Traumatic brain injury induces nociceptin/orphanin FQ expression in neurons of the rat cerebral cortex

Nociceptin/orphanin FQ (N/OFQ) is a recently identified opioid-related neuropeptide. Earlier in vitro studies revealed regulation of N/OFQ expression by injury-induced factors, such as ciliary neurotrophic factor, inflammatory cytokines, and reactive oxygen species. We have extended our studies to in vivo experiments investigating the effect of traumatic brain injury on N/OFQ gene expression and peptide levels in the rat brain. Stab wound injury to the rat cerebral cortex led to a significant increase in N/OFQ mRNA levels in the vicinity of the injury, with the largest induction being seen at 24 h post-injury. Quantitative in situ hybridization revealed an almost twofold increase in the number of cells expressing N/OFQ, and the signal intensities within cells were also elevated. Stab wound injury leads to proliferation and hypertrophy of astrocytes, which respond to injury-related factors in vitro by up-regulating N/OFQ expression. However, in vivo N/OFQ co-localized exclusively with the neuronal marker, NeuN, following injury. N/OFQ expression was not detected in caspase-3-positive neurons undergoing apoptosis following injury, and increased N/OFQ expression was spatially more extended than the secondary injury-induced responses, such as astrogliosis and neuronal degeneration. Elevation of N/OFQ immunoreactivity closely followed the increase in N/OFQ gene expression as determined by immunohistochemistry. N/OFQ selectively activates the NOP receptor (ORL-1), but we did not detect parallel changes in levels of NOP receptor mRNA following injury, indicating regulation of the nociceptin system at the peptide and not the receptor level. In summary, a profound and prolonged up-regulation of N/OFQ expression in neurons surrounding a stab wound lesion to cerebral cortex was detected. The function of N/OFQ up-regulation in injury-induced responses in the brain is currently under investigation.     

糖尿病大鼠离体心脏对缺血/再灌注的耐受性

目的评价糖尿病大鼠离体心脏缺血／再灌注后心脏功能的改变。方法链佐星(60mg／kg)诱导的糖尿病大鼠16只(D组),年龄匹配的健康雄性SD大鼠10只(C组),戊巴比妥钠(60mg／kg)麻醉后快速取出心脏,接上主动脉插管置于Langendorg装置上,Krebs-Henseleit缓冲液逆行灌注。平衡灌注20min,待心率(HR)及冠脉流量平稳后夹闭灌注道,进行全心缺血30min,复灌40min。持续监测心肌心电活动、左心室压峰值(LVPSP)、左室舒张末压(LVEDP)和左室压力最大上升／下降速率(±dp／dtmax),计算左室发展压(LVDP=LVPSP-LVEDP),用LVDP×HR(RDPP)表示左室作功。结果与C组相比,基础状态下,D组大鼠心脏HR减慢,LVDP、RDPP和±dp／dtmax降低,LVEDP升高(P<0.05或0.01);再灌注后HR、LVDP、RDPP、冠脉流出液、±dp／dtmax等心功能指标恢复百分率升高,肌酸激酶活性降低(P<0.05或0.01);心脏缺血-停搏时间延长。结论糖尿病心脏基础心功能损伤严重,但对缺血／再灌注的耐受性增强。     

Traumatic brain injury induces prolonged accumulation of cyclooxygenase-1 expressing microglia/brain macrophages in rats

