Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage

Thioredoxin (TRX) plays important biological roles both in intra- and extracellular compartments, including in regulation of various intracellular molecules via thiol redox control. We produced TRX overexpressing mice and confirmed that there were no anatomical and physiological differences between wild-type (WT) mice and TRX transgenic (Tg) mice. In the present study we subjected mice to focal brain ischemia to shed light on the role of TRX in brain ischemic injury. At 24 hr after middle cerebral artery occlusion, infarct areas and volume were significantly smaller in Tg mice than in WT mice. Moreover neurological deficit was ameliorated in Tg mice compared with WT mice. Protein carbonyl content, a marker of cellular protein oxidation, in Tg mice showed less increase than did that of WT mice after the ischemic insult. Furthermore, c-fos expression in Tg mice was stronger than in WT mice 1 hr after ischemia. Our results suggest that transgene expression of TRX decreased ischemic neuronal injury and that TRX and the redox state modified by TRX play a crucial role in brain damage during stroke.

Traumatic brain damage prevented by the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f] quinoxaline.

The mechanisms of neuronal degeneration following traumatic head injury are not well understood and no adequate treatment is currently available for the prevention of traumatic brain damage in humans. Traumatic head injury leads to primary (at impact) and secondary (distant) damage to the brain. Mechanical percussion of the rat cortex mimics primary damage seen after traumatic head injury in humans; no animal model mimicking the secondary damage following traumatic head injury has yet been established. Rats subjected to percussion trauma of the cortex showed primary damage in the cortex and secondary damage in the hippocampus. Morphometric analysis demonstrated that both cortical and hippocampal damage was mitigated by pretreatment with either the N-methyl-D-aspartate (NMDA) antagonist 3-((+/-)- 2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) or the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX). Neither treatment prevented primary damage in the cortex when therapy was started after trauma. Surprisingly, delayed treatment of rats with NBQX, but not with CPP, beginning between 1 and 7 hr after trauma prevented hippocampal damage. No protection was seen when therapy with NBQX was started 10 hr after trauma. These data indicate that both NMDA- and non-NMDA-dependent mechanisms contribute to the development of primary damage in the cortex, whereas non-NMDA mechanisms are involved in the evolution of secondary damage in the hippocampus in rats subjected to traumatic head injury. The wide therapeutic time-window documented for NBQX suggests that antagonism at non-NMDA receptors may offer a novel therapeutic approach for preventing deterioration of the brain after head injury.

It’s okay to ask : development and pilot testing of a question prompt list for patients with brain tumours

Background: Previous research identified that primary brain tumour patients have significant psychological morbidity and unmet needs, particularly the need for more information and support. However, the utility of strategies to improve information provision in this setting is unknown. This study involved the development and piloting of a brain tumour specific question prompt list (QPL). A QPL is a list of questions patients may find useful to ask their health professionals, and is designed to facilitate communication and information exchange. Methods: Thematic analysis of QPLs developed for other chronic diseases and brain tumour specific patient resources informed a draft QPL. Subsequent refinement of the QPL involved an iterative process of interviews and review with 12 recently diagnosed patients and six caregivers. Final revisions were made following readability analyses and review by health professionals. Piloting of the QPL is underway using a non-randomised control group trial with patients undergoing treatment for a primary brain tumour in Brisbane, Queensland. Following baseline interviews, consenting participants are provided with the QPL or standard information materials. Follow-up interviews four to 6 weeks later allow assessment of the acceptability of the QPL, how it is used by patients, impact on information needs, and feasibility of recruitment, implementation and outcome assessment. Results: The final QPL was determined to be readable at the sixth grade level. It contains seven sections: diagnosis, prognosis, symptoms and changes, the health professional team, support, treatment and management, and post-treatment concerns. At this time, fourteen participants have been recruited for the pilot, and data collection completed for eleven. Data collection and preliminary analysis are expected to be completed by and presented at the conference. Conclusions: If acceptable to participants, the QPL may encourage patients, doctors and nurses to communicate more effectively, reducing unmet information needs and ultimately improving psychological wellbeing.

