impact functional status and length of stay for patients with traumatic brain injury during acute hospitalization. Additional work is needed to determine how physical medicine and rehabilitation consultation impacts rehabilitation-specific medical issues, long-term functional outcome, and healthcare costs.

Adult↗
PubMed2002

Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury.

Increases in brain interstitial excitatory amino acid (EAA(I)) concentrations after ischemia are ameliorated by use-dependent Na+ channel antagonists and by supplementing interstitial glucose, but the regulation of EAA(I) after traumatic brain injury (TBI) is unknown. We studied the regulation of EAA(I) after TBI using the controlled cortical impact model in rats. To monitor changes in EAA(I), microdialysis probes were placed in the cortex adjacent to the contusion and in the ipsilateral hippocampus. Significant increases in dialysate EAA(I) after TBI were found compared to levels measured in sham controls. Treatment with the use-dependent Na+ channel antagonist 619C89 (30 mg/kg i.v.) did not significantly decrease dialysate glutamate compared to vehicle controls in hippocampus (10.4+/-2.4 vs. 11.9+/-1.6 microM), but there was significant decrease in dialysate glutamate in cortex after 619C89 treatment (19.3+/-3 vs. 12.6+/-1.1 microM, P<0.05). Addition of 30 mM glucose to the dialysate, a treatment that decreases EAA(I) after ischemia, had no significant effect upon dialysate glutamate after TBI in cortex (20.0+/-4.9 vs. 11.7+/-3.4 microM) or in hippocampus (10.9+/-2.0 vs. 8.9+/-2.4 microM). These results suggest that neither increased release of EAAs due to Na+ channel-mediated depolarization nor failure of glutamate reuptake due to glucose deprivation can explain the majority of the increase in EAA(I) following TBI.

Animals↗
PubMed2002

Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats.

Traumatic injury to the central nervous system initiates inflammatory processes such as the synthesis of proinflammatory mediators that contribute to secondary tissue damage. Hence, administration of anti-inflammatory cytokines, such as interleukin-10 (IL-10) may be neuroprotective. Moderate hypothermia (30-32 degrees C) also decreases the pro-inflammatory response to traumatic brain injury (TBI). Thus, we hypothesized that the combination of IL-10 and hypothermia would provide synergistic neuroprotective effects after TBI. To test this hypothesis, fifty isoflurane-anesthetized rats underwent a controlled cortical impact (2.7 mm tissue deformation at 4 m/s) or sham injury and then were randomly assigned to one of five conditions (TBI/VEH Normothermia (37 degrees C), TBI/VEH Hypothermia (32 degrees C for 3 h), TBI/IL-10 Normothermia, TBI/IL-10 Hypothermia, and Sham/VEH Normothermia). Human IL-10 (5 microg) or VEH was administered (i.p.) 30 min after surgery. Function was assessed by established motor and cognitive tests on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume and hippocampal CA(1)/CA(3) cell survival were quantified at 4 weeks. Brain sections from 15 additional rats were immunohistochemically assessed (MoAB RP-3) to determine neutrophil accumulation at 5 h after TBI. The administration of IL-10 after TBI produced an approximately 75% reduction in the number of RP-3-positive cells in both the normothermic and hypothermic groups vs. the normothermic vehicle-treated group (P<0.05), but did not improve functional outcome. In contrast, hypothermia alone enhanced both motor and cognitive function and increased CA(3) neuronal survival after TBI. Contrary to our hypothesis, systemic administration of IL-10 combined with hypothermia did not provide synergistic neuroprotective effects after TBI. Rather, IL-10 administration suppressed the beneficial effects produced by hypothermia alone after TBI. The mechanism(s) for the negative effects of IL-10 combined with hypothermia after TBI remain to be determined.

Animals↗
PubMed2002

Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury.

