大鼠大脑中动脉缺血和再灌注后环氧合酶-2mRNA表达的研究

目的研究大鼠大脑中动脉缺血和再灌注模型中环氧合酶－２（ＣＯＸ－２）基因的表达。方法原位杂交方法。结果缺血３０ｍｉｎ再灌注组,血流再通４ｈ后缺血区的大脑皮层有很强的表达并持续２４ｈ。缺血９０ｍｉｎ再灌注组和持续缺血组在缺血区以外的广泛大脑皮层显著表达,在海马的齿状回两侧及纹状体也发现表达。ＣＯＸ－２ｍＲＮＡ的表达可被ＭＫ－８０１抑制。而ＮＢＱＸ和倍他米松对其表达没有影响。结论在缺血区、缺血周边部、缺血远隔区有ＮＭＤＡ受体介导的ＣＯＸ－２表达,阐明上述区域花生四烯酸代谢活性化     

Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine

Functional brain imaging studies of subjects with Major Depressive Disorder (MDD) have suggested that decreased dorsolateral (DLPFC) and increased ventrolateral (VLPFC) prefrontal cortical activity mediate the depressed state. Pre- to post-treatment studies indicate that these abnormalities normalize with successful treatment. We performed [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans on 16 outpatients with MDD before and after treatment with paroxetine (target dose = 40 mg/day). Regions of interest (ROIs) for this analysis were drawn by a rater blind to subject identity on the magnetic resonance image of each subject and transferred onto their coregistered PET scans. We hypothesized that DLPFC metabolism would increase, while ventral frontal metabolism [in the VLPFC, the orbitofrontal cortex (OFC), and the inferior frontal gyrus (IFG)] would decrease with successful treatment. Treatment response was defined as a decrease in the Hamilton Depression Rating Scale of > 50% and a Clinical Global Improvement Scale rating of 'much' or 'very much' improved. By these criteria, nine of the subjects were classified as treatment responders. These responders had significantly greater decreases in normalized VLPFC and OFC metabolism than did non-responders. There were no significant effects of treatment response on change in the DLPFC or IFG in this sample. However, there was a positive correlation between change in HAM-D scores and change in normalized IFG and VLPFC metabolism. There were no significant interactions with laterality. On pre-treatment scans, lower metabolism in the left ventral anterior cingulate gyrus was associated with better treatment response. These findings implicate ventral prefrontal-subcortical brain circuitry in the mediation of response to serotonin reuptake inhibitors in MDD.     

Polymorphisms at - 174 and in the 3' flanking region of interleukin-6 (IL-6) gene in patients with myasthenia gravis

We examined the bi-allelic polymorphism at - 174 in the promoter region and the polymorphism in the 3' flanking AT rich region of the interleukin-6 (IL-6) gene in Swedish patients with myasthenia gravis (MG) and ethnically matched healthy individuals. There was no association between the polymorphisms and the disease. There was no relation of the polymorphisms to the clinical variables, the thymic histopathologies, the level of serum acetylcholine receptor antibodies or the concentrations of IgG and its subclasses. Our data yield no evidence for the IL-6 gene contributing to the disease susceptibility.     

Dendritic cells in experimental allergic encephalomyelitis and multiple sclerosis

The mechanisms by which autoimmune diseases are triggered and by which the activation of autoreactive T cells is initiated and maintained are not yet fully understood. As the most potent antigen presenting cells (APC), and also being responsible for antigen transport as well as primary sensitisation of T cells, dendritic cells (DC) are capable of breaking the state of self-ignorance and inducing aggressive autoreactive T cells. In the development of autoimmune diseases, different types of DC exhibit distinct properties for inducing Th1/Th2 cell responses. Appropriate cytokines can convert immunogenic DC to tolerogenic DC. Utilizing the possibility to promote the tolerogenic effects of DC, a new therapeutic tool might soon become available to treat multiple sclerosis and other autoimmune diseases.     

