The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging

Traumatic brain injury (TBI) is a significant cause of mortality, morbidity, and disability. Microglial activation is commonly observed in response to neuronal injury which, when prolonged, is thought to be detrimental to neuronal survival. Activated microglia can be labeled using PK11195, a ligand that binds the peripheral benzodiazepine receptor (PBR), receptors which are increased in activated microglia and sparse in the resting brain. We compared the binding properties of two PBR ligands PK11195 and DAA1106 in rats using the controlled cortical impact (CCI) model of experimental TBI. While both ligands showed relative increases with specific binding in the cortex ipsilateral to injury compared to the contralateral side, [(3)H]DAA1106 showed higher binding affinity compared with [(3)H](R)-PK11195. Combined immunohistochemistry and autoradiography in brain tissues near the injury site showed that [(3)H]DAA1106 binding co-registered with activated microglia more than astrocytes. Further, increased [(3)H]DAA1106-specific binding positively correlated with the degree of microglial activation, and to a lesser degree with reactive astrocytosis. Finally, in vivo administration of each ligand in rats with TBI showed greater retention of [(11)C]DAA1106 compared to [(11)C](R)-PK11195 at the site of the contusion as assessed by ex vivo autoradiography. These results in a rat model of TBI indicate that [(11)C]DAA1106 binds with higher affinity to microglia when compared with PK11195, suggesting that [(11)C]DAA1106 may represent a better ligand than [(11)C](R)-PK11195 for in vivo PET imaging of activated microglia in TBI.     

Effect of lactate therapy upon cognitive deficits after traumatic brain injury in the rat

Summary Background. In previous studies, it has been shown that intravenous lactate therapy can improve brain neurochemistry, adenosine triphosphate (ATP) generation and outcome after traumatic brain injury (TBI) in rats. In this study, we examined: (1) four L-lactate concentrations to determine the optimal therapeutic dose post TBI in terms of cognitive function; (2) ATP production after TBI for the L-lactate concentration found to be the optimal dose; (3) the possible production of lactic acidosis with the highest L-lactate concentration tested. Methods. Thirty minutes following a fluid percussion injury (FPI) over the left cerebral hemisphere, the animals received an intravenous infusion of 10, 28, 100, or 280 mM L-lactate (n = 10 for each group) for 3 h at a rate of 0.65 ml/h. Shams and control injured animals received a saline infusion. At 11–15 days post injury, cognitive deficits were examined using the Morris Water Maze (MWM) test. Three groups of rats were used for ATP analysis: shams, injured + saline infusion, and injury + the optimal lactate dose as determined by the MWM (n = 4/group). Additionally, a group receiving 280 mM L-lactate (n = 5) and one receiving a saline infusion (n = 3) were monitored for arterial blood variables and blood pressures. Findings. In the MWM test, only the 100 mM L-lactate-treated injured animals showed a significant reduction in cognitive deficits when compared to saline-treated injured animals (p ≤ 0.05). In the ATP study, injured animals without treatment had a 53% reduction in ATP level in the ipsilateral cortex, while animals with 100 mM lactate treatment had a 28% reduction. (p ≤ 0.05). No lactic acidosis was induced by the intravenous infusion of 280 mM L-lactate. Conclusions. This study indicates that the intravenous infusion of 100 mM L-lactate provided the optimal concentration of the substrate to ameliorate cognitive impairment, probably via the regeneration of ATP following TBI in rats.     

Statins: Mechanisms of neuroprotection

Clinical trials report that the class of drugs known as statins may be neuroprotective in Alzheimer's and Parkinson's disease, and further trials are currently underway to test whether these drugs are also beneficial in multiple sclerosis and acute stroke treatment. Since statins are well tolerated and have relatively few side effects, they may be considered as viable drugs to ameliorate neurodegenerative diseases. However, the mechanism of their neuroprotective effects is only partly understood. In this article, we review the current data on the neuroprotective effects of statins and their underlying mechanisms.     

The short- and long-term effectiveness of the LSVT for dysarthria following TBI and stroke

Objectives: To examine the effectiveness of Lee Silverman Voice Treatment (LSVT®) for the treatment of 10 individuals with dysarthria following TBI and stroke.

Research design: ABAA experimental research design.

Methods: Participants received 4 weeks of the standard LSVT® programme. To measure the effects of intervention, participants were assessed using perceptual and acoustic speech measures and everyday communication outcome measures prior to, immediately post and 6 months post-treatment.

Results: Following treatment, participants demonstrated statistically and clinically significant improvements to several acoustic and perceptual parameters. This included increased vocal loudness in sustained phonation and connected speech, increased vocal frequency range and improved word and sentence intelligibility. Improved ratings of communication initiation and participation and well-being were also found on the AusTOMs and items on participant questionnaires post-LSVT®. The majority of treatment effects were maintained 6 months following treatment.

Conclusions: LSVT® has the potential to be a viable treatment option for individuals with dysarthria featuring respiratory-phonatory impairments following TBI and stroke.     

