Ischemia aggravating effects of platelet-activating factor in acute myocardial ischemia

Summary The effect of platelet-activating factor (PAF) was studied during the acute phase of myocardial ischemia in cats. PAF infusion (0.75 g/kg/h for 4.5 h) in anesthetized, open-chest cat decreased arterial blood pressure, but did not influence heart rate or biochemical indices of cell integrity. The same dose of PAF, however, started 30 min after coronary ligation, resulted in a significantly higher elevation of plasma creatine phosphokinase (CK) activity and a reduced CK content in the region of the ischemic myocardium. Treatment with the thromboxane A₂ synthetase inhibitor, CGS-13080, significantly attenuated the PAF-aggravated ischemic cellular damage. These experiments suggest that hypoxiagenerated PAF may contribute to the aggravation of myocardial ischemia, part of which appears to be due to PAF-induced release of thromboxane A₂.Supported in part by Research Grant No. HL-5565 from the National Heart, Lung and Blood Institute of the NIH.     

Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model of Down syndrome

The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of their CNS due to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age‐related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration in TS mice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed in TS mice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition in TS mice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampal LTP in trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus of TS mice. These results indicate that the cognitive‐enhancing effects of melatonin in adult TS mice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression of DS neuropathology.     

Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice

In the course of adult hippocampal neurogenesis, the postmitotic maturation and survival phase is associated with dendrite maturation. Melatonin modulates the survival of new neurons with relative specificity. During this phase, the new neurons express microtubule-associated protein doublecortin (DCX). Here, we show that the entire population of cells expressing DCX is increased after 14 days of treatment with melatonin. As melatonin also affects microtubule polymerization which is important for neuritogenesis and dendritogenesis, we studied the consequences of chronic melatonin administration on dendrite maturation of DCX-positive cells. Treatment with melatonin increased the number of DCX-positive immature neurons with more complex dendrites. Sholl analysis revealed that melatonin treatment lead to greater complexity of the dendritic tree. In addition, melatonin increased the total volume of the granular cell layer. Besides its survival-promoting effect, melatonin thus also increases dendritic maturation in adult neurogenesis. This might open the opportunity of using melatonin as an adjuvant in attempts to extrinsically stimulate adult hippocampal neurogenesis in neuropsychiatric disease, dementia or cognitive ageing.     

肠系膜血管缺血外科诊治进展

肠系膜血管缺血(acute mesenteric ischemia,AMI)是潜在致命的血管性急腹症.死亡率很高,且发病率不断上升.形成AMI的原因是多样的,临床经过和预后取决于基础的病理状态.尽管对肠系膜缺血病理生理研究的深入和现代治疗方法上的改进,存活率没有显著的提高.AMI仍然存在诊断上的挑战,延误诊断会提高死亡率.临床表现在大多数病例没有特征性.当肠缺血迅速的发展为不可逆的肠坏死,随后出现严重的代谢紊乱,最后发展成为多器官功能不全以致死亡.及时地诊断和处理,快速有效地恢复肠系膜血流是改善预后的关键.     

Alterations in synaptosomal membrane Na,K-ATPase of the gerbil cortex and hippocampus following reversible brain ischemia

The present experiments were designed to determine the kinetic pattern of Na,K-ATPase in the presence of varying concentrations of Na⁺ and K⁺ ions in controls and gerbils exposed to 1 and 5 min of ischemia, respectively, and 60min and 4 days of recirculation following 5 min of transient ischemia. The pattern of Na,K-ATPase activity in the control cerebral cortex and hippocampus is different. The cortical Na,K-ATPase apparently is more resistant in keeping an optimal activity than the enzyme in the hippocampus. After ischemic insult of either 1 or 5 min in duration, the enzyme activity is inhibited in both brain structures. 4 days after 5 min of ischemia, indicating greater flexibility of the cortical enzyme or less damage than in the hippocampus. Furthermore, the data obtained show that only through the enzyme behavior and kinetic parameters is it possible to reach conclusions about the enzyme function or dysfunction under pathological conditions.     

