Increased injury following intermittent fetal hypoxia-reoxygenation is associated with increased free radical production in fetal rabbit brain.

Hypoxia associated with perinatal events can result in brain damage in the neonate. In labor and eclampsia, hypoxia can be intermittent, which may result in more severe damage than sustained hypoxia. The pathogenesis of brain injury in sustained ischemia involves free radical production; therefore, we investigated whether higher levels of free radicals contribute to the greater injury induced by repetitive ischemia. Brains were obtained from fetuses of near-term, pregnant rabbits subjected to repetitive ischemia-reperfusion (RIR), sustained uterine ischemia-reperfusion (IR), or a control protocol. Compared with controls, fetal brains from RIR or IR groups had more brain edema. Brains from RIR fetuses exhibited higher levels of lipid peroxidation, 3-nitrotyrosine, and nitrogen oxides, and lower total antioxidant capacity and cortical cellular viability than those of IR or control fetuses. Maternal administration of antioxidants following RIR and fetal bradycardia resulted in lower levels of fetal cortical and hippocampal cell death. Coadministration of Trolox and ascorbic acid resulted in less brain edema and liquefaction, and fewer hippocampal ischemic nuclei as compared with the saline control. Higher free radical production may be responsible for the greater fetal brain injury following repetitive hypoxia-reoxygenation. Maternal antioxidant treatment resulted in transplacental passage of antioxidants and amelioration of brain injury, and may be a viable clinical option following diagnosis of fetal distress.     

Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis

Calcineurin plays an important role in the development of neuronal excitability, modulation of receptor's function and induction of apoptosis in neurons. It has been established in kindling models that status epilepticus induces brain focal edema and astrocyte activation. However, the role of calcineurin in brain focal edema and astrocyte activation in status epilepticus has not been fully understood. In this study, we employed a model of lithium-pilocarpine-induced status epilepticus and detected calcineurin expression in hippocampus by immunoblotting, brain focal edema by non-invasive magnetic resonance imaging (MRI-7T) and astrocyte expression by immunohistochemistry. We found that the brain focal edema was seen at 24 h after status epilepticus, and astrocyte expression was obviously seen at 7 d after status epilepticus. Meanwhile, calcineurin expression was seen at24 h and retained to 7 d after status epilepticus. A FK506, a calcineurin inhibitor, remarkably suppressed the status epilepticus-induced brain focal edema and astrocyte expression. Our data suggested that calcineurin overexpression plays a very important role in brain focal edema and astrocyte expression. Therefore, calcineurin may be a novel candidate for brain focal edema occurring and intracellular trigger of astrogliosis in status epilepticus.     

Increased jugular bulb saturation is associated with poor outcome in traumatic brain injury

The objective was to compare secondary insults, particularly decreases in jugular bulb oxyhaemoglobin saturation (SjO(2)), during intensive care in patients with "poor" and "good" outcomes 12 months after traumatic brain injury. A prospective observational study of patients' physiological data collected each minute from multimodality monitoring was carried out. Patients had duration of physiological insults quantified as a percentage of their validated monitoring time (once invalid data due to technical reasons were removed). Treatment protocols were designed to minimise secondary insults by maintaining intracranial pressure (ICP) less than 20 mm Hg, and cerebral perfusion pressure (CPP) greater than 70 mm Hg, with prompt correction of hypoxia and pyrexia. Twelve months after injury patients' neurological function was assessed using the Glasgow outcome scale (GOS). A poor outcome was defined as GOS 1 to 3 (group 1) and a good outcome as GOS 4 and 5 (group 2). Seventy five patients (64 male), median age of 34 years (range 15 to 70), were studied. At 12 months 33 patients had a poor outcome (group 1), and 42 a good outcome (group 2). Group 1 spent proportionately more time with SjO(2) greater than 75% compared with group 2 (p<0.05), and more time with SjO(2) below 54% (p<0.04). Group 1 patients also spent proportionately more time with CPP less than 70 mm Hg than group 2 (p<0.04). Patients in group 1 were older (p<0.04) and had a lower postresuscitation Glasgow coma score (p<0.002). There was no difference between the groups for ICP, injury severity score, peripheral pulse saturation, and pyrexia. This study confirms that secondary insults, including an increased SjO(2), occur significantly more in patients with poor outcomes. More research into strategies to reduce the impact of secondary insults, including management of increased SjO(2), is required.     

