Cardiac MRI findings to differentiate athlete's heart from hypertrophic (HCM), arrhythmogenic right ventricular (ARVC) and dilated (DCM) cardiomyopathy.

To provide clinically relevant criteria for differentiation between the athlete's heart and similar appearing hypertrophic (HCM), dilated (DCM), and arrhythmogenic right-ventricular cardiomyopathy (ARVC) in MRI. 40 top-level athletes were prospectively examined with cardiac MR (CMR) in two university centres and compared to retrospectively recruited patients diagnosed with HCM (n = 14), ARVC (n = 18), and DCM (n = 48). Analysed MR imaging parameters in the whole study cohort included morphology, functional parameters and late gadolinium enhancement (LGE). Mean left-ventricular enddiastolic volume index (LVEDVI) was high in athletes (105 ml/m2) but significantly lower compared to DCM (132 ml/m2; p = 0.001). Mean LV ejection fraction (EF) was 61% in athletes, below normal in 7 (18%) athletes vs. EF 29% in DCM, below normal in 46 (96%) patients (p < 0.0001). Mean RV-EF was 54% in athletes vs. 60% in HCM, 46% in ARVC, and 41% in DCM (p < 0.0001). Mean interventricular myocardial thickness was 10 mm in athletes vs. 12 mm in HCM (p = 0.0005), 9 mm in ARVC, and 9 mm in DCM. LGE was present in 1 (5%) athlete, 8 (57%) HCM, 10 (56%) ARVC, and 21 (44%) DCM patients (p < 0.0001). Healthy athletes' hearts are characterized by both hypertrophy and dilation, low EF of both ventricles at rest, and increased interventricular septal thickness with a low prevalence of LGE. Differentiation of athlete's heart from other non-ischemic cardiomyopathies in MRI can be challenging due to a significant overlap of characteristics also seen in HCM, ARVC, and DCM.

Effects of the atrial antiarrhythmic drug AVE0118 on cardiac ion channels.

Previous studies in pigs and goats have demonstrated that AVE0118 prolongs atrial refractoriness without any effect on the QT-interval. The purpose of the present study was to investigate the effect of the compound on various cardiac ion channels. AVE0118 blocked the pig Kv1.5 and the human Kv1.5 expressed in Xenopus oocytes with IC(50) values of 5.4+/-0.7 microM and 6.2+/-0.4 microM respectively. In Chinese hamster ovary (CHO) cells, AVE0118 decreased the steady-state hKv1.5 current with an IC(50) of 1.1+/-0.2 microM. The hKv4.3/KChIP2.2 current in CHO cells was blocked by AVE0118 by accelerating the apparent time-constant of inactivation ( tau(inact)), and the integral current was inhibited with an IC(50) of 3.4+/-0.5 microM. At 10 microM AVE0118 tau(inact) decreased from 9.3+/-0.6 ms ( n=8, control) to 3.0+/-0.3 ms ( n=8). The K(ACh) current was investigated in isolated pig atrial myocytes by application of 10 microM carbachol. At a clamp potential of -100 mV the I(KACh) was half-maximally blocked by 4.5+/-1.6 microM AVE0118. In the absence of carbachol, AVE0118 had no effect on the inward current recorded at -100 mV. Effects on the I(Kr) current were investigated on HERG channels expressed in CHO cells. AVE0118 blocked this current half-maximally at approximately 10 microM. Comparable results were obtained in isolated guinea pig ventricular myocytes, where half-maximal inhibition of the I(Kr) tail current occurred at a similar concentration of AVE0118. Other ionic currents, like the I(Ks), I(KATP) (recorded in guinea pig ventricular myocytes), and L-type Ca(2+) (recorded in pig atrial myocytes) were blocked by 10 microM AVE0118 by 10+/-3% ( n=6), 28+/-7% ( n=4), and 22+/-13% ( n=5) respectively. In summary, AVE0118 preferentially inhibits the atrial K(+) channels I(Kur), I(to) and I(KACH). This profile may explain the selective prolongation of atrial refractoriness described previously in pigs and goats.