Peptidergic influences on proliferation, migration, and placement of neural progenitors in the adult mouse forebrain

Neural progenitor proliferation, differentiation, and migration are continually ongoing processes in the subventricular zone (SVZ) and rostral migratory stream (RMS) of the adult brain. There is evidence that peptidergic systems may be involved in the molecular cascades regulating these neurogenic processes, and we examined a possible influence of neuropeptide Y (NPY) and cholecystokinin (CCK) systems in cell proliferation and neuroblast formation in the SVZ and RMS and generation of interneurons in the olfactory bulb (OB). We show that NPY and the Y1 and Y2 receptor (R) proteins are expressed in and surrounding the SVZ and RMS and that Y1R is located on neuroblasts in the anterior RMS. Mice deficient in Y1Rs or Y2Rs have fewer Ki-67-immunoreactive (ir) proliferating precursor cells and doublecortin-ir neuroblasts in the SVZ and RMS than WT mice, and less calbindin-, calretinin-, and tyrosine hydroxylase-ir interneurons in the OB. Mice lacking CCK1Rs have fewer proliferating cells and neuroblasts than normal and a shortage of interneurons in the OB. These findings suggest that both NPY and CCK through their receptors help to regulate the proliferation of precursor cells, the amount of neuroblast cells in the SVZ and RMS, and influence the differentiation of OB interneurons.     

急性肠系膜动脉性缺血26例

目的:探讨急性肠系膜动脉性缺血的诊断及治疗.方法:回顾分析26例急性肠系膜动脉性缺血的临床特征、诊断、治疗及预后.结果:入院后确诊11例,其中:彩色多普勒超声6例,螺旋CT 9例,血管造影5例.其余15例因血性腹水探查术中确诊.全身抗凝治疗4例,Fogarty导管取栓术后完全恢复5例,小肠部分切除8例,小肠大部及右半结肠切除7例,2次探查术2例.术后6mo内死亡6例.结论:超声可作为急性肠系膜动脉性缺血患者的初步检查,发现血性腹水者及早行剖腹探查术.早期诊断与治疗使降低肠系膜血管死亡率和致残率的关键.     

Alterations in the time course of expression of the Nox family in the brain in a rat experimental cerebral ischemia and reperfusion model: effects of melatonin

Ischemia–reperfusion (I/R) injury induces the generation of reactive oxygen species (ROS), which results in a poor prognosis for ischemic stroke patients. This study was designed to evaluate the time course of expression of the Nox family, a major source of ROS, and whether melatonin, a potent scavenger of ROS, influences these parameters in a rat model of cerebral I/R caused by middle cerebral artery occlusion (MCAO). After 2‐hr occlusion, the filament was withdrawn to allow reperfusion. At 0, 3, 6, 12, 24, and 48 hr after reperfusion, brain tissue samples were obtained for assays. Among the Nox family, the mRNA and protein levels of Nox2 and Nox4 were increased both in the ischemic hemisphere and contralateral counterpart in the experimental I/R rats at 0 hr after reperfusion, peaked at 3 hr, and then returned to the basal level at 24 hr. Double‐immunofluorescence staining further confirmed the expressions of Nox2 and Nox4 in three major types of brain cells, including neurons, astrocytes, and endothelial cells. In addition, melatonin (5 mg/kg) or its vehicle was injected intraperitoneally at 0.5 hr before MCAO. Compared with I/R + vehicle group, melatonin pretreatment diminished the increased expression of Nox2 and Nox4, reduced ROS levels, and inhibited cell apoptosis. Our findings suggested that the inhibition of Nox2 and Nox4 expressions by melatonin may essentially contribute to its antioxidant and anti‐apoptotic effects during brain I/R.     

Spatial and temporal changes in tissue pH and ATP distribution in a new model of reversible focal forebrain ischemia in the rat

The effects of reversible middle cerebral artery occlusion on regional pH and ATP distribution were studied in a new stroke model in rats by a planimetric method. Thirty minutes of ischemia was followed by 2, 4 and 24 hours of reperfusion. Ischemia resulted in acidosis and ATP depletion. In some areas tissue pH reached the threshold of the umbelliferone method (about pH 6.0). Areas with ATP depletion were significantly smaller than regions of pH alteration not only at the end of ischemia but during the first 4 hours of recirculation as well. By 4 hours of reperfusion large areas with altered pH were associated with ATP depletion in smaller regions, mostly in the hippocampus and the frontal cortex. The areas of ATP depletion were acidic initially, but by 4 hours alkaline pH could also be detected. Twenty four hours after ischemia alkaline areas (pH>7.4) were found with ATP depletion, suggesting irreversible tissue damage, in cortical areas, in the hippocampus, and in the thalamus. By 24 hours of reperfusion there was no significant difference between the size of areas with altered pH and ATP depletion.     