大鼠颅脑损伤后亚低温治疗对Calpain及作用底物MAP-2表达的影响

目的探讨亚低温治疗对颅脑损伤后Calpain、MAP-2基因和蛋白表达的影响。方法将54只SD大鼠随机分为假手术组（n=6）、常温脑损伤组（n=24）和亚低温脑损伤组（n=24）。亚低温脑损伤组在液压打击伤后即接受持续4h的亚低温治疗。伤后6h、12h、24h和72h4个时间点分别处死3只常温脑损伤组和亚低温脑损伤组大鼠。荧光PCR、Western blot半定量检测皮质Calpain及MAP-2基因转录和蛋白的表达。结果颅脑损伤后12h及24h亚低温使Calpain mRNA表达增加（P〈0．05）,伤后6h、12h、24h和72h亚低温均可减少Calpain蛋白的升高,伤后12h及72h尤其显著（P〈0．05）。与假手术组比较,常温脑损伤组和亚低温脑损伤组MAP-2基因转录均减少（P〈0．05）;与常温脑损伤组比较,伤后6h、12h和24h亚低温可抑制MAP-2基因转录的下调,但亚低温脑损伤组MAP-2蛋白的表达均比同时间点常温组低（P〈0.05）。结论颅脑损伤后亚低温治疗的脑保护机制可能与调节Calpain蛋白的表达有关,而亚低温与MAP-2的关系还有待进一步研究。     

Increased stress vulnerability after a prefrontal cortex lesion in female rats

Neuroimaging studies in patients suffering from affective disorders have shown decreased volume and reduced regional cerebral blood flow in multiple areas of the prefrontal cortex, including the medial prefrontal cortex and the orbitofrontal cortex. This aberrant brain activity is among other things attributed to chronic stress. Affective disorders occur more often in women than in men. In the current experiment, female mPFC-lesioned and non-lesioned rats were subjected to 3 weeks of chronic unpredictable stress in order to determine the role of the mPFC in dealing with chronic stress, and the consequences of mPFC damage for coping with consecutive stressful events. mPFC damage in female rats intensified the stress-induced activation of the dorsomedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus as measured with Fos expression changes and markedly increased plasma catecholamine levels after 3 weeks of unpredictable stress. Additionally, an mPFC lesion significantly reduced the time of appearance of stress-induced behavioral changes in the open field. Altogether, mPFC dysfunction affects the way female rats react to chronic stress, it not only increased the activation of brain regions involved in neuroendocrine and autonomic responses to stress but it also significantly reduced the time of onset of behavioral changes.     

重型颅脑外伤气管切开患者下呼吸道感染187例分析

目的 探讨重型颅脑外伤气管切开患者下呼吸道感染病原菌耐药状况及防治措施. 方法对神经外科病区187例重型颅脑外伤气管切开患者的气道分泌物进行细菌培养,对药敏结果进行分析,并制定控制措施. 结果主要致病菌以革兰阴性菌为主,包括不动杆菌属(22.2%)、铜绿假单胞菌(19.7%)、肺炎克雷伯菌(17.6%)和大肠埃希菌(5.8%), 对亚胺培南高度敏感.革兰阳性菌以金黄色葡萄球菌(20.7%)为主,对万古霉素未发现耐药.结论 需加强消毒隔离及护理工作,合理使用抗生素,以便有效控制感染.     

Development of posttraumatic hyperthermia after traumatic brain injury in rats is associated with increased periventricular inflammation.