Characterization of a novel Kv1.5 channel blocker in Xenopus oocytes, CHO cells, human and rat cardiomyocytes.

The inhibitory effects of the novel Kv1.5 channel blocker, S9947 (2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide), on cloned human Kv1.5 (hKv1.5), expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells, and on native cardiac ultrarapid delayed rectifier potassium currents (IKur) in rat (ventricle myocytes) and human (atrial myocytes) were investigated. The influence of S9947 on the action potential was examined in rat ventricular myocytes. Using the two-electrode voltage-clamp technique in Xenopus oocytes and the patch-clamp technique (whole cell configuration) in CHO cells, hKv1.5 was inhibited by S9947 with IC50 values of 0.65 microM and 0.42 microM, respectively. In addition, inhibition of human Kv4.3 (hKv4.3) and HERG by 10 microM S9947 was low (approximately 20%) and absent, respectively. Using the patch-clamp technique in the whole cell configuration, IKur currents in rat ventricular (rIKur) cardiomyocytes and human atrial (hIKur) cardiomyocytes were inhibited by S9947 with IC50 values of 0.96 microM and 0.07 microM, respectively. In contrast, rat cardiac inward rectifier current (rIK1) and rat (rIto) and human (hIto) cardiac transient outward currents were only inhibited by approximately 20% with 10 microM S9947. In rat cardiomyocytes, using the patch-clamp technique, action potential duration was increased by S9947 in a concentration-dependent (0.3-10 microM) and rate-independent manner. The data show that S9947 suppresses both cloned (Kv1.5) and native (IKur) cardiac potassium currents. Furthermore, S9947 prolongs rat action potential in a rate-independent manner.

Synthesis and activity of novel and selective I(Ks)-channel blockers.

Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.

Therapist perceptions of ethnicity issues in family therapy: a qualitative inquiry.

A group of 29 leading family therapists presenting at a regional marriage and family therapy conference were interviewed about ethnicity issues in family therapy. Questions and discussion focused on ethnicity in the family therapy process, ethnicity issues for the family therapist, ethnicity issues for the client family, therapeutic strategies when ethnicity is an issue, and recommendations for ethnicity training and supervision of future family therapists. Qualitative methods were used to analyze the transcripts of the recorded interviews to identify themes emerging from the interviews. Results reflect multiple perspectives and approaches in the field of family therapy.

Quantum cryptography using entangled photons in energy-time bell states

We present a setup for quantum cryptography based on photon pairs in energy-time Bell states and show its feasibility in a laboratory experiment. Our scheme combines the advantages of using photon pairs instead of faint laser pulses and the possibility to preserve energy-time entanglement over long distances. Moreover, using four-dimensional energy-time states, no fast random change of bases is required in our setup: Nature itself decides whether to measure in the energy or in the time base, thus rendering eavesdropper attacks based on "photon number splitting" less efficient.

Inhibition of IKs channels by HMR 1556.

