Selective inhibitory synapse loss in chronic cortical slabs: a morphological basis for epileptic susceptibility.

Electron microscopic examination of pyramidal neurones at the edges of chronic slabs of cerebral cortex in the cat revealed a selective loss of inhibitory (symmetric axosomatic) synapses compared with pyramidal neurones in the centers of the slabs. It appears likely that the neurons at the edges, which retain excitatory input (asymmetric axodendritic synapses) in the neurophil, but totally lack the somatic inhibitory input, act as the focus for the prolonged seizure activity which occurs in chronic cortical slabs

Increased levels of amino acid neurotransmitters in the inferior colliculus of the genetically epilepsy-prone rat.

Previous studies have shown an increase in the number of GABAergic and total neurons in the inferior colliculus (IC) of the genetically epilepsy-prone rat (GEPR). Amino acid analysis of the central nucleus of the IC, as well as cerebellum, sensorimotor, temporal, and occipital cerebral cortices of GEPRs with high pressure liquid chromatography showed significant increases in the levels of GABA, taurine and glutamate. The IC of GEPR displayed a 2.3-fold increase in GABA as compared to that of non-epileptic rats, a 2.4-fold increase of taurine, and a 1.9-fold increase of glutamate. In addition, taurine and glutamate were increased in the sensorimotor and temporal cortex, respectively. These results are consistent with previous anatomical data on the GABAergic system in the IC and provide additional information. The increase in taurine and glutamate in the IC indicates that other neurotransmitters could be involved in the mechanism of seizure activity

Solubility and Permeation of Hydrogen Sulfide in Lipid Membranes

Hydrogen sulfide (H2S) is mainly known for its toxicity but has recently been shown to be produced endogenously in mammalian tissues and to be associated with physiological regulatory functions. To better understand the role of biomembranes in modulating its biological distribution and effects; we measured the partition coefficient of H2S in models of biological membranes. The partition coefficients were found to be 2.1±0.2, 1.9±0.5 and 2.0±0.6 in n-octanol, hexane and dilauroylphosphatidylcholine liposome membranes relative to water, respectively (25°C). This two-fold higher concentration of H2S in the membrane translates into a rapid membrane permeability, Pm = 3 cm s−1. We used a mathematical model in three dimensions to gain insight into the diffusion of total sulfide in tissues. This model shows that the sphere of action of sulfide produced by a single cell expands to involve more than 200 neighboring cells, and that the resistance imposed by lipid membranes has a significant effect on the diffusional spread of sulfide at pH 7.4, increasing local concentrations. These results support the role of hydrogen sulfide as a paracrine signaling molecule and reveal advantageous pharmacokinetic properties for its therapeutic applications

Hydrogen Sulfide Attenuated Tumor Necrosis Factor-α-Induced Inflammatory Signaling and Dysfunction in Vascular Endothelial Cells

S donor) on tumor necrosis factor (TNF)-α-induced human umbilical vein endothelial cells (HUVEC) dysfunction.Application of NaHS concentration-dependently suppressed TNF-α-induced mRNA and proteins expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), mRNA expression of P-selectin and E-selectin as well as U937 monocytes adhesion to HUVEC. Western blot analysis revealed that the expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1), was induced and coincident with the anti-inflammatory action of NaHS. Furthermore, TNF-α-induced NF-κB activation assessed by IκBα degradation and p65 phosphorylation and nuclear translocation and ROS production were diminished in cells subjected to treatment with NaHS.S can exert an anti-inflammatory effect in endothelial cells through a mechanism that involves the up-regulation of HO-1

Selective inhibitory synapse loss in chronic cortical slabs: a morphological basis for epileptic susceptibility.

Electron microscopic examination of pyramidal neurones at the edges of chronic slabs of cerebral cortex in the cat revealed a selective loss of inhibitory (symmetric axosomatic) synapses compared with pyramidal neurones in the centers of the slabs. It appears likely that the neurons at the edges, which retain excitatory input (asymmetric axodendritic synapses) in the neurophil, but totally lack the somatic inhibitory input, act as the focus for the prolonged seizure activity which occurs in chronic cortical slabs

Guidelines on how to assess the validity of results presented in subgroup analysis of clinical trials Critérios para avaliar a validade dos resultados apresentados em análises de subgrupo em ensaios clínicos

