Correlations between Disease Severity and Rehabilitation Outcomes in Patients Recovering from Covid-19 Infection.

OBJECTIVE: Based on long-term follow-up of patients with COVID-19, to evaluate whether the severity of acute COVID-19 infection affects rehabilitation outcomes. DESIGN: Observational cohort study. SUBJECTS: A total of 61 post-acute COVID-19 patients underwent inpatient and outpatient customized rehabilitation treatment. METHODS: The severity of acute COVID-19 infection was measured with the World Health Organization Clinical Progression Scale (WHO-CPS). Motor, cognitive, and functional variables were measured using standard and specified scales 6 months or more after acute illness. RESULTS: Of the 61 subjects, 65.6% had severe disease according to WHO-CPS. Significant improvement was found in activities of daily living functions (Functional Independence Measure (FIM) at admission 103.7 ± 18.9 vs FIM at discharge 118.7 ± 6.8) (p < 0.00). Of participants, 88% were able to wean off oxygen completely. A significant correlation was found between higher WHO-CPS, prolonged acute hospitalization, and days of ventilation were correlated with lower total and motor FIM at admission, but not with cognitive FIM or Montreal Cognitive Assessment (MoCA). No correlation was found between WHO-CPS, prolonged acute hospitalization and day of ventilation and funnctional level at discharge. CONCLUSION: The severity of acute COVID-19 infection affects the functional status of survivors at admission to rehabilitation, but, contrary to expectations, not the functional outcomes at discharge. These findings show that even patients with severe acute COVID-19 infection may improve their daily functioning significantly during rehabilitation program.

Correlations between Electro-Diagnostic Findings, the Severity of Initial Infection, and the Rehabilitation Outcomes among COVID-19 Patients.

Patients with Coronavirus-2019 (COVID-19) manifest many neuromuscular complications. We evaluated the correlations between electromyography and nerve conduction measurements among COVID-19 patients and the severity of the initial infection, as well as the rehabilitation outcomes, and searched for the factors which best predict the rehabilitation outcomes. A total of 19 COVID-19 patients (16 men; mean ± SD age 59.1 ± 10.4), with WHO clinical progression scale of 6.8 ± 2.3, received rehabilitation for 3.9 ± 2.5 months. The Functional Independence Measure (FIM), the 10 m walk test, the 6 minute walk test, and grip force were collected before and after the rehabilitation period. Motor Nerve Conduction (MNC), Sensory Nerve Conduction (SNC) and electromyographic abnormalities were measured. All of the MNC measures of the median nerve correlated with the WHO clinical progression scale and duration of acute hospitalization. The MNC and SNC measures correlated with the rehabilitation duration and with FIM at discharge. The MNC distal latency of the median and the peroneal nerves and the MNC velocity of the median and tibial nerves predicted 91.6% of the variance of the motor FIM at discharge. We conclude that nerve conduction measurements, especially in COVID-19 patients with severe illness, are important in order to predict prognosis and rehabilitation outcomes.

Characteristics of ataxic gait in familial dysautonomia patients.

INTRODUCTION AND OBJECTIVES: Progressive ataxic gait is a common symptom in individuals with Familial Dysautonomia (FD). At least 50% of adults with FD require assistance with walking. Our aims were to describe the medical condition of individuals with FD (ii) compare their gait characteristics to healthy individuals, and (iii) assess correlations between gait measures, presence of unstable gait pattern and frequency of falls. METHODS: Twelve subjects with FD (7 males, age 25.3±10.6 years) and 16 healthy participants (6 males, age 35.9±11.9 years) were recruited. Gait kinematics, gait symmetry, dynamic muscle activity, and foot deep vibration sensation were recorded. RESULTS: Ataxic gait degrees were: severe (6 out of 12), moderate (4 out of 12) and low (2 out of 12). The number of falls correlated with base width asymmetry. Crouch gait was noted in 3 out of 12 of the subjects. CONCLUSIONS: In-depth quantitative gait analysis of individuals with FD revealed ataxic gait. The ataxic pattern might be a result of combined neurological deficiencies and osseous deformities. Increasing the base of support of patients with FD might increase the symmetry of the base width during gait and decrease the number of falls. Additionally, perturbation treatment and dynamic balance exercises may be recommended in order to improve compensatory strategies. Future investigation of this population should include quantification of osseous rotations of the lower limb in order to fully understand its effect on their gait pattern and falls.

