创伤性颅脑损伤脑脊液代谢谱改变及临床意义

目的:探讨创伤性颅脑外伤患者脑脊液中代谢谱的改变及其临床意义。方法:用高分辨率质子核磁共振代谢组学检验创伤性颅脑损伤对脑化学物质和代谢的影响。在重型创伤性颅脑损伤组(n=6),损伤后的脑脊液分析脑代谢的变化,并与轻,中型颅脑损伤组(n=6)相比较。结果:与轻型,中型颅脑损伤组相比,发现了乙酰乙酸,尿酸,3-硝基酪氨酸升高的证据。3组脑脊液中乙酰乙酸,尿酸,3-硝基酪氨酸含量有显著性差异(p<0.01)。结论:颅脑创伤后脑脊液中乙酰乙酸,尿酸,3-硝基酪氨酸值均有不同程度升高,且升高越明显则病情越严重。说明乙酰乙酸,尿酸,3-硝基酪氨酸可作为颅脑创伤病情的监测指标。     

Mechanisms of neural plasticity following brain injury

Brain insults cause rapid cell death, and a disruption of functional circuits, in the affected regions. As the injured tissue recovers from events associated with cell death, regenerative processes are activated that over months lead to a certain degree of functional recovery. Factors produced by new neurons and glia, axonal sprouting of surviving neurons, and new synapse formation help to re-establish some of the lost functions. The timing and location of such events is crucial in the success of the regenerative process. Comprehensive gene expression profiling and proteomic analyses have enabled a deeper molecular and cellular mechanistic understanding of post-injury brain regeneration. These new mechanistic insights are aiding the design of novel therapeutic modalities that enhance regeneration.     

Functional disturbances in the nervous structures of the respiratory tract in rats following nitrogen dioxide inhalation

The functional state of rat's airway smooth muscle was not changed after nitrogen dioxide inhalation for 30 days. The smooth muscle contraction increased only at second stimulation of preganglionic nervous fibers. Removal of mucosa or Novocain blockade of receptors decreased control smooth contraction at nerve and muscle fiber stimulation but the repeated stimulation of nerve increased the muscle contraction. The processing of trachea and bronchus preparations by prednisolon (1-10 microg/ml) decreased muscle reactions to 12% only at nerve stimulation. Prednisolon didn't change reactions of preparations with removed or blockaded receptors induced by nerve stimulation, but prednisolon (10 microg/ml) increased contraction at muscle stimulation. The relax effect of prednisolon on airway smooth muscle realizes via tracheobronchial receptors. High doses of prednisolon may direct effect on muscle increasing its contraction.     

Eicosanoids in human ventricular cerebrospinal fluid following severe brain injury

Recent evidence has shown that a variety of prostaglandins and leukotrienes can be produced in brain tissue after injury in animals. It has also been speculated that increases in brain prostaglandins occur in humans following injury. Ventricular cerebrospinal fluid (CSF) samples have been obtained from children with static lesions (controls) as well as children with acute brain injury and eicosanoids measured by immunologic techniques. Metabolites of prostacyclin (6-keto-PGF1 a) and thromboxane A2 (thromboxane B2) were the major eicosanoids found in CSF, and levels of these compounds were increased 3-10 times in acutely injured patients. Prostaglandin E2 was also found in lower amounts, although in one case its level was very high. Prostaglandin D2 was also present, but in low amounts. No leukotrienes were found in CSF samples that were purified by HPLC prior to immunoassay. Elevated levels of hydroxyeicosatetraenoic acids (HETEs) were observed in those samples stored frozen, but these metabolites were most probably due to autooxidation of arachidonic acid in CSF. Arachidonic acid concentration in CSF was typically found to be in the range of 10-200 ng/ml, but was found to be 5-10 fold higher in one severely injured patient. Thus, elevated free arachidonic acid and various oxygenated metabolites were observed in CSF following brain injury.     

Amelioration of hypoxemia by neuromuscular blockade following brain injury

Brain injury has been commonly associated with respiratory failure and uncontrolled skeletal muscle activity. In the present study, neuromuscular (NM) blockade induced by injection of succinylcholine hydrochloride was used to block uncontrolled muscle contractions in dogs with brain injury caused by rapid elevation of intracranial pressure (ICP). Decerebrate posturing, a decrease in value (mean +/- SEM) of arterial oxygen tension (Pa02) of 26 +/- 1 torr, and an increase in arterial carbon dioxide tension (PaCO2) of 11 +/- 1 torr occurred in the dogs, which were supported by mechanical ventilation. The arterial hypoxemia developed independently of the decerebration; however, dogs that demonstrated decerebrate posturing exhibited significantly larger decreases in Pa02 than dogs that did not (P less than 0.01). NM blockade ameliorated the effects of elevated ICP on the arterial blood gases; i.e., the amount of hypoxemia in decerebrate dogs was significantly less in dogs subjected to NM blockade than in dogs not subjected to NM blockade. It is concluded that uncontrolled skeletal muscle activity that exacerbates arterial hypoxemia associated with brain injury is ameliorated by use of NM blockade as a therapeutic adjunct to mechanical ventilation.     

