The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (KCa) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB “opener”, bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhance anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors.

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BackgroundSystolic left ventricular function during therapeutic hypothermia is found both to improve and to decline. We hypothesized that this discrepancy would depend on the heart rate and the variables used to assess systolic function.MethodsIn 16 pigs, cardiac performance was assessed by measurements of invasive pressures and thermodilution cardiac output and with 2D strain echocardiography. Left ventricle (LV) volumes, ejection fraction (EF), transmitral flow, and circumferential and longitudinal systolic strain were measured. Miniaturized ultrasonic transducers were attached to the epicardium of the LV to obtain M-mode images, systolic thickening, and diastolic thinning velocities and to determine LV pressure-wall dimension relationships. Preload recruitable stroke work (PRSW) was calculated. Measurements were performed at 38 and 33°C at spontaneous and paced heart rates, successively increased in steps of 20 up to the toleration limit. Effects of temperature and heart rate were compared in a mixed model analysis.ResultsHypothermia reduced heart rate from 87 ± 10 (SD) to 76 ± 11 beats/min without any changes in LV stroke volume, end-diastolic volume, EF, strain values, or PRSW. Systolic wall thickening velocity (S′) and early diastolic wall thinning velocity decreased by approximately 30%, making systolic duration longer through a prolonged and slow contraction and changing the diastolic filling pattern from predominantly early towards late. Pacing reduced diastolic duration much more during hypo- than during normothermia, and combined with slow myocardial relaxation, incomplete relaxation occurred with all pacing rates. Pacing did not affect S′ or PRSW at physiological heart rates, but stroke volume, end-diastolic volume, and strain were reduced as a consequence of reduced diastolic filling and much more accentuated during hypothermia. At the ultimate tolerable heart rate during hypothermia, S′ decreased, probably as a consequence of myocardial hypoperfusion due to sustained ventricular contraction throughout a very short diastole.ConclusionsSystolic function was maintained at physiological heart rates during therapeutic hypothermia. Reduced tolerance to increases in heart rate was caused by lack of ventricular filling due to diastolic dysfunction and shorter diastolic duration.

Background: Haemodynamic instability during off-pump coronary artery bypass surgery (OPCAB) may appear rapidly, and continuous monitoring of the cardiac index (CI) during the procedure is advisable. With the PiCCO monitor, CI can be measured continuously and almost real time with pulse-contour analysis and intermittently with transthoracic thermodilution. The agreement between pulmonal artery thermodilution CI (Tpa), transthoracic thermodilution CI (Tpc) and pulse-contour CI (PCCI) during OPCAB surgery has not been evaluated sufficiently. Methods: In 30 patients scheduled for OPCAB surgery, a pulmonary artery catheter and a PiCCO catheter were inserted. At different time points during surgery, Tpa, Tpc and PCCI were compared. Measurements were performed after induction of anesthesia (T1), after pericardiothomy (T2), after grafting on the anterior (T3), posterior (T4) and lateral (T5) walls and after chest closure (T6). The PCCI was recalibrated at time point T2-T6. Results: Mean difference and the limits of agreements (percentage error) between Tpa and Tpc were: -0.14 AE 0.60 (22.0%) l/min/m

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Myocardial ischaemia can be detected with epicardial three-axis accelerometers. The accelerometer had the ability to distinguish ischaemia from interventions altering global myocardial function. This novel technique may be used for continuous real-time monitoring of myocardial ischaemia during and after cardiac surgery.

This is a retrospective study and no randomization has been performed. However, the results add evidence to the view that transbronchial laser treatment may be offered as a safe, stand-alone procedure in the treatment of typical carcinoid tumor in the central airways.