Non-Vitamin K Antagonist Oral Anticoagulants in Adult Congenital Heart Disease

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have several advantages over VKAs that render them an attractive option for adults with congenital heart disease (CHD). Efficacy and safety data specific to the adult CHD population are emerging. Herein, we synthesize the growing literature regarding NOACs in adults with CHD and attempt to identify subgroups for which it appears reasonable to extrapolate data from populations without CHD. Small observational studies suggest that NOACs are safe and effective in selected adults with CHD. NOACs are contraindicated in patients with a mechanical valve, in those with mitral or tricuspid valve stenosis with enlarged and diseased atria, with or without a mitral or tricuspid bioprosthesis, and after recent cardiac surgery (< 3 months). There is currently insufficient evidence to recommend NOACs in patients with a Fontan circulation or cyanotic CHD. Growing literature supports the use of NOACs in patients without CHD who have various forms of valvular heart disease. Therefore, when an indication for oral anticoagulation is established, it appears reasonable to consider a NOAC instead of a VKA in adults with CHD lesions analogous to isolated mitral regurgitation, tricuspid regurgitation, or aortic regurgitation or stenosis. The NOAC agent selected and the prescribed dose should be tailored according to bleeding risk, body weight, renal function, and comedications, especially antiepileptic drugs. The decision to initiate a NOAC should be shared between the patient and care provider. Large-scale research studies are required to further assess safety and efficacy in selected patient subgroups.     

Numerical scheme for modelling oxygen transfer in tubular oxygenators

The diffusion equation for oxygen transfer in tubular membrane oxygenators has been solved numerically by using the Crank-Nicolson method. The iterative procedure takes care of the nonlinear nature of the equations used in the model. The usual hypotheses have been used for the establishment of the nonlinear partial differential equation. Velocity profile (Newtonian, Cassonian fluid) and membrane resistance have been taken into account. Theoretical results have been compared with those obtained by the advanced front theory. Experimental results with several types of device are presented using either blood or saline. Boundary conditions are analysed. Comparisons between theory and results of experiments are presented.     

Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling

Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia–reperfusion (I/R) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or 120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion. In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3β. In hearts from STZ-induced diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3β. In contrast, in hearts from HFD-induced insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts, respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3β. Administration of GSK-3β inhibitor SB216763 was cardioprotective in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption of upstream signaling of GSK-3β. In conclusion, direct inhibition of GSK-3β may provide an alternative strategy to protect diabetic hearts against I/R injury.     

A Procedure to Measure the in-Situ Hygrothermal Behavior of Earth Walls

Rammed earth is a sustainable material with low embodied energy. However, its development as a building material requires a better evaluation of its moisture-thermal buffering abilities and its mechanical behavior. Both of these properties are known to strongly depend on the amount of water contained in wall pores and its evolution. Thus the aim of this paper is to present a procedure to measure this key parameter in rammed earth or cob walls by using two types of probes operating on the Time Domain Reflectometry (TDR) principle. A calibration procedure for the probes requiring solely four parameters is described. This calibration procedure is then used to monitor the hygrothermal behavior of a rammed earth wall (1.5 m × 1 m × 0.5 m), instrumented by six probes during its manufacture, and submitted to insulated, natural convection and forced convection conditions. These measurements underline the robustness of the calibration procedure over a large range of water content, even if the wall is submitted to quite important temperature variations. They also emphasize the importance of gravity on water content heterogeneity when the saturation is high, as well as the role of liquid-to-vapor phase change on the thermal behavior.     

Diagnosis and categorization of small bowel neoplasms: role of computed tomography

A retrospective study of 35 patients with small bowel neoplasms studied by computed tomography (CT) was performed. The tumor detection rate was 80%. Using the findings reported in the literature, an adequate histological diagnosis could be performed in 69% of the cases by CT. Lipomas, leiomyomas, leiomyosarcomas, and carcinoid tumors were well-recognized, but adenocarcinomas and lymphomas were often mistaken one for the other. An accurate preoperative staging was performed in 61% of the cases. CT failed to detect 75% of the invaded lymph nodes, 25% of the liver metastases, and 25% of the tumoral growth beyond the bowel wall. Despite major limitations in preoperative staging, a good detection rate and some features allowing a specific diagnosis advocate using CT along with the barium examination when clinical history suggests a small bowel tumor.     

Alcoholic pancreatitis:A tale of spirits and bacteria

Alcohol is a major cause of chronic pancreatitis.About5%of alcoholics will ever suffer from pancreatitis,suggesting that additional co-factors are required to trigger an overt disease.Experimental work has implicated lipopolysaccharide,from gut-derived bacteria,as a potential co-factor of alcoholic pancreatitis.This review discusses the effects of alcohol on the gut flora,the gut barrier,the liver-and the pancreas and proposes potential interventional strategies.A better understanding of the interaction between the gut,the liver and the pancreas may provide valuable insight into the pathophysiology of alcoholic pancreatitis.     