Chromanol HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylmethanesulfonamide], a novel inhibitor of the slow component of the delayed outward current in heart muscle cells (IKs), has been characterized in several in-vitro systems. mRNA encoding for the human protein minK was injected into Xenopus oocytes, leading to the expression of IKs channels. HMR 1556 inhibited this current half-maximally at a concentration of 120 nmol/l (IC50). Expression of the K+ channels Herg, Kv 1.5, Kv 1.3 and Kir2.1, and also the cationic current HCN2, were blocked little or not at all by 10 micromol/l HMR 1556. In isolated ventricular myocytes from the guinea pig the whole-cell patch-clamp method revealed inhibition of the IKs current with an IC50, of 34 nmol/l. Other current components, like IKr and IK1. were only slightly blocked at an HMR 1556 concentration of 10 micromol/l, whereas 10 micromol/l HMR 1556 inhibited the transient outward current I(to) and the sustained outward current I(sus) in rat ventricular myocytes by 25% and 36%, respectively. The L-type Ca2+ channel in guinea pig cardiomyocytes was blocked by 10 micromol/l HMR 1556 by 31%. Guinea pig right papillary muscles were investigated by the micropuncture technique at various pacing rates. In the frequency range of 0.5-7 Hz HMR 1556 (1 micromol/l) caused a prolongation of the action potential duration at 90% repolarization (APD90) by 19%-27%. In the presence of isoproterenol (10 micromol/l) the prolongation of the APD90 was more pronounced at low pacing rates (47% at 0.5 Hz and 35% at 1 Hz, compared with 25% at 7 Hz). The monophasic action potential was recorded in Langendorff-perfused guinea pig hearts. In spontaneously beating preparations, HMR 1556, at 0.1 micromol/l and 1 micromol/l, prolonged the MAPD90 by 3% and 10%, respectively, with no further prolongation at 10 micromol/l. The prolongation was much greater at low pacing rates [25% at 100 beats per min (bpm) and 13% at 150 bpm] than at fast pacing rates (9% at 350 bpm). The left ventricular pressure LVPmax was not affected at 1 micromol/l HMR 1556, but it decreased by 15% at 10 micromol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 micromol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibitor of the IKs current in guinea pig ventricular myocytes. The prolongation of the action potential duration is maintained at fast pacing rates.

Molecular impact of MinK on the enantiospecific block of I(Ks) by chromanols.

Slowly activating I:(Ks) (KCNQ1/MinK) channels were expressed in Xenopous: oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the ss-subunit MinK on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-specificity in blocking I:(Ks) and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric I:(Ks) channels. Furthermore, we expressed both WT and mutant MinK subunits to examine the involvement of particular MinK protein regions in channel block by chromanols. Through a broad variety of MinK deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (>2.5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1.

Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor.

1. This study examines the cardiovascular effects of CAS 1609 (4-hydroxymethyl-furoxan-3-carboxamide) in vitro as well as in vivo in various animal models. 2. CAS 1609 relaxed guinea-pig pulmonary artery strips without endothelium with IC50-values of 0.9 microM (phenylephrine contracted) and 15 microM (KCl-depolarized). This effect was inhibited by oxyhaemoglobin. In these arteries CAS 1609 significantly increased (+192%) guanosine 3':5'-cyclic monophosphate levels, which indicates that the compound acts as a donor of nitric oxide (NO). 3. In the anaesthetized pig, CAS 1609 (0.3-1.0 mg kg-1, i.d.) significantly lowered blood pressure and left ventricular end-diastolic pressure. Left ventricular contractility was slightly reduced and heart rate remained almost unchanged. 4. In anaesthetized dogs, i.v. or i.d. administration of CAS 1609 (0.3-3.0 mg kg-1) decreased, in a dose-related fashion, preload and afterload of the heart, cardiac output, left ventricular work and myocardial oxygen consumption. This haemodynamic profile is similar to that of known NO-donors. 5. In anaesthetized dogs with acute heart failure due to intracoronary injection of microspheres, CAS 1609 (0.3 mg kg-1, i.v.) improved the haemodynamic condition and reduced mortality by 80%. 6. In conscious dogs, oral treatment with a dose of 0.5 mg kg-1 given twice daily at 07 h 00 min and 19 h 00 min (each dose had a duration of action > or = 12 h) for 5 days showed no signs of tolerance to the haemodynamic effects of the drug. 7. All these data indicate that CAS 1609 is a potent, long-lasting orally active donor of NO, devoid of tolerance development.

Isoflurane does not vasodilate rat thoracic aortic rings by endothelium-derived relaxing factor or other cyclic GMP-mediated mechanisms.