Inflammatory cellular responses to brain injury are promoted by proinflammatory messengers. Cyclooxygenases (prostaglandin endoperoxide H synthases [PGH]) are key enzymes in the conversion of arachidonic acid into prostanoids, which mediate immunomodulation, mitogenesis, apoptosis, blood flow, secondary injury (lipid peroxygenation), and inflammation. Here, we report COX-1 expression following brain injury. In control brains, COX-1 expression was localized rarely to brain microglia/macrophages. One to 5 days after injury, we observed a highly significant (p < 0.0001) increase in COX-1+ microglia/macrophages at perilesional areas and in the developing core with a delayed culmination of cell accumulation at day 7, correlating with phagocytic activity. There, cell numbers remained persistently elevated up to 21 days following injury. Further, COX-1+ cells were located in perivascular Virchow-Robin spaces also reaching maximal numbers at day 7. Lesion-confined COX-1+ vessels increased in numbers from day 1, reaching the maximum at days 5-7. Double-labeling experiments confirmed coexpression of COX-1 by ED-1+ and OX-42+ microglia/ macrophages. Transiently after injury, most COX-1+ microglia/macrophages coexpress the activation antigen OX-6 (MHC class II). However, the prolonged accumulation of COX-1+, ED-1+ microglia/macrophages in lesional areas enduring the acute postinjury inflammatory response points to a role of COX-1 in the pathophysiology of secondary injury. We have identified localized, accumulated COX-1 expression as a potential pharmacological target in the treatment of brain injury. Our results suggest that therapeutic approaches based on long-term blocking including COX-1, might be superior to selective COX-2 blocking to suppress the local synthesis of prostanoids.     

Traumatic brain injury in anticoagulated patients

BACKGROUND: Coumadin is widely used in the elderly population. Despite its widespread use, little is known about its effect on the outcome of elderly traumatic brain-injured patients. This study was undertaken to describe the outcomes of such a cohort. METHODS: Clinical material was identified from a Level I trauma center prospective head injury database, and a database obtained from the American College of Surgeons Committee on Trauma Verification and Review Committee from 1999 to 2002. Both databases contain many relevant variables, including age, sex, Glasgow Coma Scale (GCS) score, mechanism of injury, Injury Severity Score, International Normalized Ratio (INR), computed tomography (CT) findings, operative procedure, time to operating room, complications, length of stay, and outcome at hospital discharge. RESULTS: For patients with GCS scores less than 8, average INR was 6.0, with almost 50% having an initial value greater than 5.0. Overall mortality was 91.5%. For the 77 patients with GCS scores of 13 to 15, average INR was 4.4. Overall mortality for this group was 80.6%. A subset of patients deteriorated to a GCS score of less than 10 just hours after injury, despite most having normal initial CT scans. Mortality in this group was 84%. CONCLUSIONS: All patients on warfarin should have an INR performed, and a CT scan should be done in most anticoagulated patients. All supratherapeutically anticoagulated patients, as well as any anticoagulated patient with a traumatic CT abnormality, should be admitted for neurologic observation and consideration given to short term reversal of anticoagulation. Routine repeat CT scanning at 12 to 18 hours or when even subtle signs of neurologic worsening occur is a strong recommendation. A multi-institutional, prospective trial using these guidelines would be a first step toward demonstrating improved outcomes in the anticoagulated patient population after head trauma.     

Traumatic brain injury in pediatric patients

Traumatic brain injury (TBI) in children is frequent, sometimes lethal, and may have life-long consequences in survivors. Prevention at school and in sports, including both kids and families, is of paramount importance. Scarce data are available in terms of epidemiology, physiopathology, management and prognosis. This non-systematic review suggests that rational organization of rescue and transport to designated hospitals, linked with early diagnosis/removal of surgical masses and comprehensive monitoring and intensive care, offer the best chances for reducing mortality and morbidity in severe cases. After the acute phase rehabilitation and families play a fundamental role.     

Age and tolerance to secondary ischemia in rat epigastric flaps

The use of microvascular procedures is increasing as the population continues to age. The purpose of this study was to observe the survival of skin flaps after ischemic injury. Skin flaps (n = 50) underwent either 3 hours of primary (1°) or secondary (2°) venous occlusion in young (2–3 mo) and old (18–22 mo) rats. Skin flap survival was assessed on postoperative day 7. Survival rates for young and old after 3 hours of 1° ischemia was 100% and 90% (ns). Survival rats for young and old after 2° ischemia were 67% and 47% (ns). © 1994 Wiley-Liss, Inc.     