Chronic hypoxia modulates the function and expression of melatonin receptors in the rat carotid body

Melatonin modulates the carotid chemoreceptor response to chemical stimuli, and chronic hypoxia changes circadian activities and carotid body function. The purpose of this study was to test the hypothesis that chronic hypoxia alters the function and expression of melatonin receptors in the rat carotid body. Effects of melatonin on the carotid responses to hypercapnic acidosis and to hypoxia were determined by spectrofluorometric measurement of cytosolic calcium ([Ca(2+)](i)) in fura-2-loaded type-I (glomus) cells dissociated from carotid bodies obtained from normoxic (Nx) or chronically hypoxic (CH) rats breathing 10% oxygen for 4 wk. In the Nx control, melatonin concentration dependently attenuated the peak [Ca(2+)](i) response to hypercapnic acidosis, whereas it augmented the [Ca(2+)](i) response to cyanide or deoxygenated buffer. Yet, melatonin enhanced the peak [Ca(2+)](i) responses to hypercapnic acidosis or hypoxia in the CH glomus cells. An agonist of melatonin receptors, iodomelatonin also elevated the hypercapnic or hypoxic responses in the CH groups. The melatonin-induced changes in the [Ca(2+)](i) responses were abolished by pretreatment with nonselective mt(1)/MT(2) antagonist, luzindole, and by MT(2) antagonists, 4-phenyl-2-propionamidotetraline or DH97. These findings suggest a functional modulation of melatonin receptors in the glomus cells in chronic hypoxia. To evaluate the level of expression of the melatonin receptors, in situ hybridization study with antisense mt(1) and MT(2) receptor mRNA oligonucleotide probes was performed on the Nx and CH carotid bodies. There were significant increases in the expression of mt(1) and MT(2) receptors in the CH comparing with the Nx group. Taken together, our results suggest an upregulation of the carotid expression of melatonin receptors by chronic hypoxia, which modulates the carotid response to melatonin for the circadian influence on breathing.     

Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice

Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder “jet lag” disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro‐neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag‐induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro‐neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate “jet lag” by shortening the dark period every third day by 6 hours for 3 weeks. We found that “jet lag” simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag‐induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.     

Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1

Melatonin has previously been shown to be neuroprotective in rodent models of ischemic stroke. Herein, we tested whether this antioxidant may also be suitable for prophylactic use against stroke. To clarify this issue, melatonin was administrated orally for 9 wk (4 mg/kg/day) in mice and its effects on subsequent injury development after 90 min of intraluminal middle cerebral artery (MCA) occlusion were tested. To evaluate its neuroprotective properties, the protective actions of prophylactic melatonin were compared with both acute melatonin (4 mg/kg, i.p.) administration and with a diluent (sham)-treated control condition. MCA occlusion resulted in reproducible ischemia, as revealed by laser Doppler flowmetry; this was followed by a rapid restoration of blood flow immediately after reperfusion onset. Laser Doppler flow values after reperfusion onset were moderately elevated by melatonin, both when the indole was given prophylactically and when acutely administrated after stroke. In control animals, reproducible brain infarcts were observed 24 hr after reperfusion onset. Treatment with melatonin significantly reduced the infarct size by approximately 30-35%, independent of whether the indole was given prophylactically before or acutely after ischemia. To test whether brain protection involved vascular mechanisms, as suggested earlier, the effects of melatonin on endothelin converting enzyme-1 (ECE-1) levels were studied using Western blots. Interestingly, delivery of melatonin was accompanied by a marked inhibition of ECE-1 levels, which was similarly seen after both acute and chronic melatonin treatment. Our data suggest that melatonin, given at pharmacological doses, may be suitable as a prophylaxis against stroke. Tissue protection may involve an inhibition of ECE-1, which improves vasodilation, after ischemia.     