Tocotrienol Treatment in Familial Dysautonomia: Open-Label Pilot Study.

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy, primarily presented in Ashkenazi Jews. The most common mutation in FD patients results from a single base pair substitution of an intronic splice site in the IKBKAP gene which disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP). To date, treatment of FD patients remains preventative, symptomatic and supportive. Based on previous in vitro evidence that tocotrienols, members of the vitamin E family, upregulate transcription of the IKBKAP gene, we aimed to investigate whether a similar effects was observed in vivo. In the current study, we assessed the effects of tocotrienol treatment on FD patients' symptoms and IKBKAP expression in white blood cells. The initial daily doses of 50 or 100 mg tocotrienol, doubled after 3 months, was administered to 32 FD patients. Twenty-eight FD patients completed the 6-month study. The first 3 months of tocotrienol treatment was associated with a significant increase in IKBKAP expression level in FD patients' blood. Despite doubling the dose after the initial 3 months of treatment, IKBKAP expression level returned to baseline by the end of the 6-month treatment. Clinical improvement was noted in the reported clinical questionnaire (with regard to dizziness, bloching, sweating, number of pneumonia, cough episodes, and walking stability), however, no significant effect was observed in any clinical measurements (weight, height, oxygen saturation, blood pressure, tear production, histamine test, vibration threshold test, nerve conduction, and heart rate variability) following Tocotrienol treatment. In conclusion, tocotrienol treatment appears significantly beneficial by clinical evaluation for some FD patients in a few clinical parameters; however it was not significant by clinical measurements. This open-label study shows the complexity of effect of tocotrienol treatment on FD patients' clinical outcomes and on IKBKAP expression level compared to in vitro results. A longitudinal study with an increased sample size is required in the future to better understand tocotrienol affect on FD patients.

A novel technique for conduction studies of the infrapatellar nerve.

OBJECTIVE: To introduce a noninvasive method for electrodiagnostic evaluation of the infrapatellar nerve (IPN). DESIGN: A prospective cohort study. SETTING: Electrodiagnostic laboratory, rehabilitation department, Hadassah University Hospital. PARTICIPANTS: A total of 38 healthy adults; 57 asymptomatic limbs were studied. METHODS: Sensory nerve action potential of the IPN was recorded with surface electrodes placed 2.5 cm below the distal pole of the patella and 2 cm medially from the medial border of the patellar tendon. Transcutaneous antidromic electrical stimulation of IPN was applied above the medial femoral condyle and 8-10 cm proximally from the active surface electrode. RESULTS: The sensory nerve action potential mean (n = 38) onset latency was 1.69 ± 0.32 ms. Peak latency was 2.36 ± 0.47 ms, and amplitude was 6.96 ± 3.68 µV. CONCLUSIONS: This article describes a novel and simple technique for IPN conduction electrodiagnostic examination. The method used provides a new tool to evaluate IPN injury in reference to anterior or inferior knee pain with associated sensory deficit.

Rehabilitation outcomes of stroke patients treated with tissue plasminogen activator.