Posttraumatic hyperthermia (PTH) is a noninfectious elevation in body temperature that negatively influences outcome after traumatic brain injury (TBI). We sought to (1) characterize a clinically relevant model and (2) investigate potential cellular mechanisms of PTH. In study I, body temperature patterns were analyzed for 1 week in male rats after severe lateral fluid percussion (FP) brain injury (n=75) or sham injury (n=17). After injury, 27% of surviving animals experienced PTH, while 69% experienced acute hypothermia with a slow return to baseline. A profound blunting or loss of circadian rhythmicity (CR) that persisted up to 5 days after injury was experienced by 75% of brain-injured animals. At 2 and 7 days after injury, patterns of cell loss and inflammation were assessed in selected brain thermoregulatory and circadian centers. Significant cell loss was not observed, but PTH was associated with inflammatory changes in the hypothalamic paraventricular nucleus (PVN) by one week after injury. In brain-injured animals with altered CR, reactive astrocytes were bilaterally localized in the suprachiasmatic nucleus (SCN) and the PVN. Occasional IL-1beta+/ED-1+ macrophages/microglia were observed in the PVN and SCN exclusively in brain-injured animals developing PTH. In animals with PTH there was a significant positive correlation (r=0.788, P<0.01) between the degree of postinjury hyperthermia and the total number of cells positive for inflammatory markers within selected thermoregulatory and circadian nuclei. In study II, a separate group of animals underwent the same injury and temperature monitoring paradigm as in study I, but had additional physiologic data obtained, including vital signs, arterial blood gases, white blood cell counts, and C-reactive protein levels. All parameters remained within normal ranges after injury. These data suggest that PTH and the alteration in CR of temperature may be due, in part, to acute reactive astrocytosis and inflammation in hypothalamic centers responsible for both thermoregulation and CR.     

甲基强的松龙对大鼠颅脑损伤后一氧化氮合成酶活性的影响

目的观察甲基强的松龙对大鼠颅脑损伤后血、脑组织中NOS含量的影响,并探讨其作用机制。方法将45只SD大鼠随机分为3组:实验组(20只)、对照组(20只)、正常组(5只),均采用骨窗形成后硬膜外打击法造成鼠脑挫裂伤。正常组麻醉后,只行开颅手术,不作头颅打击,治疗组大鼠致伤后即刻腹腔内注射30mg/kg甲基强的松龙,对照组则注射30mg/kg生理盐水。对照组和治疗组大鼠分别在伤后1h、6h、12h、24h断头取脑,对大鼠脑外伤后脑组织中一氧化碳合成酶(NOS)含量进行检测。结果大鼠脑皮质中的NOS活性在伤后1h较正常组显著性升高(P <0.01),6h开始下降,12～24h降至基础水平。甲基强的松龙治疗组在伤后1h(P <0.01)、6h(P <0.05)NOS活性较损伤组显著性降低。结论颅脑损伤后,受损脑组织中NOS活性升高,甲基强的松龙可通过抑制损伤后NOS活性起到保护创伤神经元的作用。     

Increased xanthine oxidase activity after traumatic brain injury in rats.

Oxidative stress may contribute to many of the pathophysiologic changes that occur after traumatic brain injury (TBI). There are a number of potential sources and mechanisms for oxygen free radical (OFR) production and lipid peroxidation after TBI. In this study, we investigate the time-dependent changes in xanthine oxidase (XO) activity and lipid peroxidation using a focal TBI animal model. We demonstrate that there is an immediate increase in lipid peroxidation by-products and in XO enzyme activity after TBI.     

DEGS2 polymorphism associated with cognition in schizophrenia is associated with gene expression in brain

A genome-wide association study of cognitive deficits in patients with schizophrenia in Japan found association with a missense genetic variant (rs7157599, Asn8Ser) in the delta(4)-desaturase, sphingolipid 2 (DEGS2) gene. A replication analysis using Caucasian samples showed a directionally consistent trend for cognitive association of a proxy single-nucleotide polymorphism (SNP), rs3783332. Although the DEGS2 gene is expressed in human brain, it is unknown how DEGS2 expression varies during human life and whether it is affected by psychiatric disorders and genetic variants. To address these questions, we examined DEGS2 messenger RNA using next-generation sequencing in postmortem dorsolateral prefrontal cortical tissue from a total of 418 Caucasian samples including patients with schizophrenia, bipolar disorder and major depressive disorder. DEGS2 is expressed at very low levels prenatally and increases gradually from birth to adolescence and consistently expressed across adulthood. Rs3783332 genotype was significantly associated with the expression across all subjects (F_3,348=10.79, P=1.12 × 10⁻³), particularly in control subjects (F_1,87=13.14, P=4.86 × 10⁻⁴). Similar results were found with rs715799 genotype. The carriers of the risk-associated minor allele at both loci showed significantly lower expression compared with subjects homozygous for the non-risk major allele and this was a consistent finding across all diagnostic groups. DEGS2 expression showed no association with diagnostic status after correcting for multiple testing (P>0.05). Our findings demonstrate that a SNP showing genome-wide association study significant association with cognition in schizophrenia is also associated with regulation of DEGS2 expression, implicating a molecular mechanism for the clinical association.     