Measurement of nitric oxide and brain tissue oxygen tension in patients after severe subarachnoid hemorrhage

OBJECTIVE: Nitric oxide (NO), one of the most powerful endogenous vasodilators, is thought to play a major role in the development of delayed vasospasm in patients with subarachnoid hemorrhage (SAH). However, the role of the production of cerebral NO in patients with SAH is not known. In other SAH studies, NO metabolites such as nitrite and nitrate have been demonstrated to be decreased in cerebrospinal fluid and in plasma. METHODS: In this study, a microdialysis probe was used, along with a multiparameter sensor, to measure NO metabolites, brain tissue oxygen tension, brain tissue carbon dioxide tension, and pH in the cortex of patients with severe SAH who were at risk for developing secondary brain damage and vasospasm. NO metabolites, glucose, and lactate were analyzed in the dialysates to determine the time course of NO metabolite changes and to test the interrelationship between the analytes and clinical variables. RESULTS: Brain tissue oxygen tension was strongly correlated to dialysate nitrate and nitrite (r2 = 0.326; P < 0.001); however, no correlation was noted between brain tissue oxygen tension and NO metabolites in cerebrospinal fluid (r2 = 0.018; P = 0.734). No significant correlation between NO production, brain tissue carbon dioxide tension, and dialysate glucose and lactate was observed. CONCLUSION: Cerebral ischemia and compromised substrate delivery are often responsible for high morbidity rates and poor outcomes after SAH. The relationship between brain tissue oxygen and cerebral NO metabolites that we demonstrate suggests that substrate delivery and NO are linked in the pathophysiology of vasospasm after SAH.

Improving brain injury cognitive rehabilitation by personalized telerehabilitation services: Guttmann neuropersonal trainer

Cognitive rehabilitation aims to remediate or alleviate the cognitive deficits appearing after an episode of acquired brain injury (ABI). The purpose of this work is to describe the telerehabilitation platform called Guttmann Neuropersonal Trainer (GNPT) which provides new strategies for cognitive rehabilitation, improving efficiency and access to treatments, and to increase knowledge generation from the process. A cognitive rehabilitation process has been modeled to design and develop the system, which allows neuropsychologists to configure and schedule rehabilitation sessions, consisting of set of personalized computerized cognitive exercises grounded on neuroscience and plasticity principles. It provides remote continuous monitoring of patient's performance, by an asynchronous communication strategy. An automatic knowledge extraction method has been used to implement a decision support system, improving treatment customization. GNPT has been implemented in 27 rehabilitation centers and in 83 patients' homes, facilitating the access to the treatment. In total, 1660 patients have been treated. Usability and cost analysis methodologies have been applied to measure the efficiency in real clinical environments. The usability evaluation reveals a system usability score higher than 70 for all target users. The cost efficiency study results show a relation of 1-20 compared to face-to-face rehabilitation. GNPT enables brain-damaged patients to continue and further extend rehabilitation beyond the hospital, improving the efficiency of the rehabilitation process. It allows customized therapeutic plans, providing information to further development of clinical practice guidelines.

Systematic review of interventions to improve the provision of information for adults with primary brain tumors and their caregivers

Background: Adults with primary brain tumors and their caregivers have significant information needs. This review assessed the effect of interventions to improve information provision for adult primary brain tumor patients and/or their caregivers. Methods: We included randomized or nonrandomized trials testing educational interventions that had outcomes of information provision, knowledge, understanding, recall, or satisfaction with the intervention, for adults diagnosed with primary brain tumors and/or their family or caregivers. PubMed, MEDLINE, EMBASE and Cochrane Reviews databases were searched for studies published between 1980 and June 2014. Results: Two randomized controlled, one non-randomized controlled, and 10 single group pre-post trials enrolled more than 411 participants. Five group, four practice/process change and four individual interventions assessed satisfaction (12 studies), knowledge (four studies) or information provision (2 studies). Nine studies reported high rates of satisfaction. Three studies showed statistically significant improvements over time in knowledge and two showed greater information was provided to intervention than control group participants, although statistical testing was not performed. Discussion: The trials assessed intermediate outcomes such as satisfaction, and only 4/13 reported on knowledge improvements. Few trials had a randomized controlled design and risk of bias was either evident or could not be assessed in most domains.