T vector and loop characteristics in coronary artery disease and during acute ischemia

OBJECTIVE: Three-dimensional characterization of the ventricular repolarization by the T vector and T vector loop morphology in coronary artery disease (CAD), and their response to short-term (no flow) ischemia induced by coronary occlusion during a percutaneous intervention (PCI). BACKGROUND: The risk for sudden cardiac death is increased in conditions of acute or permanently heterogeneous ventricular repolarization, for which ischemia is a risk factor. METHODS: Fifty-six CAD patients without visible collateral circulation were studied during an elective single-vessel PCI, and 10 healthy controls twice at rest. T vector parameters (Televation, Tazimuth, and QRS-T angle), and T loop parameters (Tarea, Tavplan, and Teigenv) were measured by vectorcardiography. ST vector magnitude (ST-VM) and its change (STC-VM) were used for reference. RESULTS: At rest, T vector loop morphology (Tarea, Teigenv) was significantly different in CAD patients and controls, while T vector angles did not separate the groups. Ischemia induced significant changes in T loop parameters in the entire CAD group, whereas in the LAD subgroup significant changes were seen also in T vector angle. The T loop morphology was significantly different at baseline and a more pronounced response to ischemia (Tarea) was seen in patients with, than in those without, a history of hypertension. CONCLUSION: T loop morphology, rather than the T vector angle, separated CAD patients from healthy controls. Coronary occlusion had significant impact on ventricular repolarization, as assessed by T vector and morphology analysis, and most prominently in the LAD group. Hypertensive patients appeared especially vulnerable to ischemia.     

Randomized controlled trial for the efficacy of hepatic arterial occlusion during radiofrequency ablation for small hepatocellular carcinoma--direct ablative effects and a long-term outcome.

OBJECTIVE: To evaluate the efficacy of temporary balloon arterial occlusion during radiofrequency ablation (RFA), randomized controlled trial was performed. METHODS: Twenty patients with hypervascular hepatocellular carcinoma measuring 相似文献   

Pinealectomy exaggerates and melatonin treatment suppresses neuroma formation of transected sciatic nerve in rats: gross morphological, histological and stereological analysis

At present, an intensive effort for prevention of neuroma formation following peripheral nerve section continues. It has been recently suggested that surgical pinealectomy (Px) induces elevation of the collagen content in the granulation tissue of a wound, while melatonin application after Px suppresses elevation of the collagen accumulation in the tissue. The aim of the present study was to assess whether melatonin had the ability to suppress collagen production and neuroma formation following peripheral nerve transection. A total of 40 male rats (four groups of 10) were left intact (intact controls) or sham operated (sham group), were Px, or were Px and given melatonin (Px + melatonin group). All animals underwent a surgical intervention consisting of right sciatic nerve neurectomy. After 4 wk, the animals were killed following intracardiac perfusion. Gross morphology of neuroma formation in the proximal nerve segment was examined and proximal neuroma evaluated. Macroscopic and microscopic findings revealed that Px caused a proliferation of connective tissue and large neuroma formation at the proximal ends of transected nerves. Stereological analysis showed that there was a statistically significant reduction in connective tissue content of the same region in Px animals treated with melatonin (P < 0.005). The results achieved in a rodent model of sciatic nerve neuroma formation showed that there was a positive correlation between macroscopic and microscopic observations, and that melatonin enhanced axonal regeneration presumably due to its inhibitory effect on neuroma formation.     

