Heterodetic bicyclic decapeptide cyclo (Glu1 -Leu2 -Pro3-Gly4-Ser5-Ile6-Pro7-Ala8) cyclo-(1γ-5β) Phe9-Gly10

Bycyclic peptides are useful model molecules that can mimic the constrained local folding of a great number of natural peptides and proteins, such as ionophoric peptides, enzyme active site, and ligand-receptor active site. The synthesis of the bicyclic title compound with the liquid phase method is described with experimental details. Of particular interest is the heterodetic closure of the second ring. The peptide showed a complexing activity with metal cations like Ba²⁺, Ca²⁺, and Mg²⁺ . The free bicyclic peptide conformation in solution has been studied by means of NMR spectroscopy and a plausible structure model worked out with model building on NMR constraints is proposed.     

Frequency and prognostic value of HLA antigens in osteosarcoma patients

A homogeneous group of 53 Caucasian subjects with high-grade osteosarcoma (OS) was typed for HLA-A and B locus antigens. Although no significant differences in the distribution of these antigens were found in comparison with 425 local controls, a trend towards an increase of HLA-B18 and decrease of HLA-B21 was observed. All the patients underwent amputation plus adjuvant chemotherapy and among the 29 patients with a follow-up longer than one year, 9 out of 10 subjects with HLA-A3 antigens developed metastases within a few months. None of the OS patients had the HLA-A3, B7 haplotype which is present in linkage-disequilibrium in the control population.     

Alcohol-free red wine prevents arterial thrombosis in dietary-induced hypercholesterolemic rats: experimental support for the ''French paradox''

The concept of the 'French paradox' has been recently challenged. As it is difficult in a short period to produce direct clinical evidence of the protective effect of red wine on thrombosis, we evaluated such a possibility in an experimental model mimicking the conditions of the 'French paradox'. Normolipidemic rats (FNL) were fed a standard diet or a 2% cholesterol-rich-diet (Ch-rich-diet) for 5 months: the latter was given either alone (FNL + D) or in combination with 'alcohol-free' red wine (FNL + D + 5 W). Arterial thrombosis was measured as the occlusion time (OT) of an artificial prosthesis inserted into the abdominal aorta. Lipid levels, platelet adhesion to fibrillar collagen, factor VII (FVII) clotting activity and fibrinogen levels were also measured. Compared to animals fed a standard diet, Ch-rich diet induced in FNL rats a several-fold increase in lipids and FVII levels with a concomitant significant increase in both thrombotic tendency (shortening of the OT) and platelet adhesion. 'Alcohol-free' red wine supplementation almost completely reverted the prothrombotic effect of the Ch-rich-diet. Indeed, the OT was prolonged from 78 +/- 3 to 122 +/- 10 h (P < 0.01), while platelet adhesion to fibrillar collagen was reduced from 49 +/- 3.5% to 30 +/- 2.8%. Neither the increase in lipid levels induced by Ch-rich diet nor FVII or fibrinogen levels were modified by wine supplementation. In conclusion, in experimental animals, this study supports the concept of the 'French paradox' that regular consumption of wine (rather than alcohol) was able to prevent arterial thrombosis associated with dietary-induced hypercholesterolemia, an effect mediated by downregulation of platelet function.     

Two-to-One AV Block Associated with the Congenital Long QT Syndrome

2:1 AV Block in LQTS. Introduction Conduction abnormalities associated with long QT syndrome (LQTS) have been reported as "pseudo 2:1 AV block" due to sinus intervals shorter than ventricular refractoriness.
Method and Results: We report the electrophysiologic characteristics of a patient suffering from congenital LQTS with episodes of true 2:1 AV block. Induction of 2:1 infra-Hisian blocks and return to 1:1 conduction were observed using single atrial and ventricular extrastimuli. The block was located in the Purkinje network but not in the myocardium.
Conclusion: The His-Purkinje system of our LQTS patient displayed dynamic properties with a strong increase in refractoriness for short-long sequences and a decrease for long-short sequences that triggered intermittent 2:1 AV blocks.     

Koch's Triangle in Pediatric Age: Correlation with Extra- and Intracardiac Parameters

The atrioventricular node is situated in the lower atrial septum, at the apex of the Koch's triangle. The dimensions of the Koch's triangle are studied in adult humans, while no data exist about tbem in pediatric age. the knowledge of the dimensions of Koch's triangle in childhood is very important for safe and correct application of radiofrequency energy during transcatheter ablation. The dimensions of Koch's triangle were determined in 69 human pediatric hearts. the median age of the children was 3 months. with a range from 1 day to 14 years, 30 were female and 39 were male. Relations between body weight (extracardiac parameter) and tricuspid valve diameter (intracardiac parameter) were determined in all hearts to sbow morpbometric modifications with growth. the distribution of body weight was not Gaussian and no correlation could be obtained between Koch's triangle dimensions and body weight. However, it was possible to identify that the mean ratio between the cathetus of the Koch's triangle corresponding to the annulus of the tricuspid valve and the tricuspid valve diameter was 0.45 ± 0.16, with a highly significant correlation coefficient (r = 0.653, P < 0.001). Therefore, by knowing: (1) the diameter of the tricuspid valve, and (2) the constant ratio between the cathetus of the Koch's triangle and the tricuspid valve diameter, it is possible to calculate the lengtb of the segment of the tricuspid annulus along wbich the transcatheter application of radiofrequency current can be applied to ablate the slow-pathway, tbus reducing the risks of damage of the atrioventricular node.     