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients

AIM:To assess,in a routine practice setting,the sus-tained virologic response(SVR) to telaprevir(TPV) or boceprevir(BOC) in hepatitis C virus(HCV) nullresponders or relapsers with severe liver fibrosis.METHODS:One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon(peg-INF) α2a + ribavirin(PR) according to standard treatment schedules without randomization.These patients were treated in routine practice settings in 10 public or private health care centers,and the data were prospectively collected.Only patients with severe liver fibrosis(Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography),genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.RESULTS:The Metavir fibrosis scores were F3 in 35(28%) and F4 in 90(72%) of the patients.In total,62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy.The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%.The SVR was 65.9% in the TPV group and 44.1% in the BOC group.Independent predictive factors of an SVR included a response to previous treatment,relapsers vs null-responders [OR = 3.9;(1.4,10.6),P = 0.0084],a rapid virological response(RVR) [OR 6.9(2.6,18.2),P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2(2.3,29.5),P = 0.001].During treatment,63 patients(50.8%) had at least one severe adverse event(SAE) of grade 3 or 4.A multivariate analysis identified two factors associated with SAEs:female gender [OR = 2.4(1.1,5.6),P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3(2.3,12.4),P ≤ 0.001].CONCLUSION:More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting.The SVR rate was influenced by the response to previous PR treatment,the RVR and liver stiffness.     

Comparison of data from exercise tests and continuous electrocardiographic recording in patients with ventricular extrasystole. Apropos of 131 cases

A series of 131 patients aged from 4 to 70 years old with significant ventricular arrhythmias corresponding to at least Grade 2 of Lown's classification underwent exercise stress testing and continuous 24 hour electrocardiography. There were two objectives: to compare exercise electrocardiography and Holter monitoring in the detection and assessment of the seriousness of the arrhythmia, and to assess the arrhythmia's modifications on exercise. The patients were divided into 4 types: "chronic coronary insufficiency", "mitral valve prolapse", "other cardiac disease" and "idiopathic" arrhythmias. The maximum grade of arrhythmia corresponded to salvos of ventricular extrasystoles in 44 cases (33,5 p. 100), doublets in 44 cases (33,5 p. 100), polymorphic extrasystoles in 10 cases (7,6 p. 100) and monomorphic extrasystoles in 33 cases (25,2 p. 100). A significant arrhythmia was found in 90,8 p. 100 of cases by Holter and in 82,4 p. 100 of cases on exercise stress testing. The maximum grade of arrhythmia was also better appreciated on Holter monitoring (84,7 p. 100) compared to exercise stress testing (46,5 p. 100). The difference being more clear cut for repetitive forms. The superiority of Holter monitoring for assessing the grade of arrhythmia was obvious in the "idiopathic", "other cardiac disease" and "coronary" groups (79,4 p. 100 compared to 41,2 p. 100) but was not significant in the mitral valve prolapse group (73,9 p. 100 compared to 65,2 p. 100). Aggravation of the arrhythmia on exercise defined as a large increase, even transient of the number of extrasystoles (7 cases) or changing to a higher grade (59 cases) was significantly less common (p less than 0,01) in the idiopathic group (30 p. 100) than in the other groups (64,1 p. 100 in the coronary, 65,2 p. 100 in the mitral valve prolapse group). Aggravation of the arrhythmia in the coronary group was not observed more often in positive than in negative exercise electrocardiography. Complete regression of extrasystoles in the last two minutes was observed in 50 cases and significantly more often in idiopathic arrhythmias (p less than 0,01). There was no correlation between the behavior of the arrhythmia on exercise and the presence of salvos of extrasystoles, previous syncope or electrical cardioversion. Important individual differences were observed in all groups of patients. These observations suggest that the statistical superiority of Holter monitoring is debatable and imply that it is often necessary to request both investigations for the exact diagnosis of the arrhythmia and for the eventual therapeutic management of the patient and his mode of life.     

Piperine,a major constituent of black pepper,inhibits human P-glycoprotein and CYP3A4

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC(50) values of 15.5 and 74.1 microM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K(i) values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 microM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.     

Methyl-laudanosine: a new pharmacological tool to investigate the function of small-conductance Ca(2+)-activated K(+) channels

Small-conductance Ca(2+)-activated K(+) channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-laudanosine, and ethyl-laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC(50) values of 152, 15, and 47 microM, respectively. The benzyl and butyl derivatives were less potent. Methyl-laudanosine had no effect on the I(h) current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABA(A) receptors. Interestingly, 100 microM methyl-laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC(50) 4 microM) is superior to its affinity for muscarinic (IC(50) 114 microM) and neuronal nicotinic (IC(50) > or =367 microM) receptors. Methyl-laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models.