Endothelium-derived relaxing factor (EDRF) is a potent endogenous vasodilator that has been indirectly suggested to play a role in isoflurane-mediated vasodilation. To examine directly the possible role of EDRF in isoflurane-mediated vasodilation, isolated rat thoracic aortic rings were suspended for isometric tension measurements, equilibrated to a resting tension of 2 g, and constricted with a 50% maximal concentration (EC50) dose of phenylephrine or KCl. Three groups of rings were studied: endothelium-intact, endothelium-denuded, and endothelium-intact rings treated with nitro-L-arginine methyl ester (L-NAME), a specific inhibitor of EDRF synthase. Isoflurane was then added at 1, 2, and 3% in a cumulative manner, allowing 10 min for each concentration to equilibrate. Indomethacin was present in all experiments to prevent the formation of vasoactive prostanoid metabolites. Since EDRF causes vascular relaxation by stimulating soluble guanylyl cyclase and increasing cyclic GMP, the effect of isoflurane on vascular ring cyclic GMP content was determined as an additional indicator of EDRF-mediated dilation. Rings with intact and denuded endothelium were isolated as described above, constricted with phenylephrine, and challenged with methacholine (positive control) or 1, 2, or 3% isoflurane. After 8 min exposure, the rings were flash-frozen in dry-ice-cooled acetone and homogenized in 1 N HCl for subsequent analysis of cyclic GMP content by radioimmunoassay. Isoflurane caused dose-dependent vasodilation of both KCl- and phenylephrine-constricted rings. In the phenylephrine group, at 2% and 3% isoflurane, endothelium-denuded and L-NAME-treated rings relaxed to a greater extent than endothelium-intact rings (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of indomethacin and L-cysteine on histamine and peptidoleukotriene release from superfused tracheas taken from guinea pigs passively sensitized with IgG1 and IgE antibodies.

We have previously reported differences in mediator release during equivalent levels of antigen (Ag)-induced smooth muscle contraction of guinea pig pulmonary tissues after passive sensitization with IgG1 versus IgE antibodies (Abs). In the present study, we have examined the influence of indomethacin (5 x 10(-6) mol/L) and L-cysteine (3 or 10 mmol/L) on mediator release from superfused trachea taken from guinea pigs passively sensitized with IgG1 or IgE Ab 1 day before in vitro studies. Tissues were challenged with Ag (oxazolone-human serum albumin conjugate), and contractions and superfusate histamine and peptidoleukotrienes were monitored at discrete time intervals thereafter. Superfusate mediator contents were determined by spectrophotofluorimetry (histamine) and RAST (peptidoleukotrienes). The profiles of peptidoleukotrienes were examined with high-pressure liquid chromatography. At equivalent levels of contraction, significantly less histamine and peptidoleukotrienes were found in superfusate samples after sensitization with IgE Abs. None of the drug pretreatments significantly altered Ag-induced histamine release after IgG1 or IgE sensitization. Indomethacin resulted in an increase in total measurable peptidoleukotrienes found only after IgG1 receptor activation, but it did prolong tracheal contractions with both Abs. L-cysteine, 10 mmol/L, resulted in an increase in total measurable superfusate peptidoleukotriene content under all experimental conditions. The percentage increase in peptidoleukotriene content from that found without drug pretreatment was larger in the case of IgE compared to IgG1 sensitization. During early time periods, after Ag challenge, measurable peptidoleukotriene levels in superfusate samples were similar for both Abs in the presence of L-cysteine, 10 mmol/L. These data suggest that there is a differential pattern of peptidoleukotriene metabolism after activation of IgG1 versus IgE receptors in guinea pig trachea.

Studies of desensitization and cross-desensitization to immunologic and nonimmunologic stimuli that evoke contraction and histamine release in superfused guinea pig trachea.