Increased cerebrospinal fluid glutamate and taurine concentrations are associated with traumatic brain edema formation in rats

Glutamate-mediated excitotoxicity results in cell swelling and contributes to brain edema formation. Since increased extracellular taurine reflects glutamate-induced cell swelling in vitro, elevated CSF taurine could therefore unmask glutamate-mediated cytotoxic edema formation under in vivo conditions. For this, the temporal profile of brain edema and changes in cisternal CSF glutamate and taurine levels were determined in 28 rats following focal traumatic brain injury. Compared to six non-traumatized rats, CSF glutamate (4. 8+/-0.3 vs. 10+/-0.9 microM) and taurine levels (12+/-1.3 vs. 41+/-3 microM) were significantly increased at 8 h after trauma (P<0.001). Over time, CSF glutamate and taurine were significantly increased by 24 (glutamate: 38+/-4.4 microM) and 48 h (taurine: 51+/-4 microM), respectively. While CSF glutamate closely reflected changes in hemispheric water content, alterations in CSF taurine occurred diametrically to those seen for glutamate. Under the present study design, increased CSF taurine could reflect glutamate-induced cell swelling. In addition, neuronal release of taurine with its inhibitory and antiexcitotoxic functions could explain the observed diametric changes in CSF glutamate, CSF taurine, and hemispheric water content. Therefore, increasing taurine could be a therapeutic approach in attenuating post-traumatic glutamate-mediated cell damage.     

Serum soluble CD40 Ligand levels are associated with severity and mortality of brain trauma injury patients

Background

Serum soluble CD40 Ligand (sCD40L) levels, which exhibit prothrombotic and proinflammatory properties, have not been studied in patients with traumatic brain injury (TBI). Thus, the objective of this study was to determine whether serum sCD40L levels are associated with severity and mortality in patients with severe TBI.

Methods

This was a prospective, observational and multicenter study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of sCD40L were measured on the day of TBI. Endpoint was established in 30-day mortality.

Results

We found higher serum sCD40L levels (P < 0.001) in non-surviving TBI patients (N = 27) than in survivor ones (N = 73). Logistic regression analysis showed that serum sCD40L levels were associated with 30-day mortality (OR = 1.58; 95% CI = 1.12-2.21; P = 0.008) controlling for APACHE-II score and computer tomography findings. The area under the curve (AUC) for serum sCD40L levels as predictor of 30-day mortality was 0.79 (95% CI = 0.70-0.86; P < 0.001). Survival analysis showed that patients with serum sCD40L levels higher than 2.11 ng/mL presented increased 30-day mortality than patients with lower levels (Hazard ratio = 9.0; 95% CI = 4.25-19.27; P < 0.001). We found an association between serum sCD40L levels and APACHE-II (rho = 0.33; P = 0.001), and GCS score (rho = -0.21; P = 0.04).

Conclusions

To our knowledge, this is the first study reporting data on serum sCD40L levels in patients with severe TBI. The most relevant and newer findings of our study are that serum sCD40L levels in non-surviving patients with severe TBI are higher than in surviving ones, and that there are an association between serum sCD40L levels and TBI severity and mortality.     

Childhood trauma is associated with social anhedonia and brain gray matter volume differences in healthy subjects

Brain Imaging and Behavior - The present study tested the effects of childhood trauma (CT) on trait social anhedonia (SA) and on gray matter volume (GMV) and explored the possible relationships...     