The tyrosine kinase inhibitor genistein directly inhibits GABAA receptors

The protein tyrosine kinase (PTK) inhibitor genistein has been widely used to examine potential effects of tyrosine phosphorylation on neurotransmitter function. We report here that genistein inhibits GABAA receptors through a direct effect. Extracellular application of genistein and GABA reversibly inhibited GABA-activated currents recorded from HEK293 cells expressing rat alpha1beta2gamma2S or alpha1beta2 receptors, even when genistein was preequilibrated in the intracellular solution. Daidzein, an analog of genistein that does not block PTK, also inhibited GABA-activated current. Coapplication of lavendustin A, a specific inhibitor of PTK, had no effect on the GABA response. Our results demonstrate that genistein has a direct inhibitory effect on GABAA receptors that is not mediated via inhibition of tyrosine kinase.     

Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia

OBJECTIVE: Tracer constants (Ki) for blood-to-brain diffusion of sucrose were measured in the rat to profile the time course of blood-brain barrier injury after temporary focal ischemia, and to determine the influence of post-ischemic hypothermia. METHODS: Spontaneously hypertensive rats were subjected to transient (2 hours) clip occlusion of the right middle cerebral artery. Reperfusion times ranged from 1.5 min to 46 hours, and i.v. 3H-sucrose was circulated for 30 min prior to each time point (1 h, 4 h, 22 h, and 46 h; n = 5-7 per time point). Ki was calculated from the ratio of parenchymal tracer uptake and the time-integrated plasma concentration. Additional groups of rats (n = 7-8) were maintained either normothermic (37.5 degrees C) or hypothermic (32.5 degrees C or 28.5 degrees C) for the first 6 hours of reperfusion, and Ki was measured at 46 hours. RESULTS: Rats injected after 1.5-2 min exhibited a 10-fold increase in Ki for cortical regions supplied by the right middle cerebral artery (p < 0.01). This barrier opening had closed within 1 to 4 hours post-reperfusion. By 22 hours, the blood-brain barrier had re-opened, with further opening 22 and 46 hours (p < 0.01), resulting in edema. Whole body hypothermia (28 degrees C-29 degrees C) during the first six hours of reperfusion prevented opening, reducing Ki by over 50% (p < 0.05). CONCLUSIONS: Transient middle cerebral artery occlusion evokes a marked biphasic opening of the cortical blood-brain barrier, the second phase of which causes vasogenic edema. Hypothermic treatment reduced infarct volume and the late opening of the blood-brain barrier. This opening of the blood-brain barrier may enhance delivery of low permeability neuroprotective agents.     

Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.     

Diaschisis in chronic viral encephalitis with Koshevnikov syndrome.

The authors report a 61-year-old man with chronic viral encephalitis and Koshevnikov syndrome occurring 42 months after initial symptom of right hemiparesis. Serial computed tomography of the brain showed changes in the attenuation of the left temporal lobe lesion over time. Magnetic resonance images of the brain showed enlargement of left temporoparietooccipital lobes with cortical gyral enhancement on T1-weighted images following intravenous administration of gadolinium-DTPA. 99mTc-HMPAO single-photon emission computerized tomography showed increased radioactivity and hyperperfusion in the left temporoparietal region with paradoxically decreased local tissue perfusion at the contralateral right hemisphere. Follow-up magnetic resonance images of the brain 4 years later showed atrophy of bilateral cerebral hemispheres. We postulate that a "transcallosal diaschisis" with subsequent degeneration is a possible mechanism. A brain biopsy from the left temporal lobe lesion showed pictures compatible with viral encephalitis probably herpes simplex encephalitis.     

Intra-arterial infusion chemotherapy for penile carcinoma with deep inguinal lymph node metastasis

From July 1994 to January 1999, three patients with penile squamous cell carcinoma with deep inguinal lymph node metastases without distant metastases were treated with multimodality treatment including intra-arterial infusion chemotherapy mainly with monthly courses of cisplatin, methotrexate and bleomycin. One patient achieved a complete response and 2 achieved a partial response. It appears to be reasonable to presume that intra-arterial chemotherapy has a beneficial effect in the management of penile cancer with fixed metastatic inguinal lymph nodes, but a larger number of patients and longer follow-up are required to confirm these results.