The changing “epidemiology” of pediatric head injury and its impact on the daily clinical practice

Aim  This article focuses on the developments that occurred during the last two decades in the management of pediatric head injury. It describes the changes in incidence, various advancements in diagnosis, management, prognosis, prevention and strategies required for better outcome, and control of head injury. Materials and methods  Thorough evaluation of various papers, research, and our experience revealed that in developed countries, there has been a decreasing trend in head trauma incidence and trauma-related deaths as compared to developing countries. Results  This is mainly attributed to the widespread implementation of preventive measures. The development in imaging facilities, better characterization and grading of severe trauma (see, for example, diffuse axonal injury), an advanced understanding of the pathophysiology of secondary brain injury, endocrinological disturbances, predictive factors of outcome, development in neurophysiological monitoring, management advances in critical care units, implementation of safely measures, etc. have brought a significant change in overall outcome and profile of pediatric head injury Conclusion  The further developments in field of brain plasticity, stem cell, rehabilitation, evolution of new drugs, preventive community measures, and global policies to deal with head trauma are expected to play a major role in days to come. The development of future pediatric trauma centers based on current evolutions (in order to achieve a good outcome), global and emphatic preventions of trauma will be required to establish equilibrium between developed and developing countries.     

Cyclic,low-dose total body irradiation for metastatic neuroblastoma

Total body irradiation (TBI) can be thought of as a systemic anticancer agent. It therefore might best be given like an adjuvant drug, i.e. in tolerable doses, cyclically. The therapeutic ratio between normal bone marrow stem cells and suitably sensitive cancer cells should be widened by these means. Fourteen children with advanced (Stage IV) neuroblastomas were given 100–150 rad TBI in 50 rad daily fractions along with each three-week cycle of standard triple-agent chemotherapy (vincristine, DTIC, cyclophosphamide). Two patients died of toxicity and one is still undergoing therapy. Four of the remaining 12 survive free of disease for 12+ to 31 + months. The regimen is well tolerated, but prolonged, pronounced bone marrow depression, especially thrombocytopenia, commonly occurs after doses of 300–450 rad.     

Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach

Based upon observations in murine models, we have developed protocols to induce renal allograft tolerance by combined kidney and bone marrow transplantation (CKBMT) in non-human primates (NHP) and in humans. Induction of persistent mixed chimerism has proved to be extremely difficult in major histocompatibility complex (MHC)-mismatched primates, with detectable chimerism typically disappearing within 30–60?days. Nevertheless, in MHC mismatched NHP, long-term immunosuppression-free renal allograft survival has been achieved reproducibly, using a non-myeloablative conditioning approach that has also been successfully extended to human kidney transplant recipients. CKBMT has also been applied to the patients with end stage renal disease with hematologic malignancies. Renal allograft tolerance and long-term remission of myeloma have been achieved by transient mixed or persistent full chimerism. This review summarizes the current status of preclinical and clinical studies for renal and non-renal allograft tolerance induction by CKBMT. Improving the consistency of tolerance induction with less morbidity, extending this approach to deceased donor transplantation and inducing tolerance of non-renal transplants, are critical next steps for bringing this strategy to a wider range of clinical applications.     

脑干听觉诱发电位分级对脑创伤长期意识障碍患者预后评估的价值

目的通过对脑干听觉诱发电位（BAEP）的检测,探讨BAEP分级对长期昏迷脑损伤患者预后评估的临床价值。方法根据93例脑损伤后意识障碍超过2周的患者清醒前BAEP检测结果,将BAEP分为I级、Ⅱ级和Ⅲ级。采用格拉斯哥预后评分（GOS）作为判断标准对患者的预后进行评估,并进一步分析BAEP分级与预后评估之间的关系。结果I级的预后不良率为36．48％,Ⅱ级和Ⅲ级的总预后不良率为94．55％。分级与预后差异有统计学意义（P〈O．05）,分级越高,患者预后越差。结论BAEP能客观敏感地反映中枢神经系统功能,因而BAEP分级科学地反映了不同程度的脑功能损伤,进而准确预测预后情况,具有较好的临床应用价值。     

Influence of Self-Efficacy and Coping on Quality of Life and Social Participation After Acquired Brain Injury: A 1-Year Follow-Up Study

ObjectivesTo investigate the relations linking self-efficacy and coping to quality of life (QOL) and social participation and what effect self-efficacy, changes in self-efficacy, and coping style have on long-term QOL and social participation.DesignProspective clinical cohort study.SettingGeneral hospitals, rehabilitation centers.ParticipantsPatients with newly acquired brain injury (ABI) (N=148) were assessed at baseline (start outpatient rehabilitation or discharge hospital/inpatient rehabilitation; mean time since injury, 15wk) and 1 year later (mean time since injury, 67wk).InterventionsNot applicable.Main Outcome MeasuresQOL was measured with the EuroQuol 5D (the EQ-5D index and the EQ-5D visual analog scale [EQ VAS]) and the 9-item Life Satisfaction Questionnaire (LiSat-9), social participation with the modified Frenchay Activities Index, coping with the Coping Inventory for Stressful Situations, and self-efficacy with the Traumatic Brain Injury Self-efficacy Questionnaire.ResultsAt baseline, self-efficacy moderated the effect of emotion-oriented coping on the EQ-5D index and of avoidance coping on the EQ VAS. Self-efficacy mediated the relation between emotion-oriented coping and LiSat-9. An increase in self-efficacy over time predicted better scores on the EQ-5D index (β=.30), the EQ VAS (β=.49), and LiSat-9 (β=.44) at follow-up. In addition, higher initial self-efficacy (β=.40) predicted higher LiSat-9 scores at follow-up; higher initial emotion-oriented coping (β=−.23) predicted lower EQ VAS scores at follow-up. Higher modified Frenchay Activities Index scores at follow-up were predicted by higher self-efficacy (β=.19) and higher task-oriented coping (β=.14) at baseline (combined R²=5.1%).ConclusionsSelf-efficacy and coping predict long-term QOL but seem less important in long-term social participation. High self-efficacy protects against the negative effect of emotion-oriented coping. Enhancing self-efficacy in the early stage after ABI may have beneficial long-term effects.