Increased lipid peroxidation in vulnerable brain regions after transient forebrain ischemia in rats

We examined cerebral lipid peroxidation, estimated by a thiobarbituric acid test, in rat brain regions after 30 minutes of severe forebrain ischemia and at recirculation periods of up to 72 hours. The lipid peroxide levels remained unaltered in all brain regions during ischemia and during the first hour of recirculation but were selectively increased between 8 and 72 hours of recirculation in the ischemia-sensitive regions of the hippocampus, striatum, and cortex. The most pronounced increases (30-37%) were seen at 48 hours of recirculation. In contrast, lipid peroxide levels were unchanged in infarcted brain regions 24 hours after intracarotid injection of microspheres, indicating that reoxygenation of the ischemic brain is a prerequisite for lipid peroxidation. We assessed the lipid peroxidation capacity of cerebral homogenates obtained from rats subjected to ischemia and recirculation by measuring the production of lipid peroxides after aerobic incubation. The homogenates from rats exposed to 30 minutes of ischemia or to 1 hour of recirculation were not more susceptible to peroxidation. However, the production of lipid peroxides was selectively increased in the hippocampus, striatum, and cortex at 8-48 hours of recirculation, suggesting a loss of efficacy of the antioxidant systems. These results, showing a delayed and long-lasting increase in lipid peroxidation that occurs in ischemia-sensitive brain regions and parallels the development of neuronal necrosis, support the hypothesis that free radical processes participate in postischemic neuronal damage.     

Inferior olivary hypertrophy is associated with a lower functional state after pontine hemorrhage

BACKGROUND: Inferior olivary hypertrophy (IOH) may develop after pontine hemorrhage and may become a pacemaker for symptomatic palatal tremor (SPT). However, there is no information available that elucidates how IOH may affect the functional outcome. The purpose of this study was to investigate how frequently IOH was associated with clinical manifestations of involuntary movements, including ocular myoclonus (OM) and SPT, and whether IOH influenced the functional outcome after pontine hemorrhage. METHODS: In 20 consecutive patients undergoing inpatient multidisciplinary rehabilitation after pontine hemorrhage, the location of lesions (tegmental vs. ventral) and the presence of IOH were examined by magnetic resonance imaging, and the functional outcome was assessed by means of Fugl-Meyer scale for neurological impairment and Functional Independence Measure for disability on admission and discharge. RESULTS: In 10 patients, IOH was detected, and the tegmentum was involved in 7 of the 10 patients. OM or SPT was present in 7 of these 10 patients. In the remaining 10 patients, IOH was not detected, and the tegmentum was involved only in 2 of these 10 patients. None of them had OM or SPT. The presence of IOH was associated with a lower functional status on admission and discharge. CONCLUSION: After pontine hemorrhage, IOH may be associated with tegmental lesions with OM or SPT and may impose a detrimental effect on the functional outcome.     

Spatial alterations in endothelin receptor expression are temporally associated with the altered microcirculation after brain trauma

OBJECTIVES: To study the cellular distribution of endothelin receptors A and B (ETrA and ETrB) in the post-traumatic sensorimotor cortex and hippocampus. MATERIALS AND METHODS: We inflicted closed head trauma to male Sprague-Dawley rats and visualized ETrA and ETrB immunoreactivity with 3,3'-diaminobenzidine. RESULTS: ETrA immunolabeling was the most prominent in pyramidal neurons 24 and 48 hours post-trauma, while it reached its peak in the microvasculature at hour 4. ETrB immunolabeling was observed in endothelial cells, perivascular neurons, smooth muscle cells (SM) and pericytes, the expression being the most pronounced 24 hours post-trauma. DISCUSSION: The results suggest that the vasoconstrictor effect of endothelin-1 (ET-1) is mediated primarily by ETrA. The dual effects of ETrB are reflected in its vasoconstrictor role at the vascular bed and conversely, in the attenuation of ET-1 availability and synthesis. We conclude that both receptors play a role in the disturbed microvascular autoregulation and in the sustained reduction of blood flow following trauma to the brain.