OBJECTIVE: To investigate the influence of thrombolysis on functional outcomes after rehabilitation. BACKGROUND: Systemic thrombolysis with tissue plasminogen activator (tPA) is considered the mainstay of acute stroke therapy and was found to improve short-term outcome. DESIGN: Matched case-controlled design. SETTING: Inpatient neurology and rehabilitation departments. PARTICIPANTS: Thirty-seven patients given tPA and 37 control patients not treated with lytics because of protocol limits. METHODS: We retrospectively analyzed data from a cohort of stroke patients who were treated with systemic tPA. The rehabilitation outcome of thrombolysis-treated patients was compared with that observed for tPA-ineligible and age- and stroke severity-matched patients treated at the same neurology and rehabilitation departments. MAIN OUTCOME MEASURE: Neurological evaluation was assessed with the National Institutes of Health stroke scale (NIHSS). Activity of daily living was measured using the Functional Independence Measure (FIM) instrument. Functional outcome was measured using the modified Rankin scale (mRS). RESULTS: The treatment group included 37 patients given tPA; 37 tPA-ineligible patients served as controls. On admission to rehabilitation, there were no significant differences in functional, neurological, and rehabilitation parameters between the groups. At the end of the rehabilitation period, NIHSS scores were significantly lower in the thrombolysis group (P = .036). More patients in the thrombolysis group reached functional independence defined as mRS < or =2 (20/37 versus 10/37; P = .03). At the end of rehabilitation, total FIM score (mean 102.8 versus 93.9; P = .039), total FIM gain (mean 27.8 versus 21.4; P = .09), and total FIM efficiency scores (0.8 versus 0.43; P = .013) were higher in the thrombolysis group and more patients in this group were discharged home. CONCLUSIONS: Although the bulk of neurological improvement occurred before the inpatient rehabilitation, thrombolysis-treated patients continue to improve faster and to a larger extent during the rehabilitation period suggesting that the beneficial effects of thrombolysis continue beyond the acute phase.

CD38 facilitates recovery from traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It causes progressive tissue atrophy and consequent neurological dysfunctions. TBI is accompanied by neuroinflammation, a process mediated largely by microglia. CD38 is an ectoenzyme that promotes transmembrane signaling via the synthesis of potent calcium mobilizing agents or via its receptor activity. CD38 is expressed in the brain in various cell types including microglia. In previous studies, we showed that CD38 regulates microglial activation and response to chemokines. In view of the important role of neuroinflammation in TBI and the effects of CD38 on microglial responses, the present study examines the role of CD38 in the recovery of mice from closed head injury (CHI), a model of focal TBI. For this purpose, CD38-deficient and wild-type (WT) mice were subjected to a similar severity of CHI and the effect of the injury on neurobehavioral and cognitive functions was assessed by the Neurological Severity Score (NSS) and the Object Recognition Test, at various time points post-injury. The results show that recovery after CHI (as indicated by the NSS) was significantly lower in CD38-deficient mice than in WT mice and that the object recognition performance after injury was significantly impaired in injured CD38-deficient mice than in WT mice. In addition, we also observed that the amount of activated microglia/macrophages at the injury site was significantly lower in CD38-deficient mice compared with WT mice. Taken together, our findings indicate that CD38 plays a beneficial role in the recovery of mice from CHI and that this effect is mediated, at least in part, via the effect of CD38 on microglia responses.

Dynamic changes in the recovery after traumatic brain injury in mice: effect of injury severity on T2-weighted MRI abnormalities, and motor and cognitive functions.