The presence of executive deficits in patients with Obstructive Sleep Apnoea

Obstructive sleep apnoea (OSA) is a chronic condition in which the upper airways collapse repeatedly during sleep, completely or partially obstructing breathing. This obstruction leads to chronic intermittent hypoxia and severe sleep fragmentation, disrupting the restorative functions of sleep. Beebe and Gozal (2002)a developed a theory which hypothesises that disruption of the restorative functions of sleep lead to a chronic low level brain damage most evident in executive functions (EF). Neuropsychological testing of EF, volumetric MRI, magnetic resonance spectroscopy, event related potentials and CSF biomarkers all provide support for this theory. Little research has been done to explore the nature of the subjective complaint and it’s impact on the activities of daily living.

Genetic and modifying factors that determine the risk of brain tumors

Some modifying factors may determine the risk of brain tumors. Until now, it could not be attempted to identify people at risk and also to improve significantly disease progression. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. Despite of these treatments, the prognosis for patients is poor. In this review, we highlight general aspects concerning genetic alterations in brain tumors, namely astrocytomas, glioblastomas, oligodendrogliomas, medulloblastomas and ependymomas. The influence of these genetic alterations in patients' prognosis is discussed. Mutagen sensivity is associated with cancer risk. The convincing studies that linked DNA damages and DNA repair alterations with brain tumors are also described. Another important modifying factor is immunity. General immune response against cancer, tumor microenvironment and immune response, mechanisms of tumor escape, CNS tumor immunology, immune defects that impair anti-tumor systemic immunity in brain tumor patients and local immunosuppressive factors within CNS are also reviewed. New hope to treatment perspectives, as dendritic-cell-based vaccines is summarized too. Concluding, it seems well established that there is association between brain tumor risk and mutagen sensivity, which is highly heritable. Primary brain tumors cause depression in systemic host immunity; local immunosuppressive factors and immunological characteristics of tumor cells may explain the poor prognosis and DNA damages responses can alert immune system. However, it is necessary to clarify if individuals with both constitutional defects in immune functions and genetic instability have higher risk of developing brain tumors. Cytogenetic prospective studies and gene copy number variations analysis also must be performed in peripheral lymphocytes from brain tumor patients. © 2011 Bentham Science Publishers Ltd.

Histological evidence of delayed ischemic brain tissue damage in the rat double-hemorrhage model

The rat double-SAH model is one of the standard models to simulate delayed cerebral vasospasm (CVS) in humans. However, the proof of delayed ischemic brain damage is missing so far. Our objective was, therefore, to determine histological changes in correlation with the development of symptomatic and perfusion weighted imaging (PWI) proven CVS in this animal model. CVS was induced by injection of autologous blood in the cisterna magna of 22 Sprague-Dawley rats. Histological changes were analyzed on day 3 and day 5. Cerebral blood flow (CBF) was assessed by PWI at 3 tesla magnetic resonance (MR) tomography. Neuronal cell count did not differ between sham operated and SAH rats in the hippocampus and the cerebral cortex on day 3. In contrast, on day 5 after SAH the neuronal cell count was significantly reduced in the hippocampus (p<0.001) and the inner cortical layer (p=0.03). The present investigation provides quantitative data on brain tissue damage in association with delayed CVS for the first time in a rat SAH model. Accordingly, our data suggest that the rat double-SAH model may be suitable to mimic delayed ischemic brain damage due to CVS and to investigate the neuroprotective effects of drugs.