Increases in brain interstitial excitatory amino acid (EAA(I)) concentrations after ischemia are ameliorated by use-dependent Na+ channel antagonists and by supplementing interstitial glucose, but the regulation of EAA(I) after traumatic brain injury (TBI) is unknown. We studied the regulation of EAA(I) after TBI using the controlled cortical impact model in rats. To monitor changes in EAA(I), microdialysis probes were placed in the cortex adjacent to the contusion and in the ipsilateral hippocampus. Significant increases in dialysate EAA(I) after TBI were found compared to levels measured in sham controls. Treatment with the use-dependent Na+ channel antagonist 619C89 (30 mg/kg i.v.) did not significantly decrease dialysate glutamate compared to vehicle controls in hippocampus (10.4+/-2.4 vs. 11.9+/-1.6 microM), but there was significant decrease in dialysate glutamate in cortex after 619C89 treatment (19.3+/-3 vs. 12.6+/-1.1 microM P<0.05). Addition of 30 mM glucose to the dialysate, a treatment that decreases EAA(I) after ischemia, had no significant effect upon dialysate glutamate after TBI in cortex (20.0+/-4.9 vs. 11.7+/-3.4 microM) or in hippocampus (10.9+/-2.0 vs. 8.9+/-2.4 microM). These results suggest that neither increased release of EAAs due to Na+ channel-mediated depolarization nor failure of glutamate reuptake due to glucose deprivation can explain the majority of the increase in EAA(I) following TBI.

Animals↗
PubMed2002

Attenuation of working memory and spatial acquisition deficits after a delayed and chronic bromocriptine treatment regimen in rats subjected to traumatic brain injury by controlled cortical impact.

Cognitive impairments are pervasive and persistent sequelae of human traumatic brain injury (TBI). In vivo models of TBI, such as the controlled cortical impact (CCI) and fluid percussion (FP), are utilized extensively to produce deficits reminiscent of those seen clinically with the hope that empirical study will lead to viable therapeutic interventions. Both CCI and FP produce spatial learning acquisition deficits, but only the latter has been reported to impair working memory in rats tested in the Morris water maze (MWM). We hypothesized that a CCI injury would impair working memory similarly to that produced by FP, and that delayed and chronic treatment with the D2 receptor agonist bromocriptine would attenuate both working memory and spatial learning acquisition deficits. To test these hypotheses, isoflurane-anesthetized adult male rats received either a CCI (2.7 mm deformation, 4 m/sec) or sham injury, and 24 h later were administered bromocriptine (5 mg/kg, i.p.) or vehicle, with continued daily injections until all behavioral assessments were completed. Motor function was assessed on beam balance and beam walking tasks on postoperative days 1-5 and cognitive function was evaluated in the MWM on days 11-15 for working memory (experiment 1) and on days 14-18 for spatial learning acquisition (experiment 2). Histological examination (hippocampal CA1 and CA3 cell loss/survival and cortical lesion volume) was conducted 4 weeks after surgery. All injured groups exhibited initial impairments in motor function, working memory, and spatial learning acquisition. Bromocriptine did not affect motor function, but did ameliorate working memory and significantly attenuated spatial acquisition deficits relative to the injured vehicle-treated controls. Additionally, the injured bromocriptine-treated group exhibited significantly more morphologically intact CA3 neurons than the injured vehicle-treated group (55.60 +/- 3.10% vs. 38.34 +/- 7.78% [p = 0.03]). No significant differences were observed among TBI groups in CA1 cell survival (bromocriptine, 40.26 +/- 4.74% vs. vehicle, 29.13 +/- 6.63% [p = 0.14]) or cortical lesion volume (bromocriptine, 17.78 +/- 0.62 mm3 vs. vehicle, 19.01 +/- 1.49 mm3 [p > 0.05]). These data reveal that CCI produces working memory deficits in rats that are similar to those observed following FP, and that the delayed and chronic bromocriptine treatment regimen conferred cognitive and neural protection after TBI.

Animals↗
PubMed2002

Hypothermia on admission in patients with severe brain injury.