Memory and neurobehavioral dysfunctions are among the sequelae of traumatic brain injury (TBI). The Neurological Severity Score (NSS) includes 10 tasks and was previously designed to assess the functional status of mice after TBI. The object recognition task (ORT) measures specific episodic memory and is expressed by the percent time spent by an animal at a novel, unfamiliar object (Discrimination Index [DI]). It is an ideal tool for evaluating cognitive function after TBI. The present study sought to validate the use of the NSS and ORT in severe and mild focal TBI in mice, and to confirm that the spontaneous recovery and the radiological abnormalities, shown by T2-weighted magnetic resonance imaging (MRI), are dependent upon injury severity. Mice were subjected to severe and mild closed head injury (NSS at 1 h 7.52 +/- 0.34 and 4.62 +/- 0.14, respectively). NSS was evaluated for 25 days and showed a decrease by 3.86 +/- 0.26 and 2.54 +/- 0.35 units in the severely and mildly injured mice, respectively. ORT revealed DI in severely injured group of 51.7 +/- 6.15%, (vs approximately 75-80% in uninjured animal) on day 3 and 66.2 +/- 6.81% on day 21. In contrast, the mildly injured mice did not show cognitive impairment throughout the same period. The damage seen by MRI at 24 h after injury, strongly correlated with NSS(1h) (R = 0.87, p < 0.001). We conclude that NSS is a reliable tool for evaluation of neurological damage in head-injured mice, NSS(1h) predicts the motor dysfunction, cognitive damage, and brain-damage characteristics as depicted by T2-weighted MRI. The combined assessment of neurobehavioral and cognitive function along with MRI is most useful in evaluating recovery from injury, especially when testing effectiveness of novel treatments or genetic manipulations.

Incensole acetate: a novel neuroprotective agent isolated from Boswellia carterii.

Boswellia resin has been used as a major anti-inflammatory agent and for the healing of wounds for centuries. Incensole acetate (IA), isolated from this resin, was shown to inhibit the activation of nuclear factor-kappaB, a key transcription factor in the inflammatory response. We now show that IA inhibits the production of inflammatory mediators in an in vitro model system of C6 glioma and human peripheral monocytes. Given the involvement of postinjury inflammation in the pathophysiology and outcome of traumatic brain injury, we examined the effect of IA on the inflammatory process and on the recovery of neurobehavioral and cognitive functions in a mouse model of closed head injury (CHI). In the brains of post-CHI mice, IA reduced glial activation, inhibited the expression of interleukin-1beta, and tumor necrosis factor-alpha mRNAs, and induced cell death in macrophages at the area of trauma. A mild hypothermic effect was also noted. Subsequently, IA inhibited hippocampal neurodegeneration and exerted a beneficial effect on functional outcome after CHI, indicated by reduced neurological severity scores and improved cognitive ability in an object recognition test. This study attributes the anti-inflammatory activity of Boswellia resin to IA and related cembranoid diterpenes and suggests that they may serve as novel neuroprotective agents.

Differential neuroprotective properties of endogenous and exogenous erythropoietin in a mouse model of traumatic brain injury.

Both heat acclimation (HA) and post-injury treatment with recombinant human erythropoietin (Epo, rhEpo, exogenous Epo) are neuroprotective against traumatic brain injury (TBI). Our previous data demonstrated that HA-induced neuroprotection includes improved functional recovery and reduced cerebral edema formation. Additionally, in earlier Western-blot analyses, we found that HA mice display increased expression of the specific erythropoietin receptor (EpoR) and of hypoxia-inducible factor-1 alpha (HIF-1 alpha), the inducible subunit of the transcription factor, which regulates Epo gene expression, but not of Epo itself. In light of this, the aim of the current study was threefold: (1) to assess Epo expression in the trauma area and hippocampus following HA, rhEpo administration, or combined HA-rhEpo treatment, using immunohistochemical methods that offer enhanced anatomical resolution; (2) to examine the effects of endogenous and exogenous Epo on edema formation in normothermic (NT) mice; and (3) to evaluate the effects of exogenous Epo administration on neuroprotective outcome measures in HA animals. HA induced enhanced expression of endogenous Epo in the trauma area and the hippocampus. Treatment with anti-Epo antibody given to NT mice increased edema formation, whereas rhEpo induced no beneficial effect. Cognitive performance testing and immunohistochemical findings reinforced HA and rhEpo as separate protective interventions but showed no advantage to combining the two strategies. We therefore suggest that HA-induced neuroprotection is shaped by pre-existing mediators but cannot be modified by post-injury treatment aimed at increasing the levels of neuroprotective agents.

Cognitive and functional outcomes of terror victims who suffered from traumatic brain injury.