Opposing roles for reactive astrocytes following traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Current medical therapies exhibit limited efficacy in reducing neurological injury and the prognosis for patients remains poor. While most research is focused on the direct protection of neuronal cells, non-neuronal cells, such as astrocytes, may exert an active role in the pathogenesis of TBI. Astrocytes, the predominant cell type in the human brain, are traditionally associated with providing only structural support within the CNS. However, recent work suggests astrocytes may regulate brain homeostasis and limit brain injury. In contrast, reactive astrocytes may also contribute to increased neuroinflammation, the development of cerebral edema, and elevated intracranial pressure, suggesting possible roles in exacerbating secondary brain injury following neurotrauma. The multiple, opposing roles for astrocytes following neurotrauma may have important implications for the design of directed therapeutics to limit neurological injury. As such, a primary focus of this review is to summarize the emerging evidence suggesting reactive astrocytes influence the response of the brain to TBI.     

Blood brain barrier breakdown in brain edema following cold injury is mediated by microvascular polyamines

A focal freeze injury to rat cerebral cortex induces an early (less than 5 min) increase in brain ornithine decarboxylase activity and an accumulation of polyamines involving cerebral microvessels. This polyamine synthesis correlates with the abnormal increase in microvascular permeability, monitored by uptake of Evans Blue and sod. fluorescein. The ornithine decarboxylase inhibitor alpha-difluoromethylornithine suppressed the injury-induced increment in spermidine and spermine and microvascular permeability. Putrescine nullified alpha-difluoromethylornithine inhibition and restored microvessel spermidine and spermine and the pathological increase in microvascular permeability. These results indicate that polyamine synthesis is obligatory for blood-brain barrier breakdown. alpha-Difluoromethylornithine may be useful in the treatment of vasogenic brain edema.     

大鼠液压冲击脑损伤脑干c—jun mRNA表达的定位观察

目的：研究大鼠中度侧位液压冲击脑损伤时脑干c-jun mRNA及其表达产物Jun变化规律。方法：雄性SD大鼠,随机分为正常对照组、手术对照组和损伤组。损伤组动物均给以0.2MPa液压冲击脑损伤,按冲击后处死时间不同再分为5min、15min、30min、1h、2h、4h、8h和12h组。应用免疫组织化学和原位杂交方法观察c-jun在脑干的表达。结果：脑冲击后15min-12h,Jun阳性细胞数逐渐增多。冲击后5min,c-jun mRNA表达开始增强,2h表达最强,然后逐渐减弱。结论：侧位液压冲击脑损伤后c-jun在脑干表达迅速增强,持续时间较长。     

Differential regulation of metallothionein-I and metallothionein-II mRNA expression in the rat brain following traumatic brain injury

In this study, we investigated the expression of metallothionein (MT)-I and MT-II in the rat brain following traumatic brain injury (TBI). In the early stage, significant induction of MT-I and MT-II were observed in various regions including ventricle walls, pia mater, and dentate gyrus. At 12-24 h after TBI, strong induction of MT-I mRNA was observed in cerebral cortical layer II/III, amygdala, and piriform cortex where neurons reside. On the other hand, MT-II appeared to be expressed mainly in glial cells localized in the cerebral cortex and hippocampal formation. Three days after TBI, MTs were observed in the vimentin-positive astrocytes in the penumbra as revealed by double immunohistochemistry. The differences in expression of MT-I and MT-II in different brain regions and cell types (neuron vs. glial cells) suggests that multiple regulatory mechanisms are involved in the control of MT expression following brain injury.     

Decrease in total and free magnesium concentration following traumatic brain injury in rats

31P magnetic resonance spectroscopy was used to determine the intracellular free Mg2+ concentration prior to and following fluid percussion induced traumatic brain injury in rats. Prior to injury, cerebral intracellular free Mg2+ concentration in the rat was 0.93 +/- 0.19 mM (mean +/- SE; n = 5). Following injury, free Mg2+ in the injured cortex declined by 70% within the first hour, and did not recover over the next 3 hours. Total Mg2+ also declined by 10% over this time period; however, there were no changes in brain Na+ or tissue water content. Because of its primary role in cellular metabolism, the early decline in tissue Mg2+ following brain trauma may be a critical factor in the development of irreversible tissue injury.     

