Neurobiological mechanisms and therapeutic impact of electroconvulsive therapy (ECT).

Electroconvulsive therapy (ECT) is an efficient therapeutic resource for psycho-pharmacotherapeutic resistant forms of depression. ECT is a form of electrical brain stimulation involving the induction of a controlled seizure, clinically similar to an epileptic seizure, that is initiated in the prefrontal region of the brain and spreads to the cortex and subcortex, including the diencephalic structures. This is achieved by creating a transcranial electric field and synchronously depolarizing neuronal membranes. The mechanisms of action of ECT are not yet fully understood, but several hypotheses have been proposed to explain how it affects the brain: neurotransmitter changes, neuroplasticity, network connectivity, endocrine system regulation and changes in regional cerebral blood flow and regional metabolism.

New carbocyclic N(6)-substituted adenine and pyrimidine nucleoside analogues with a bicyclo[2.2.1]heptane fragment as sugar moiety; synthesis, antiviral, anticancer activity and X-ray crystallography.

New nucleoside analogues with an optically active bicyclo[2.2.1]heptane skeleton as sugar moiety and 6-substituted adenine were synthesized by alkylation of 6-chloropurine intermediate. Thymine and uracil analogs were synthesized by building the pyrimidine ring on amine 1. X-ray crystallography confirmed an exo-coupling of the thymine to the ring and an L configuration of the nucleoside analogue. The library of compounds was tested for their inhibitory activity against influenza virus A∖California/07/09 (H1N1)pdm09 and coxsackievirus B4 in cell culture. Compounds 13a and 13d are the most promising for their antiviral activity against influenza, and compound 3c against coxsackievirus B4. Compounds 3b and 3g were tested for anticancer activity.

Computational assessment of airway wall stiffness in vivo in allergically inflamed mouse models of asthma.

Allergic inflammation is known to cause airway hyperresponsiveness in mice. However, it is not known whether inflammation affects the stiffness of the airway wall, which would alter the load against which the circumscribing smooth muscle shortens when activated. Accordingly, we measured the time course of airway resistance immediately following intravenous methacholine injection in acutely and chronically allergically inflamed mice. We estimated the effective stiffness of the airway wall in these animals by fitting to the airway resistance profiles a computational model of a dynamically narrowing airway embedded in elastic parenchyma. Effective airway wall stiffness was estimated from the model fit and was found not to change from control in either the acute or chronic inflammatory groups. However, the acutely inflamed mice were hyperresponsive compared with controls, which we interpret as reflecting increased delivery of methacholine to the airway smooth muscle through a leaky pulmonary endothelium. These results support the notion that acutely inflamed BALB/c mice represent an animal model of functionally normal airway smooth muscle in a transiently abnormal lung.

The synergistic interactions of allergic lung inflammation and intratracheal cationic protein.

RATIONALE: Airways hyperresponsiveness (AHR) is a hallmark feature of asthma, and can be caused by various disparate mechanisms. Mouse models of AHR have been useful for studying these mechanisms in isolation, but such models still typically do not exhibit the same degree of AHR as seen in severe human asthma. We hypothesized that more severe AHR in mice could be achieved by imbuing them with more than one mechanism of AHR. OBJECTIVES: We sought to determine if the airway wall thickening accompanying allergic inflammation and the exaggerated smooth muscle shortening induced by intratracheal cationic protein could act together to produce a severe form of AHR. METHODS: We used the forced oscillation technique to measure methacholine responsiveness in BALB/c mice that had been sensitized and challenged with ovalbumin followed by an intratracheal instillation of poly-l-lysine. MEASUREMENTS AND MAIN RESULTS: We found that both ovalbumin and poly-l-lysine treatment alone caused moderate levels of AHR. When the two treatments were combined, however, they synergized in terms of their effect on lung stiffness to an extent that could even be fatal, reflecting a significantly enhanced level of airway closure. CONCLUSIONS: Our results suggest that mechanistic synergy between airway wall thickening and exaggerated smooth muscle shortening produces a more germane mouse model of asthma that may have particular relevance to the pathophysiology of the acute severe asthma exacerbation.

Bronchodilatory effect of deep inspiration on the dynamics of bronchoconstriction in mice.

We recently developed a computational model of an airway embedded in elastic parenchyma (Bates JH, Lauzon AM. J Appl Physiol 102: 1912-1920, 2007) that accurately mimics the time dependence of airway resistance on tidal volume and positive end-expiratory pressure (PEEP) following methacholine injection in normal animals. In the present study, we compared the model predictions of bronchodilation induced by a deep inflation (DI) of the lung following administration of the bronchial agonist methacholine to corresponding experimental measurements made in mice. We found that a DI in mice caused an immediate reduction in airway resistance when it was administered soon after intravenous injection of methacholine, while the airway smooth muscle was in the process of contracting. However, the magnitude of the reduction in resistance was greater and its subsequent rate of increase less than that predicted by the model. We found that this effect was most pronounced when the DI was given within approximately 3 s following methacholine injection, again in contrast to the predictions of the model. The reduction of airway resistance was virtually independent of the rate of lung inflation during the DI, however, which agrees with model predictions. We conclude that while the model accounts for a substantial fraction of the post-DI reduction in airway resistance seen experimentally, there remain important differences between prediction and experiment that suggest that the effects of a DI are not simply due to eccentric contraction of the airway smooth muscle.