PRIMARY OBJECTIVE: To describe the outcomes of terror victims suffered from traumatic brain injury (TBI). RESEARCH DESIGN: Retrospective chart review of 17 terror and 39 non-terror TBI patients treated in a rehabilitation department during the same period. METHODS AND PROCEDURE: Variables include demographic data, Injury Severity Scale (ISS), length of stay (LOS) and imaging results. ADL was measured using the Functional Independence Measurement (FIM), cognitive and memory functions were measured using the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) battery and the Rivermead Battery Memory Test (RBMT), respectively. MAIN OUTCOME AND RESULTS: Terror TBI patients were significantly younger, had higher ISS score and higher rates of intracerebral haemorrhage (ICH), brain surgery and penetrating brain injuries than the non-terror TBI group. There was no difference in mean LOS, mean FIM values, mean FIM gain and mean cognitive and memory improvement between groups. Terror victims suffered from a higher percentage of post-traumatic epilepsy (35% vs. 10%, p=0.05), whereas the rate of PTSD and the rate of return to previous occupation were similar between groups. CONCLUSIONS: Although TBI terror victims had more severe injury, they gained most of ADL functions and their rehabilitation outcomes were similar to non-terror TBI patients. These favourable results were achieved due to a comprehensive interdisciplinary approach to terror victims and also by national support which allowed an adequate period of treatment and sufficient resources as needed.

[Rehabilitation outcomes of terror victims with multiple trauma: the experience in Hadassah University Hospital 2000-2004].

From late September 2000 until 2005, the State of Israel was attacked by continuing acts of terrorism known as the Al Aqsa Intifada. During this period the number of terror victims treated in rehabilitation facilities has escalated significantly. The city of Jerusalem has a unique place in the heart of the Israel-Palestinian conflict and, therefore, almost 20% of national atrocities have been carried out in Jerusalem. Between September.2000 and September 2004, 72 terror victims were treated in the department of rehabilitation in Hadassah University Hospital. Among them, 47 (65%) suffered from multiple trauma without CNS involvment, 19 (26%) suffered from traumatic brain injury and 6 (8%) suffered from spinal cord injury. The rehabilitation outcomes of terror victims was compared to the rehabilitation outcomes of non-terror multiple trauma patients treated in the same rehabilitation facility over the same period. The rehabilitation outcomes were evaluted using the following parameters: length of hospitalization (LOH) in acute care departments, inpatient and outpatient rehabilitation departments, functional outcome (Functional Independence Measurement, FIM), occupational outcome (returning to previous occupation) and psychological outcome (Salomon PTSD questionnaire). The mean LOH of terror victims was 218 +/- 131 days as opposed to 152 +/- 114 days for the non-terror group (p < 0.01). The difference between FIM value at entry and discharge (delta FIM) was significantlly higher in terror victims as compared to controls (41.1 +/- 21.6 vs. 30.8 +/- 21.8, p = 0.002). The rate of PTSD was higher among terror victims than non-terror control (40.9% vs. 24.2%, p = 0.04). The rate of returning to previous occupation was similar between terror and non-terror victims (53% vs. 46.9% respectively). Long term study showed that terror victims still suffer from lower quality of life and life satisfaction 2 years after the insult. In summary, terror victims spent longer periods in rehabilitation and regained most of the Activities of Daily Living (ADL) functions similar to the non-terror group. In spite of the higher rate of PTSD, terror victims succeeded in returning to their previous occupation similar to the non-terror group.

Akt phosphorylation is required for heat acclimation-induced neuroprotection.