Supernormal Conduction in the Left Bundle Branch Unmasked by the Linking Phenomenon

This presentation reflects a case of phase-3 left bundle branch block (LBBB). Analysis reveals that relatively early QRS complexes are wide, whereas beats occurring later than a critical time are narrow. There are, however, two unexpected phenomena: (1) an overlap occurs between the range of R-R intervals resulting in normal intraventricular conduction and the range of R-R intervals resulting in LBBB pattern. Complexes that follow a wide beat are often wide although they are associated with relatively long R-R intervals, whereas complexes that follow a normal beat tend to be normal even after relatively short R-R cycles. This is due to concealed retrograde penetration of the bundle branch that is blocked in anterograde direction (the so-called linking phenomenon). (2) Some early supraventricular impulses, paradoxically, resulted in normal intraventricular conduction. The phenomenon is a manifestation of supernormal LBB conduction, and only occurs following a wide QRS complex associated with retrograde activation of the LBB. The linking phenomenon reveals or unmasks the supernormal phase of LBB conduction. Following a retrograde and delayed activation of the LBB, the refractory period of the bundle branch is postponed, in such a way that a supraventricular impulse is allowed to occur during the early phase of supernormal conduction.     

A Short‐Term,Randomized, Double‐Blind,Parallel‐Group Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial Fibrillation: The DIONYSOS Study

Dronedarone versus Amiodarone in Patients with AF. Introduction: We compared the efficacy and safety of amiodarone and dronedarone in patients with persistent atrial fibrillation (AF). Methods: Five hundred and four amiodarone‐naïve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months. Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation. Main safety endpoint (MSE) was occurrence of thyroid‐, hepatic‐, pulmonary‐, neurologic‐, skin‐, eye‐, or gastrointestinal‐specific events, or premature study drug discontinuation following an adverse event. Results: Median treatment duration was 7 months. The primary composite endpoint was 75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.28–1.98; P < 0.0001), mainly driven by AF recurrence with dronedarone compared with amiodarone (63.5 vs 42.0%). AF recurrence after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively. Premature drug discontinuation tended to be less frequent with dronedarone (10.4 vs 13.3%). MSE was 39.3 and 44.5% with dronedarone and amiodarone, respectively, at 12 months (HR = 0.80; 95% CI 0.60–1.07; P = 0.129), and mainly driven by fewer thyroid, neurologic, skin, and ocular events in the dronedarone group. Conclusion: In this short‐term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants. (J Cardiovasc Electrophysiol, Vol. 21, pp. 597‐605, June 2010)     

Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug?

BACKGROUND: Polymorphonuclear leukocytes (PMN) from healthy subjects can produce and store tissue factor (TF), which is expressed on PMN surface upon in vitro stimulation with P-selectin. RESULTS: We report here that platelets and PMN from 12 patients with myeloproliferative disorders (MPD) (six with polycythemia vera, six with essential thrombocythemia) show up regulation of P-selectin and TF, respectively, in the absence of any in vitro challenge. The number of circulating mixed platelet-PMN aggregates was also increased. PMN TF expression as well as mixed platelet-PMN aggregates, but not platelet P-selectin, were significantly reduced in six MPD patients after treatment with hydroxyurea (HU). In vitro studies performed on PMN separated from healthy donors confirmed HU effects (0-1400 microm). HU prevented both P-selectin-induced TF expression and mixed cell aggregate formation. The inhibitory effect of HU was specific for P-selectin-induced PMN activation, as it did not affect formyl-methionyl-leucyl-phenylalanine-induced PMN TF expression. CONCLUSIONS: In MPD patients, platelet P-selectin-mediated TF expression on circulating PMN may play a role in thrombus formation and represents a novel target for the antithrombotic activity of HU.     

A Case of Atrial Tachycardia Treated with Ivabradine as Bridge to Ablation

Ivabradine is indicated in cardiac failure and ischemia to reduce sinus rate by inhibition of the pacemaker I(f) current in sinoatrial node. We report a case of an 18‐year‐old woman with left atrial tachyarrhythmia resistant to several antiarrhythmic drugs and to electric cardioversion who responded only to ivabradine, which significantly reduced heart rate without abolishing the arrhythmia itself. An ectopic focus in the ostium of left pulmonary veins was found and the patient was successfully ablated. We suggest that ivabradine might be therefore useful in the treatment of supraventricular tachyarrhythmias due to an enhanced automaticity.