急性坏死性胰腺炎胰腺组织中褪黑激素受体表达及褪黑激素干预作用

目的 探讨急性坏死性胰腺炎(ANP)胰腺组织中褪黑激素受体MT1表达及褪黑激素(MT)干预作用.方法 54只SD大鼠随机分为假手术组(SO组)、急性坏死性胰腺炎组(ANP组)、MT干预组(MT组),每组18只.应用胰胆管逆行注射牛磺胆酸钠的方法诱导ANP模型,MT组于诱导模型前30 min腹腔注射MT.术后4 h、8 h和12 h分批处死大鼠(每个时间点6只),以免疫组化和实时定量PCR分别检测胰腺组织中MT1蛋白及MT1 mRNA的表达;检测血清淀粉酶、胰腺组织中丙二醛(MDA)、超氧化物歧化酶(SOD)及TNFα的含量,并行胰腺病理检查.结果 (1)ANP组胰腺病理损伤呈进行性加重,MT组胰腺病理损伤较ANP组明显减轻(P＜0.05).(2)淀粉酶、MDA、TNFα水平在ANP组较S0组明显增高(P＜0.05或P＜0.01),而MT组较相应时间点ANP组显著降低[12 h,(2348.00±278.90)U/L比(3194.83±538.10)U/L,(2.255±0.472)μmol/L比(2.960±0.722)μmol/L,(102.929±29.399)ng/L比(378.544±183.454)ng/L,P＜0.05].SOD水平在ANP组各时点较SO组显著降低(P＜0.01),而MT组较ANP组显著升高[12 h,(11.448±1.594)U/L比(8.427±1.950)U/L,P＜0.05].(3)与SO组相比,MT1蛋白及MT1 mRNA表达在ANP组胰腺组织中明显下降(P＜0.05),且随ANP病变加重表达减弱,而MT组表达较ANP组明显增多.结论 MT干预可提高SOD活力,降低MDA、TNFα水平,故能显著减轻ANP时胰腺病理损伤,MT1在ANP发病机制中可能具有重要作用,MT对ANP中的干预作用可能与上调胰腺组织中MT1的表达有关.     

Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients

BACKGROUND: Uric acid (UA) may be involved in chronic heart failure (HF) pathogenesis, entailing a worse outcome. The purpose of this study was to examine the role of hyperuricaemia as a prognostic marker after hospital discharge in acute HF patients. METHODS: We studied 212 patients consecutively discharged after an episode of acute HF with LVEF<40%. Blood samples for UA measurement were extracted in the morning prior to discharge. The evaluated endpoints were death and new HF hospitalization. RESULTS: Mean UA levels were 7.4+/-2.4 mg/dl (range 1.6 to 16 mg/dl), with 127 (60%) of patients being within the range of hyperuricaemia. Hyperuricaemia was associated with a higher risk of death (n=48) (HR 2.0, 95% CI 1.1-3.9, p=0.028), new HF readmission (n=67) (HR 1.8, 95% CI 1.1-3.1, p=0.023) and the combined event (n=100) (HR 1.9, 95% CI 1.2-2.9, p=0.004). At 24 months, cumulative event-free survival was lower in the two higher UA quartiles (36.9% and 40.7% vs. 63.5% and 59.5%, log rank=0.006). After adjustment for potential confounders, hyperuricaemia remains an independent risk factor for adverse outcomes (HR 1.6, 95% CI 1.1-2.6, p=0.02). CONCLUSIONS: In hospitalized patients with acute HF and LV systolic dysfunction, hyperuricaemia is a long-term prognostic marker for death and/or new HF readmission.     

Long-term observations in gerbil brain following transient cerebral ischemia: Autoradiographic and histological study

We investigated the long-term changes that occur in the gerbil brain following transient cerebral ischemia using histology and receptor autoradiography. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for 8 months. A histological study showed that 3-min ischemia caused neuronal damage and mild atrophy only in the hippocampal CA1 sector, and that 10-min ischemia produced severe neuronal damage and marked shrinkage in the hippocampal CA1 and CA3 sectors. Furthermore, severe neuronal damage was seen in the striatum after 10-min ischemia. Autoradiography study revealed that 3-min ischemia caused a significant reduction in [³H] naloxone binding in the frontal cortex, striatum, dentate gyrus, and thalamus, whereas [³H]SCH 23390 and [³H] forskolin binding was not significantly altered in all regions, In contrast, 10-min ischemia produced marked alteration in these binding sites in the striatum, hippocampus, thalamus, and substantia nigra. The alteration was especially notable in the hippocampal region and substantia nigra. These results indicate that hippocampal damage after transient ischemia, compared with that in other regions, is not static, but particularly progressive. Furthermore, they demonstrate a reduction in adenylate cyclase system in the striatum and substantia nigra after transient ischemia. Moreover, our results suggest that long-term survival after ischemia may induce synaptic modification of neurotransmitter and adenylate cyclase system in the hippocampus.