Carvedilol protects ischemic cardiac mitochondria by preventing oxidative stress.

Ischemia negatively affects mitochondrial function by inducing the mitochondrial permeability transition (MPT). The MPT is triggered by oxidative stress, which occurs in mitochondria during ischemia as a result of diminished antioxidant defenses and increased reactive oxygen species production. It causes mitochondrial dysfunction and can ultimately lead to cell death. Therefore, drugs able to minimize mitochondrial damage induced by ischemia may prove to be clinically effective. We analyzed the effect of carvedilol, a beta-blocker with antioxidant properties, on mitochondrial dysfunction. Carvedilol decreased levels of TBARS (thiobarbituric acid reactive substances), an indicator of oxidative stress, which is consistent with its antioxidant properties. Regarding cell death by apoptosis, although ischemia did increase caspase-8-like activity, there were no changes in caspase-3-like activity, which is activated downstream of caspase-8; this may indicate that the apoptotic cascade is not activated by 60 minutes of ischemia. We conclude that carvedilol protects ischemic mitochondria by preventing oxidative mitochondrial damage, and, by so doing, it may also inhibit the formation of the MPT pore.     

A flow visualization study of an anatomic coronary artery anastomosis model with an implant.

Flow Streamlining Devices is a new tool in Coronary Artery Bypass Grafting (CABG). They aim in: a) Performing a sutureless anastomosis to reduce thrombosis at the veno-arterial junction, and b) Providing a hemodynamically efficient scaffolding to reduce secondary flow disturbances. Thrombosis and flow disturbances are factors that have been reported as contributing factors to the development of intimal hyperplasia (IH) and failure of the graft. By reducing thrombosis and flow disturbances, it is expected that IH will be inhibited and the lifetime of the graft extended. To evaluate the hemodynamic benefits of such an implant, two models were designed and fabricated. One simulated the geometry of the conventional anastomosis without an implant, and the other simulated an anastomosis with a flow streamlining implant. Identical flow conditions relevant to a coronary anastomosis were imposed on both models and flow visualization was performed with dye injection and a digital camera. Results showed reduction of disturbances in the presence of the implant. This reduction seems to be favorable to hemodynamic streamlining which may create conditions that may inhibit the initialization of IH. However, the compliance and geometric mismatch between the anastomosis and the implant created a disturbance at the rigid compliant wall interface, which should be eliminated prior to clinical applications.     

Effective high-capacity gutless adenoviral vectors mediate transgene expression in human glioma cells.

Glioblastoma multiforme (GBM) is the most common subtype of primary malignant brain tumor. Although serotype 5 adenoviral vectors (Ads) have been used successfully in clinical trials for GBM, the capacity of Ads to infect human glioma cells and the expression of adenoviral receptors in GBM cells have been challenged. In this report, we studied the expression of three molecules that have been shown to mediate adenoviral entry into cells, i.e., coxsackie and adenovirus receptor (CAR), integrin alphavbeta3 (INT), and major histocompatibility complex class I (MHCI), in rodent glioma cell lines and low-passage primary cultures and cell lines from human GBM. We correlated levels of expression of CAR, INT, and MHCI with transduction efficiency elicited by several high-capacity helper-dependent adenoviral vectors (HC-Ads). Expression levels of adenoviral receptors were variable among the different GBM cells studied. HC-Ad-mediated therapeutic gene expression was efficient, ranging between 20 and 80% of the total target cells expressing the encoded transgenes. Our results show no correlation between the levels of CAR, INT, or MHCI molecules and the levels of transgene expression or the number of GBM cells transduced. We conclude that expression levels of adenoviral receptors do not predict their transduction efficiency or biological function.     

Involvement of IL-1beta in acute stress-induced worsening of cerebral ischaemia in rats.

Stress is known to be one of the risk factors of stroke. Most of the knowledge on the effects of stress on cerebrovascular disease in humans is restricted to catecholamines and glucocorticoids effects on blood pressure and/or development of atherosclerosis. However, few experimental studies have examined the possible mechanisms by which stress may affect stroke outcome. We have used an acute stress protocol consisting of the exposure of male Fischer rats to an acute, single exposure immobilisation protocol (6 h) prior to permanent middle cerebral artery occlusion (MCAO), and we have found that stress worsens behavioural and neurological outcomes and increased infarct size after MCAO. The possible regulatory role of the TNFalpha and IL-1beta was studied by looking at the release of these cytokines in brain. The results of the present study showed an increase in IL-1beta release in cerebral cortex after exposure to acute stress. Brain levels of IL-1beta are also higher in previously stressed MCAO rats than in MCAO animals without stress. Pharmacological blockade of IL-1beta with an antibody anti-IL-1beta led to a decrease in the infarct size as well as in neurological and behavioural deficits after MCAO. In summary, our results indicate that IL-1beta, but not TNFalpha, accounts at least partly for the worsening of MCAO consequences in brain of rats exposed to acute stress.     

Modeling the current distribution during transcranial direct current stimulation.

OBJECTIVE: To investigate the spatial distribution of the magnitude and direction of the current density in the human head during transcranial direct current stimulation (tDCS). METHODS: The current density distribution was calculated using a numerical method to implement a standard spherical head model into which current was injected by means of large electrodes. The model was positioned in 'MNI space' to facilitate the interpretation of spatial coordinates. RESULTS: The magnitude and direction of the current density vector are illustrated in selected brain slices for four different electrode montages. Approximately half of the current injected during tDCS is shunted through the scalp, depending on electrode dimension and position. Using stimulating currents of 2.0 mA, the magnitude of the current density in relevant regions of the brain is of the order of 0.1 A/m2, corresponding to an electric field of 0.22 V/m. CONCLUSIONS: Calculations based on a spherical model of the head can provide useful information about the magnitude and direction of the current density vector in the brain during tDCS, taking into account the geometry and position of the electrodes. Despite the inherent limitations of the spherical head model, the calculated values are comparable to those used in the most recent in vitro studies on modulation of neuronal activity. SIGNIFICANCE: The methodology presented in this paper may be used to assess the current distribution during tDCS using new electrode montages, to help optimize montages that target a specific region of the brain or to preliminarily investigate compliance with safety guidelines.     

Prediction of the Deposition of Dry Powder Aerosols

The trajectory, mass fluxes, and deposition of aerosolized particles in a complex tubular system have been predicted. A procedure based on Lagrangian stochastic modeling is proposed to enable the anticipation of such phenomena, taking advantage of experimental results to characterize the air flow. The predictions have been obtained for pharmaceutical aerosols delivered by dry powder inhalers. A critical assessment of the dispersion model has been carried out using data available in the literature. The procedure assumes a low volume fraction of particles in the simulation of turbulent dispersion, but deposition is physically based on the interaction between the particles and both solid and liquid surfaces. The results were confirmed by experimental tests of powder deposition, run according to the European Pharmacopoeia. A parametric study was also carried out with the aim of providing a more complete evaluation of the model’s performance. The comparison between predictions and experimental results has shown that the model properly describes the deposition of aerosolized particles.