Data from the "National Acute Brain Injury Study: Hypothermia" were examined to identify the impact of hypothermia on admission. In all patients, temperature was measured at randomization using bladder catheters with thermistors. Patients assigned to hypothermia were cooled using fluid-circulating pads. Outcome was assessed at 6 months using the dichotomized Glasgow Outcome Scale (good outcome = good recovery/moderate disability; poor outcome = severe disability/vegetative/dead). One-hundred and two patients (hypothermia, 62; normothermia, 40) were hypothermic on admission (< or =35.0 degrees C). Hypothermia-on-admission patients assigned to normothermia (n = 40) had a 78% poor outcome, and normothermia-on-admission patients assigned to normothermia had a 52% poor outcome (p < 0.004). Hypothermia-on-admission patients assigned to hypothermia had a lower percentage of poor outcomes than those assigned to normothermia (hypothermia, 61%; normothermia, 78%; p = 0.09). Patients over 45 years of age had an adverse effect of hypothermia regardless of admission temperature due to medical complications. Patients who were hypothermic on admission, age < or = 45 years (n = 81), and assigned to hypothermia had a significantly lower percentage of poor outcomes than those assigned to normothermia (hypothermia, 52%; normothermia, 76%; p = 0.02). Factors associated with hypothermia on admission were increased age, prehospital hypotension, smaller size, positive blood alcohol, larger volume of pre-hospital fluids, slightly higher injury severity, and winter enrollment The treatment effect was found in all of the four centers, which randomized the majority (80%) of the patients. It is unclear whether the improved outcome when hypothermia is maintained is a beneficial effect of very early hypothermia induction or an adverse effect of permitting the patients to rewarm passively.

Adult↗
PubMed2002

Clinical trials in head injury.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Brain Injuries↗
PubMed2002

Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats.

There is increasing evidence linking neurodegenerative mechanisms in Alzheimer's disease (AD) and traumatic brain injury (TBI), including increased production of amyloid precursor protein (APP), and amyloid-beta (Abeta) peptide. In vitro data indicate that expression of APP may be regulated in part by the inflammatory cytokine IL-1beta. To further investigate the mechanisms involved, we measured APP and IL-1beta protein levels and examined immunohistochemical localization of APP in brain tissue from rats subjected to controlled cortical impact (CCI) injury. Animals were examined at time intervals ranging from 3 h to 4 weeks after TBI. The 24-h time point revealed a dramatic increase in APP immunoreactivity, detected with both N- and C-terminal antibodies, in the hippocampus and cortex ipsilateral to injury. This finding was sustained up to 3 days post-injury. At these early time points, APP increase was particularly robust in the white matter axonal tracts. By 14 days after injury, APP immunoreactivity was not significantly different from sham controls in cortex, but remained slightly elevated in hippocampus. Western blot data corroborated early increases in hippocampal and cortical APP in injured versus control animals. Despite profound APP changes, no Abeta deposits were observed at any time after injury. Hippocampal and cortical IL-1beta increases were even more robust, with IL-1beta levels peaking by 6 h post-injury and returning to baseline by 24-72 h. Our results demonstrate that both APP and IL-1beta are rapidly elevated after injury. Because of the rapidity in the IL-1beta peak increase, it may serve a role in regulation of APP expression after TBI.

Amyloid beta-Protein Precursor↗
PubMed2002

Effect of hyperventilation on extracellular concentrations of glutamate, lactate, pyruvate, and local cerebral blood flow in patients with severe traumatic brain injury.