Traumatic brain injury: from model to man

Brain injury is the leading cause of death in trauma patients and produces a large amount of disability. Unfortunately, it is particularly prevalent in young adults, with all the suffering and socio-economic loss this implies. It has a complex neurobiology that has been elucidated largely in animal models, but it has been more difficult to apply the knowledge gained to man, partly due to the heterogeneous nature of human brain injuries.Clinical management consists of trying to prevent and treat ongoing injury processes. This is achieved by early and excellent critical care combining management of intracranial and cerebral perfusion pressure, with drug therapy where needed. New monitoring modalities are arriving and providing new insights, but the majority have yet to prove their worth in terms of improving patient outcome. The knowledge gleaned from experimental work has also begun to have an impact, and new therapies based on control of the elucidated pathophysiology are now in development.     

Traumatic brain injury rehabilitation.

Improved survival from severe traumatic brain injury has prompted the development of dedicated rehabilitation programs. Ideally, rehabilitation should begin during acute care in order to prevent later complications. Medically stable patients should be referred from acute care to acute rehabilitation programs for evaluation and then treatment or transfer as appropriate. Dedicated brain injury rehabilitation programs follow a method in which treatment is adapted to the major physical and cognitive impairments at each stage of recovery. Specialized treatment protocols have been developed for unconscious or agitated patients, partly on the basis of advances in neuropharmacology. Because of the long recovery course after severe brain injury, many patients are appropriate for postacute rehabilitation programs directed at community reentry, including return to work. Newer program models for patients with traumatic brain injuries, especially programs using cognitive rehabilitation techniques, are controversial because of inadequate research support and uncertain cost-effectiveness.     

移植肝热缺血损伤后糖原及酶组织化学活性的动态变化

目的：探讨不同热缺血时间下大鼠移植肝组织糖原及酶组织化学活性变化规律，预测供肝耐受热缺血性的安全时限。方法：用组织化学和细胞化学的方法，对大鼠移植肝组织进行动态观察，按热缺血时间随机分为0、15、30、45、60min5组，观察肝移植后的恢复性变化。结果：随热缺血时间的延长，肝组织琥珀酸脱氢酶（SDH）、细胞色素氧化酶（CO）和三磷酸腺苷酸（Mg^2 ,ATPase)活性逐渐降低，糖原减少，热缺血30min以前各组酶活性变化轻微，而45、60min组均出现明显的酶活性降低和高碘酸－无色品红（PAS）反应减低，15、30min组，在复流后24h糖原颗粒逐渐增多，呈明显的恢复，酶活性逐渐恢复至接近正常水平，45、60min组，复流后24hPAS反应和酶活性仍无明显恢复趋势，结论：移植肝热缺血在30min以内，肝组织损伤仍处在可复性阶段，复流后能逐渐恢复至正常的形态和功能，移植肝糖原含量，酶组织化学活性的变化以及术后其恢复性的潜能可作为衡量供肝质量的重要标准。     

移植肝热缺血损伤后糖原及酶组织化学性的动态变化

目的探讨不同热缺血时间下大鼠移植肝组织糖原及酶组织化学活性变化规律,预测供肝耐受热缺血的安全时限.方法用组织化学和细胞化学的方法,对大鼠移植肝组织进行动态观察.按热缺血时间随机分为0、15、30、45、60min 5组,观察肝移植后的恢复性变化.结果随热缺血时间的延长,肝组织琥珀酸脱氢酶(SDH)、细胞色素氧化酶(CO)和三磷酸腺苷酶(Mg2+-AT Pase)活性逐渐降低,糖原减少.热缺血30min以前各组酶活性变化轻微,而45、60min组均出现明显的酶活性降低和高碘酸-无色品红(PAS)反应减低.15、30min组,在复流后24h糖原颗粒逐渐增多,呈明显的恢复,酶活性逐渐恢复至接近正常水平.45、60min组,复流后24h PAS反应和酶活性仍无明显恢复趋势.结论移植肝热缺血在30?min以内,肝组织损伤仍处在可复性阶段,复流后能逐渐恢复至正常的形态和功能.移植肝糖原含量、酶组织化学活性的变化以及术后其恢复性的潜能可作为衡量供肝质量的重要标准.     