Long-term heat exposure, known as heat acclimation (HA; 30 days at 34 +/- 1 degrees C) is neuroprotective against traumatic brain injury. Acclimated mice were previously found to display improved functional recovery as well as an increase in the levels of the specific erythropoietin receptor. As the activation of this receptor is known to facilitate functional recovery on one hand and the phosphorylation and activation of Akt, an intracellular kinase which regulates anti-apoptotic pathways on the other, in this study we investigated whether HA affects Akt phosphorylation prior to and following injury and whether this step is required for development of HA-induced neuroprotection. Akt phosphorylation was blocked using Triciribine (TCN), a compound shown to block the phosphorylation process without affecting upstream effectors of this kinase, and several post-injury functional end-point measures were subsequently evaluated. Acclimation led to a post-injury increase in the levels of phosphorylated Akt, resulting in higher levels when compared with normothermic controls at 4 h post-injury (63.6 +/- 5.2% and 42.7 +/- 3.7%, respectively, p

Rehabilitation outcomes of terror victims with multiple traumas.

OBJECTIVES: To describe the rehabilitation outcomes of terror victims with multiple traumas, and to compare those outcomes with those of patients with nonterror-related multiple traumas treated in the same rehabilitation facility over the same time period. DESIGN: Retrospective chart reviews. SETTING: Rehabilitation department in a university hospital in Jerusalem, Israel. PARTICIPANTS: Between September 2000 and September 2004, we treated 72 victims of terrorist attacks who had multiple traumas. Among them, 47 (65%) had multiple traumas without central nervous system involvement (MT subgroup), 19 (26%) had multiple traumas with traumatic brain injury (TBI subgroup), and 6 (8%) had multiple traumas with spinal cord injury (SCI subgroup). We matched, according to their types of injury and demographic data, each terror victim with a control patient treated in the same period in our rehabilitation department. INTERVENTION: Interdisciplinary inpatient and outpatient rehabilitation. MAIN OUTCOME MEASURES: Hospital length of stay (LOS) in acute care departments, inpatient and outpatient rehabilitation departments, functional outcome (FIM instrument score), occupational outcome (returning to previous occupation), and psychologic outcome (Solomon PTSD [post-traumatic stress disorder] Inventory). RESULTS: The mean LOS of terror victims was 218+/-131 days; for the nonterror group it was 152+/-114 days (P<.01). In comparison with the control subgroups, the MT subgroup of terrorist victims had significantly longer LOS in the acute care and outpatient rehabilitation departments (P=.06) and the terror TBI subgroup had a longer LOS in outpatient department only (P<.05). The LOS of the SCI patients, both terror victims and control patients, was significantly longer than that of the other 2 subgroups. The difference between FIM value at entry and discharge (DeltaFIM) was significantly higher for terror victims than for the controls (41.1+/-21.6 vs 30.8+/-21.8, P=.002). This difference was mainly the result of the significantly higher DeltaFIM achieved by the terror MT subgroup than by the MT controls. The rate of PTSD was higher among terror victims than among controls (40.9% vs 24.2%, P=.04). The rate of return to previous occupations was similar between terror victims and nonterror patients (53% vs 46.9%, respectively). CONCLUSIONS: Victims of terror spent longer periods in rehabilitation than the nonterror group; however, they regained most activity of daily living functions similar to the nonterror group. Despite the higher rate of PTSD, terror victims succeeded in returning to their previous occupations at a similar rate to that of the nonterror group.

D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.

Traumatic brain injury triggers a massive glutamate efflux, activation of NMDA receptor channels, and cell death. Recently, we reported that NMDA receptors in mice are down-regulated from hours to days following closed head injury (CHI), and treatment with NMDA improved recovery of motor and cognitive functions up to 14 d post-injury. Here we show that a single injection of a low dose of D-cycloserine (DCS), a partial NMDA receptor agonist, in CHI mice 24 h post-injury, resulted in a faster and greater recovery of motor and memory functions as assessed by neurological severity score and object recognition tests, respectively. Moreover, DCS treatment of CHI mice led to a significant improvement of hippocampal long-term potentiation (LTP) in the CA1 region that was completely blunted in CHI control mice. However, DCS did not improve CHI-induced impairment in synaptic glutamate release measured by paired pulse facilitation (PPF) ratio in hippocampal CA1 region. Finally, CHI-induced reduction of brain-derived neurotrophic factor (BDNF) was fully restored following DCS treatment. Since DCS is in clinical use for other indications, the present study offers a novel approach to treat human brain injury.