Functional gastrointestinal disturbances; recognition and treatment

The recognition of functional gastrointestinal diseases depends essentially on certain positive features characteristic of them. When there are evidences of associated functional disturbances in other organ systems or in the patient as a whole, or characteristic clinical syndromes are present, and there is lack of symptomatic or objective evidence of organic disease on careful examination, the diagnosis of functional gastrointestinal disorder is likely. Treatment of functional gastrointestinal disturbances rests fundamentally on the art of medicine in the treatment of the patient and not on the science of medicine in the treatment of a disease. The essential steps in successful treatment include convincing the patient of the diagnosis, improving and relieving symptoms and avoiding or adequately controlling recurrences.Psychotherapy is a keystone in the treatment of functional gastrointestinal disorders. Not often, however, are the services of a psychiatrist necessary. Given, as needed, mild sedatives, certain forms of specific treatment in specific conditions, general measures and good hygiene and sympathetic understanding, the patient may be expected to recover or improve.     

Oxygen radical mechanisms of brain injury following ischemia and reperfusion.

This review addresses current understanding of oxygen radical mechanisms as they relate to the brain during ischemia and reperfusion. The mechanism for radical production remains speculative in large part because of the difficulty of measuring radical species in vivo. Breakdown of lipid membranes during ischemia leads to accumulation of free fatty acids. Decreased energy stores during ischemia result in the accumulation of adenine nucleotides. During reperfusion, metabolism of free fatty acids via the cyclooxygenase pathway and metabolism of adenine nucleotides via the xanthine oxidase pathway are the most likely sources of oxygen radicals. Although leukocytes have been found to accumulate in some models of ischemia and reperfusion, their mechanistic role remains in question. Therapeutic strategies aimed at decreasing brain injury have included administration of radical scavengers at the time of reperfusion. Efficacy of traditional oxygen radical scavengers such as superoxide dismutase and catalase may be limited by their inability to cross the blood-brain barrier. Lipid-soluble antioxidants appear more efficacious because of their ability to cross the blood-brain barrier and because of their presence in membrane structures where peroxidative reactions can be halted.     

Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia

Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking. Following neonatal H-I brain injury in mice (a model of cerebral palsy), there was evidence of apoptotic changes (neuronal caspase-3 activation), as well as accumulation of clusterin in dying neurons. Clusterin-deficient mice had 50% less brain injury following neonatal H-I. Surprisingly, the absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation-induced necrotic death. These results indicate that clusterin may be a new therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury.     

Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury.This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation.     

Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury

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Mitochondrial respiratory chain and creatine kinase activities following trauma brain injury in brain of mice preconditioned with N-methyl-d-aspartate

Traumatic brain injury (TBI) induces glutamatergic excitotoxicity through N-methyl-d-aspartate (NMDA) receptors, affecting the integrity of the mitochondrial membrane. Studies have pointed to mitochondria as the master organelle in the preconditioning-triggered endogenous neuroprotective response. The present study is aimed at understanding energy metabolism in the brains of mice after preconditioning with NMDA and TBI. For this purpose, male albino CF-1 mice were pre-treated with NMDA (75 mg/kg) and subjected to brain trauma. Mitochondrial respiratory chain and creatine kinase activities were assessed at 6 or 24 h after trauma. The mice preconditioned and subjected to TBI exhibited augmented activities of complexes II and IV in the cerebral cortex and/or cerebellum. Creatine kinase activity was also augmented in the cerebral cortex after 24 h. We suggest that even though NMDA preconditioning and TBI have similar effects on enzyme activities, each manage their response via opposite mechanisms because the protective effects of preconditioning are unambiguous. In conclusion, NMDA preconditioning induces protection via an increase of enzymes in the mitochondria.     

Liver ultrastructural changes following portal circulation disturbances

Liver cell changes produced in rats by the ligature of the portal vein and of the spleen pedicle were studied by electron microscopy. There were differences in the liver response to the various types of circulatory disturbances. The earliest and most marked lesions of hepatic cells were noticed in the case of portal vein ligature, and occurred at the level of rough endoplasmic reticulum, mitochondria and lysosomes. No significant changes in Kupffer cells. When the spleen pedicle was ligated, the hepatic cell changes were less obvious, but the Kupffer cells changes were more prominent, testifying and increased hetero- and autophagy.