This study examined the possibility that there is cross-desensitization between immunologic and nonimmunologic stimuli that evoke contraction and histamine release (HR) in the isolated guinea pig trachea. Compound 48/80 and D-tubocurarine were found to cause homologous and heterologous desensitization for both contraction and HR from superfused trachea. Specific antigen challenge of trachea obtained from animals sensitized with either IgG1 (ovalbumin [OA]) or IgE (oxazalone-human serum albumin [OX-HSA]) also resulted in homologous desensitization for both contraction and HR. However, in experiments with animals sensitized with both IgG1 and IgE antibodies, prechallenge with OA resulted in cross-desensitization to OX-HSA, whereas the reverse sequence was ineffective in eliciting this phenomenon. This may be related to the type of desensitization produced by each antigen (specific versus nonspecific) or to heterogeneity of mast cells in the tissue. Prechallenge of the trachea with compound 48/80 or D-tubocurarine failed to alter subsequent effects of antigen after active sensitization with OA or passive sensitization with either IgG1 or IgE antibodies. Small but statistically significant decreases in tracheal responses to D-tubocurarine were observed after antigen prechallenge to active both IgG1 and IgE antibodies. This is the first study to demonstrate a cross-desensitization between compound 48/80 and D-tubocurarine and the first to examine cross-desensitization with IgG1 and IgE antibodies in the guinea pig trachea. The overall conclusion is that there is no major overlap in the desensitization mechanisms between immunologic and nonimmunologic stimuli in the guinea pig trachea.

[Pseudotumoral xanthogranulomatous pyelonephritis. Apropos of a case]. / Pyélonéphrite xanthogranulomateuse pseudo-tumorale. A propos d'un cas.

Xanthogranulomatous pyelonephritis may, rarely, occur as a renal tumour syndrome (simulating mainly a renal cell carcinoma). We report one case. The diagnosis is often difficult (even with surgical findings) and frequently a histological surprise. This points out the importance of identifying it in preoperative staging; the diagnosis may be suggested by the association of chronic pyelonephritis, renal stones and hypovascular renal tumour syndrome without specificity at sonography and CT.

Comparative studies of mediator release from guinea pig lung mast cells and basophils.

Guinea pig lung mast cells and blood basophils were isolated and purified and their mediator release characteristics were compared. Upon stimulation with the antigen ovalbumin (OA) of cells passively sensitized with antiovalbumin (anti-OA) antibody, both cell types released histamine. The sensitivity and maximal response (20 to 25% histamine release) to OA was similar for both cells and was unaffected by cell purification. Antigen-induced histamine release (HR) was dependent upon added calcium to a similar extent (1 mM Ca++ maximal release) in both cell types; OA stimulation of passively sensitized mast cells also released leukotriene bioactivity (maximal release, 52 +/- 7 units/10(6) mast cells). There was no correlation between OA-induced leukotriene release and mast cell purity. No leukotriene bioactivity was detected in actively (sheep blood sensitization) or passively (anti-OA) sensitized basophils. Both lung mast cells and blood basophils released histamine in response to the secretagogues calcium ionophore A23187 and 12-O-tetradecanoylphorbol-13-acetate (TPA); TPA-induced HR from mast cells was independent of added calcium. In basophils, TPA-induced HR was only partially independent of added calcium. While both cell types were poorly responsive to the secretagogue 48/80, only the lung mast cell demonstrated inconsistent HR to concanavalin A (Con-A). Phosphatidylserine had no effect on HR provoked by antigen, Con-A, or compound 48/80. These observations demonstrate similarities and differences in mediator release characteristics between guinea pig lung mast cells and blood basophils that are similar to those observed with human lung mast cells and basophils. These observations also suggest a lack of influence on mediator release by other cell types present in dispersed lung cell and mixed leukocyte preparations.

Isolation of guinea pig basophils using anti-leukocyte antibody and density gradient centrifugation on Percoll.

Peripheral blood basophils were isolated from guinea pigs using a 2-step procedure. Initial enrichment of basophils was achieved by treating leukocyte preparations obtained from whole blood with antibody to contaminating granulocytes and mononuclear cells. Basophil populations of 82% purity (mean; range 65-99%) were obtained by subsequent application of the antibody treated preparation to discontinuous Percoll gradients. The isolated basophils were viable and shown to be functional by histamine release upon stimulation with various secretogogues.