CuZn-SOD deficiency, rather than overexpression, is associated with enhanced recovery and attenuated activation of NF-kappaB after brain trauma in mice.

Superoxide-dismutases (SOD) catalyze O2- conversion to hydrogen peroxide (H2O2) and with other antioxidant enzymes and low molecular weight antioxidants (LMWA) constitute endogenous defense mechanisms. We first assessed the effects of SOD1 levels on outcome after closed head injury (CHI) and later, based on these results, the effects of SOD1 deficiency on cellular redox homeostasis. Superoxide-dismutase 1-deficient (SOD1-/-) and -overexpressing (transgenic (Tg)) mice and matched wild-type (WT) controls were subjected to CHI and outcome (neurobehavioral and memory functions) was assessed during 14 days. Brain edema, LMWA, and SOD2 activity were measured along with histopathological analysis. Transactivation of nuclear factor-kappa B (NF-kappaB) was evaluated by electromobility shift assay. Mortality, motor, and cognitive outcome of Tg and WT mice were comparable. Mortality and edema were similar in SOD1-/- and WT mice, yet, unexpectedly, SOD1-/- displayed better neurobehavioral recovery (P<0.05) at 14 days after CHI. Basal LMWA were higher in the cortex and liver of SOD1-/- mice (P<0.05) and similar to WT in the cerebellum. Five minutes after CHI, cortical LMWA decreased only in SOD1-/- mice. One week after CHI, SOD2 activity decreased fourfold in WT cortex (P<0.001), but was preserved in the SOD1-/-. Constitutive NF-kappaB transactivation was comparably low in SOD1-/- and WT; however, CHI induced a robust NF-kappaB activation that was absent in SOD1-/- cortices (P<0.005 versus WT). At the same time, immunohistochemical analysis of brain sections revealed that astrogliosis and neurodegeneration were of lesser severity in SOD1-/- mice. We suggest that SOD1 deficiency impairs H2O2-mediated activation of NF-kappaB, decreasing death-promoting signals, and leading to better outcome.

Heat acclimation increases hypoxia-inducible factor 1alpha and erythropoietin receptor expression: implication for neuroprotection after closed head injury in mice.

Experimental evidence indicates that long-term exposure to moderately high ambient temperature (heat acclimation, HA) mediates cross-tolerance to various types of subsequently applied stress. The transcriptional activator hypoxia-inducible factor 1 (HIF-1) has been implicated in playing a critical role in HA. It also regulates the expression of Erythropoietin (Epo), whose neuroprotective effects have been shown in a variety of brain injuries. The aim of the present study was to examine whether HA exerts a beneficial effect on the outcome of closed head injury (CHI) in mice and to explore the possible involvement of HIF-1 and Epo in this process. Heat acclimated mice and matched normothermic controls were subjected to CHI or sham surgery. Postinjury motor and cognitive parameters of acclimated mice were compared with those of controls. Mice were killed at various time points after injury or sham surgery and brain levels of HIF-1alpha, the inducible subunit of HIF-1, Epo, and the specific erythropoietin receptor (EpoR) were analyzed by Western immunoblotting. Motor and cognitive functions of acclimated mice were significantly better than those of controls. Heat acclimation was found to induce a significant increase in expression of nuclear HIF-1alpha and EpoR. The EpoR/Epo ratio was also significantly higher in acclimated mice as compared with controls. Nuclear HIF-1alpha and EpoR were higher in the acclimated group at 4 h after injury as well. The improved outcome of acclimated mice taken together with the basal and postinjury upregulation of the examined proteins suggests the involvement of this pathway in HA-induced neuroprotection.

Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits.

Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (> or =7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (> or =24 h) time window easily attainable for treatment of human accidental head injury.