In observational studies, identification of associations within particular subgroups is the usual method of investigation. As an exploratory method, it is the bread and butter of epidemiological research. Nearly everything that has been learned in epidemiology has been derived from the analysis of subgroups. In a randomized clinical trial, the entire purpose is the comparison of the test subjects and the controls, and when there is particular interest in the results of treatment in a certain section of trial participants, a subgroup analysis is performed. These subgroups are examined to see if they are liable to a greater benefit or risk from treatment. Thus, analyzing patient subsets is a natural part of the process of improving therapeutic knowledge through clinical trials. Nevertheless, the reliability of subgroup analysis can often be poor because of problems of multiplicity and limitations in the numbers of patients studied. The naive interpretation of the results of such examinations is a cause of great confusion in the therapeutic literature. We emphasize the need for readers to be aware that inferences based on comparisons between subgroups in randomized clinical trials should be approached more cautiously than those based on the main comparison. That is, subgroup analysis results derived from a sound clinical trial are not necessarily valid; one must not jump to conclusions and accept the validity of subgroup analysis results without an appropriate judgment.<br>Em estudos de observação, a identificação de associações dentro de subgrupos particulares é o método habitual de investigação. Como um método exploratório, faz parte do dia-a-dia da pesquisa epidemiológica. Quase tudo o que se sabe hoje em Epidemiologia foi derivado da análise de subgrupo. Em ensaios clínicos randomizados, o propósito principal é a comparação dos indivíduos sob experimentação e os controles, e quando nós estamos particularmente interessados nos resultados do tratamento em uma certa seção de participantes do ensaio, uma análise de subgrupo é executada. Estes subgrupos são examinados para verificar se eles foram objeto de um maior benefício ou malefício secundário ao tratamento. Assim, analisar subconjuntos de pacientes é uma parte natural do processo de melhorar o conhecimento terapêutico através de ensaios clínicos randomizados. Não obstante, a confiança na análise de subgrupo pode ser pobre devido a problemas de multiplicidade de comparações e limitações em números de pacientes estudados. A interpretação simplista dos resultados de tal técnica é uma causa de grande confusão na literatura terapêutica. Nós enfatizamos a necessidade de chamar a atenção dos leitores que as conclusões baseadas em comparações entre subgrupos em ensaios clínicos randomizados sejam examinadas com mais cautela do que aquelas baseadas na comparação principal. Ou seja, resultados de análise de subgrupo provenientes de ensaios clínicos corretamente desenhados não são necessariamente válidos, portanto, não devemos tirar conclusões precipitadas e aceitar a validade dos resultados sem um julgamento judicioso

Cocaine and neuronal uptake in the canine saphenous vein

This study was designed to investigate the effects of the neuronal uptake inhibitor, cocaine on the adrenergic neuroeffector interaction in the canine saphenous vein. Tissues were incubated with 3H-noradrenaline in control solution or in presence of the cocaine. The tissue content of 3H-noradrenaline and its metabolites was determined after the incubation. As the concentration of cocaine in the incubation medium increased, gradually less 3H-noradrenaline and DOPEG were detected in the tissue, while the content of DOMA, NMN, MOPEG and, in particular that of VMA increased; comparable results were obtained with high concentrations of cocaine and desmethylimipramine (DMI). Helical strips of canine saphenous veins were incubated with 3H-noradrenaline and mounted for isometric tension recording and for measurement of the efflux of labelled transmitter and its metabolites. Cocaine, but not DMI, slightly increased the spontaneous efflux of DOPEG, suggesting that cocaine enters the nerve terminals and displaces noradrenaline from its storage sites. During electrical stimulation, cocaine at 3 x 10-5 mol/l increased the contractile response and the overflow of 3H-noradrenaline, DOMA, NMN and MOPEG and decreased the appearance of DOPEG. Similar results were obtained with DMI (10-6 mol/l) except that it did not increase the overflow of DOMA and MOPEG. During electrical stimulation in presence of DMI, cocaine did not affect the contractile response and decreased the appearance of intact labelled transmitter. Electrical stimulation, cocaine and DMI did not affect the overflow of VMA. The present experiments indicate that in the canine saphenous vein: (1) DOPEG is formed intraneuronally, but DOMA, MOPEG, NMN and VMA extraneuronally; (2) VMA is retained in the tissue much longer than the other metabolites; (3) determination of total 3H-content after incubation with 3H-noradrenaline in presence of inhibitors of neuronal uptake underestimates the degree of inhibition of the neuronal amine carrier; and (4) the quantification of the effect of cocaine on the neuronal uptake of released transmitter is complicated by several other actions of the drug (local anesthetic properties, displacement of stored transmitter, activation of effector cells) and that of the effect of DMI by its inhibitory effect on monoamine oxidase, in particular at extraneuronal sites.link_to_subscribed_fulltex