Traumatic brain injury in an aging population

The epidemiology of traumatic brain injury (TBI) is changing in several Western countries, with an increasing proportion of elderly TBI patients admitted to the intensive care unit (ICU). We describe a series of 1366 adult patients admitted to three neuro-ICUs in which 44% of cases were 50 years of age or older. The health status before trauma (rated using the APACHE score) was worse in older patients. In all 604 patients had emergency removal of intracranial masses, with extradural hematomas more frequent in young cases and subdural hematomas more frequent in older patients. Outcomes were classified according to the Glasgow Outcome Scale (GOS) 6 months post-trauma, as favorable (GOS score 4-5), or unfavorable (GOS score 1-3). Favorable outcomes were achieved by 50% of patients, but the proportions of unfavorable outcomes rose with age. Mortality was the main cause of unfavorable outcomes 6 months after injury in older patients. Logistic regression analysis indicates that several parameters independently contributed to outcome, including the motor component of the Glasgow Coma Scale (GCS), pupils, CT findings, and early hypotension. Additionally, the odds ratios were very high for age and health status before TBI. Patients admitted to the ICU are increasingly older, have co-morbidities, and have specific types of intracranial lesions. Early rescue, surgical treatment, and intensive care of these patients may produce excellent results up to the age of 59 years, with favorable outcomes still possible for 39% of cases aged 60-69 years, without an excessive burden of severely disabled patients.     

1,6二磷酸果糖对大鼠脑缺血-再灌注损伤后凋亡细胞及p38和Ref-1的研究

目的探讨1,6二磷酸果糖（FDP）对大鼠脑缺血-再灌注（I-R）损伤的作用及其机制。方法雄性SD大鼠90只,随机分为果糖治疗（F）组、脑缺血（I）组和假手术对照（c）组,每组30只。I组和F组大鼠在凝断双侧椎动脉24h后夹闭双侧颈总动脉,5min后重新开放,制作全脑缺血模型。F组再灌注开始时静脉注射FDP 1．5ml／kg,I组及C组分别静脉注射生理盐水1．5ml／kg。各组在再灌注后2、6、12、24、48、72h时取标本,制备脑组织病理切片,采用免疫组织化学染色方法测定p38蛋白和Ref-1蛋白的表达,TUNEL检测凋亡细胞数目。结果与C组比较,I组凋亡细胞显著增多（P〈0．05）;与C组比较,I组在再灌注后各时点p38蛋白、Ref-1蛋白表达均显著增强（P〈0．05）,F组较C组表达增强但较I组表达显著减弱（P〈0．05）。结论FDP对全脑I-R损伤有保护作用,其机理可能与其参与细胞信号转导减弱p38、Ref-1蛋白表达强度有关。     

The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury

BACKGROUND: Oxidative stress contributes to the pathogenesis of hepatic ischemia-reperfusion injury. This study aimed to determine whether fatty degeneration affects the oxidative damage during warm ischemia reperfusion and whether mitochondria, the major intracellular site of energy synthesis, represent a preferential target of this injury. MATERIALS AND METHODS: Fed rats with control or fatty liver induced by choline deficiency underwent 60' lobar ischemia and reperfusion. Oxidative damage was assessed by measuring in whole liver tissue and in isolated mitochondria the thiobarbituric acid-reactive substances (TBARs), protein carbonyls (PC), and total and oxidized glutathione (GSH and GSSG) concentrations. The mitochondrial F0-F1-ATPase content and the oxidative phosphorylation activity were also determined. Rat survival and ALT release were assessed as parameters of liver injury. RESULTS: In the whole liver tissue, with the exception of TBARs, no differences were observed for GSH, GSSG, and PC between the two groups throughout all of the experiment. In contrast, in isolated mitochondria, fatty infiltration was associated with a mild oxidative imbalance already under basal conditions. The preischemic differences in the mitochondrial TBARs, PC, and GSSG levels were significantly amplified by reperfusion in the presence of steatosis. The enhanced oxidative damage was associated to a reduced F0-F1-ATPase content and oxidative phosphorylation activity in fatty liver mitochondria. Finally, serum ALT levels were significantly greater and survival significantly lower in rats with steatotic liver. CONCLUSIONS: Fatty infiltration exacerbates mitochondrial oxidative injury during warm ischemia reperfusion. The increased oxidative stress can alter mitochondrial functions, including key processes for ATP synthesis, thus, contributing to the reduced tolerance to reperfusion injury.