Rapid measurement of S-100B serum protein levels by Elecsys S100 immunoassay in patients undergoing carotid artery stenting or endarterectomy

OBJECTIVES:: This study was designed to apply the rapid Elecsys(R) S100 immunoassay for real-time measurement of S100 protein serum levels indicating acute brain damage in patients undergoing carotid artery stenting (CAS) or endarterectomy (CEA). DESIGN AND METHODS:: Data of 14 CAS patients were compared to those of 43 CEA and 14 control patients undergoing coronary angiography (CA). S100 serum levels were measured by the full-automatic Elecsys(R) S100 immunoassay and compared to those obtained by the well-established LIA-mat(R) S100 system. RESULTS:: In contrast to CAS and CA patients, median S100 serum levels of CEA patients significantly increased to 0.24 ng/mL before declamping, but subsequently returned to baseline. Three CEA patients with neurological deficits showed sustained elevated S100 levels 6 h after extubation. Absolute S100 values were not significantly different between the two methods. Bland-Altman plot analyses displayed a good agreement, mostly indicating slightly smaller values applying the Elecsys(R) S100 system. CONCLUSIONS:: The Elecsys(R) S100 system appears to be suitable for rapid real-time detection of neurological deficits in patients undergoing CAS and CEA. Persistent elevations of Elecsys(R) S100 levels during CEA were associated with prolonged neurological disorders, whereas transient increases seem to represent impaired blood-brain barrier integrity without neurological deficits.

Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury

OBJECT: Early impairment of cerebral blood flow in patients with severe head injury correlates with poor brain tissue O2 delivery and may be an important cause of ischemic brain damage. The purpose of this study was to measure cerebral tissue PO2, lactate, and glucose in patients after severe head injury to determine the effect of increased tissue O2 achieved by increasing the fraction of inspired oxygen (FiO2). METHODS: In addition to standard monitoring of intracranial pressure and cerebral perfusion pressure, the authors continuously measured brain tissue PO2, PCO2, pH, and temperature in 22 patients with severe head injury. Microdialysis was performed to analyze lactate and glucose levels. In one cohort of 12 patients, the PaO2 was increased to 441+/-88 mm Hg over a period of 6 hours by raising the FiO2 from 35+/-5% to 100% in two stages. The results were analyzed and compared with the findings in a control cohort of 12 patients who received standard respiratory therapy (mean PaO2 136.4+/-22.1 mm Hg). The mean brain PO2 levels increased in the O2-treated patients up to 359+/-39% of the baseline level during the 6-hour FiO2 enhancement period, whereas the mean dialysate lactate levels decreased by 40% (p < 0.05). During this O2 enhancement period, glucose levels in brain tissue demonstrated a heterogeneous course. None of the monitored parameters in the control cohort showed significant variations during the entire observation period. CONCLUSIONS: Markedly elevated lactate levels in brain tissue are common after severe head injury. Increasing PaO2 to higher levels than necessary to saturate hemoglobin, as performed in the O2-treated cohort, appears to improve the O2 supply in brain tissue. During the early period after severe head injury, increased lactate levels in brain tissue were reduced by increasing FiO2. This may imply a shift to aerobic metabolism.

Residual oculomotor and exploratory deficits in patients with recovered hemineglect

Several studies on hemineglect have reported that patients recover remarkably well when assessed with neuropsychological screening tests, however, they show deficits on novel or complex tasks. We investigated whether such deficits can be revealed with eye movement analysis, applying two basic oculomotor tasks as well as two exploratory tasks. Eye movements were recorded in eight hemineglect patients at least eleven months after right-hemisphere brain damage had occurred. Sixteen healthy volunteers participated in the control group. Regarding the basic oculomotor tasks, only the overlap task revealed residual deficits in patients, suggesting that a directional deficit in disengaging attention persisted during recovery. Further residual deficits were evident in the exploratory tasks. When everyday scenes were explored, patients showed a bias in early orienting towards the ipsilateral hemispace. In a search task, they demonstrated the same orienting bias as well as a non-directional deficit concerning search times. Moreover, patients preferentially fixated in the contralateral hemispace, but did not benefit from this asymmetry in terms of search times, i.e. they did not detect contralateral targets faster than ipsilateral ones. This suggests a dissociation between oculomotor processes and attentional ones. In conclusion, we have identified behavioural aspects that seem to recover slower than others. A disengagement deficit and biases in early orienting have been the most pronounced residual oculomotor deficits.