OBJECTIVE: To determine the potential adverse effects of brief periods of hyperventilation commonly used for acute neurologic deterioration. DESIGN: Prospective clinical trial. SETTING: University medical school. PATIENTS: Twenty patients with severe traumatic brain injury. INTERVENTIONS: The effect of 30 mins of hyperventilation (mean PaCO2, 24.6 mm Hg) on the extracellular metabolites associated with ischemia, and on local cerebral blood flow was studied by using microdialysis and local cerebral blood flow techniques. Normal appearing brain adjacent to evacuated hemorrhagic contusions or underlying evacuated subdural hematomas was studied. Hyperventilation trials were done 24-36 hrs after injury and again at 3-4 days after injury. Dialysate concentrations of glutamate, lactate, and pyruvate were measured before and for 4 hrs after the hyperventilation trials. MEASUREMENTS AND MAIN RESULTS: At 24-36 hrs, hyperventilation led to a >or=10% increase in the extracellular concentrations of glutamate in 14 of 20 patients, with concentrations in those 14 patients 13.7-395% above baseline; a >or=10% increase in lactate in 7 of 20 patients (11.6-211% above baseline); and a >or=10% increase in the lactate/pyruvate ratio in eight of 20 patients (10.8-227% above baseline). At 3-4 days after injury, ten of 13 patients had an increase in glutamate of >or=10%, while only three of 13 patients had an increase in extracellular lactate and two of 13 patients had an increase in the lactate/pyruvate ratio of this magnitude. The hyperventilation associated increases in extracellular glutamate and lactate concentrations were significant ( P<.05; one-sample Student's -test) at both time points after injury, as was the lactate/pyruvate ratio at 24-36 hrs. A >or=10% decline in local cerebral blood flow was observed with hyperventilation in five of 20 patients at 24-36 hrs (range, 10.2-18.7% below baseline), and in ten of 13 patients studied at 3-4 days (11.3-54% below baseline). There was no correlation with the presence or absence of local CO2 vasoresponsivity and increases in the extracellular metabolites at either the early or late time points. CONCLUSIONS: In brain tissue adjacent to cerebral contusions or underlying subdural hematomas, even brief periods of hyperventilation can significantly increase extracellular concentrations of mediators of secondary brain injury. These hyperventilation-induced changes are much more common during the first 24-36 hrs after injury than at 3-4 days.

Adult↗
PubMed2002

Using the SF-36 for characterizing outcome after multiple trauma involving head injury.

BACKGROUND: The purpose of this study was to evaluate the validity of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) for examining outcomes after multiple trauma and to investigate whether the addition of items selected to measure cognitive function could improve the sensitivity of the SF-36 for identifying differences in outcomes for patients with and without head injury. METHODS: One thousand two hundred thirty patients discharged from 12 trauma centers were interviewed 1 year after injury. The interview included the SF-36 supplemented with four items chosen to assess cognitive function. RESULTS: The resulting cognitive function scale is internally consistent and measures a component of health that is independent of the dimensions incorporated in the SF-36. It correlates well with established measures of brain injury severity and discriminates among patients with and without brain injury. CONCLUSION: This study underscores the need to supplement the SF-36 with a measure of cognitive function when evaluating outcome from multiple trauma involving head injury. Further studies are needed to validate the specific items chosen for measuring cognitive function.

Adult↗
PubMed2002

Absence of a diastolic velocity notch does not indicate hyperemia in traumatic brain injured patients without elevated cerebral blood flow velocity.

Elevated blood flow velocity (BFV), measured by transcranial Doppler (TCD), has been associated with hyperemia and cerebral vasospasm. This study examined whether the lack of a diastolic notch within the TCD waveform was associated with relative hyperemia within 5 days after injury in 35 traumatic brain injured (TBI) patients. Hyperemia (avD(O2) of < 4 ml/dL) was present in 16 patients and absent in 19 patients. Two clinicians independently coded TCD waveforms based on the presence of a diastolic notch (88% agreement). There was no significant difference in the presence of a diastolic notch by group; a diastolic notch was present in 57% (11/19) of patients without hyperemia and 81% (13/16) of patients with hyperemia. Sensitivity and specificity of detecting hyperemia using the diastolic notch was 18.7% and 57.9% respectively. The results showed that relative hyperemia was present without an elevation in blood flow velocities, and that the lack of a diastolic notch did not detect the presence of hyperemia in the TBI patient.

APACHE↗