Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352

The novel anti-ischemic compound, BMS-204352 ((3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one)), strongly activates the voltage-gated K+ channel KCNQ5 in a concentration-dependent manner with an EC50 of 2.4 microM. At 10 microM, BMS-204352 increased the steady state current at -30 mV by 12-fold, in contrast to the 2-fold increase observed for the other KCNQ channels [Schr?der et al., 2001]. Retigabine ((D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) induced a smaller, yet qualitatively similar effect on KCNQ5. Furthermore, BMS-204352 (10 microM) did not significantly shift the KCNQ5 activation curves (threshold and potential for half-activation, V1/2), as observed for the other KCNQ channels. In the presence of BMS-204352, the activation and deactivation kinetics of the KCNQ5 currents were slowed as the slow activation time constant increased up to 10-fold. The M-current blockers, linopirdine (DuP 996; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) and XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), inhibited the activation of the KCNQ5 channel induced by the BMS-204352. Thus, BMS-204352 appears to be an efficacious KCNQ channels activator, and the pharmacological properties of the compound on the KCNQ5 channel seems to be different from what has been obtained on the other KCNQ channels.     

Three-dimensional load analysis of indentation stimulators

The properties of three types of indentation stimulators: filament indenters, a spring gauge indenter, and an electromechanical stimulator, were evaluated by actuating each device against a 3-direction load cell. The on-axis loads produced by filament indenters were independent of the degree of buckling. The off-axis loads produced by a filament increased with the degree of buckling of the filament, and had magnitudes that were up to 25% of the on-axis load. Repeated applications of a filament produced loads whose magnitudes were very consistent. Offsetting the handle of a filament indenter altered the magnitude and the direction of the off-axis load. Because these factors were poorly controlled in hand held trials, off-axis loads were more variable in hand held trials. The spring gauge stimulator was, when hand held, very susceptible to creating large off-axis loads. When the off-axis loads were large, the spring gauge indicator underestimated the true on-axis loads. The electromechanical stimulator produced loads with a very high degree of consistency and could be arranged so that it produced very small off-axis loads.     

Neurodevelopmental outcome of patients after the fontan operation: A comparison between children with hypoplastic left heart syndrome and other functional single ventricle lesions

OBJECTIVE: To compare neurodevelopmental outcome (NDO) in patients with hypoplastic left heart syndrome (HLHS), other functional single ventricle lesions, and the standard population and to investigate predictors of NDO in the population of children with functional single ventricle (FSV). STUDY DESIGN: A time- and age-defined cohort of patients with the Fontan circulation was recruited to participate in neurodevelopmental testing, behavioral evaluation, and imaging of the central nervous system. The Wechsler Intelligence test was the primary measure of NDO. Analysis included comparison of patients with HLHS with other patients with functional single ventricles. Other potential clinical predictors of NDO were investigated. RESULTS: The mean Full Scale Wechsler Intelligence score was 101.4+/-5.4. For the HLHS subgroup the mean Full Scale Wechsler score was 93.8+/-7.3, and for the non-HLHS subgroup it was 107.0+/-7.0. Although the HLHS group had significantly lower scores than the non-HLHS subgroup, neither subgroup scored significantly different from the standard population on the Wechsler Scales. Socioeconomic status, circulatory arrest, and perioperative seizures also were predictive of neurodevelopmental outcome. CONCLUSION: Neurodevelopmental and behavioral outcome in patients who have undergone the Fontan procedure including patients with HLHS is good in the preschool and early school years, with Wechsler Intelligence scores generally in the normal range.     

A nutraceutical based approach to reduce cholesterolaemia in patients previously intolerant of more than a statin: a pilot study

This study was aimed at evaluating the tolerability of a nutraceutical combination with anticholesterolaemic action in patients intolerant of statin treatment. A total of 32 hypercholesterolaemic patients, all intolerant to at least two statin treatments, were enrolled in the ambulatory service. None of the enrolled patients was diabetic or undergoing secondary prevention of cardiovascular disease. Patients consumed one yoghurt with 2 g of added phytosterols each morning (Pro-Activ, Unilever, Milan, Italy) and one tablet of a registered combined nutraceutical (Armolipid Plus, Rottapharm, Monza, Italy). We tested the efficacy of the treatment after 4 and 6 months. One tablet of Armolipid Plus contains: berberine 500 mg, monacolin 3 mg, and policosanol 10 mg. After 3 months of treatment the patients showed a significant decrease in total cholesterol, low-density lipoprotein cholesterol and triglycerides, and a significant increase in the plasma level of high-density lipoprotein cholesterol. These results were maintained after 6 months of treatment without a significant change in the mean values.     

Severe mitral insufficiency in mucopolysaccharidosis type III-B (Sanfilippo syndrome)

Summary A 6-year-old girl with mucopolysaccharidosis (MPS) III-B (Sanfilippo syndrome) who developed severe mitral regurgitation and congestive heart failure requiring surgery (valvuloplasty) is reported. One year after surgery the patient remains well, with marked improvement in her physical activity, and without signs of heart failure. This is only the second report of severe mitral regurgitation in MPS III, and is the first report of a successful repair (valvuloplasty) of a dysplastic mitral valve in the MPS. Mitral valvuloplasty should be considered instead of valve replacement in any MPS patient with mitral valve regurgitation requiring surgery.     

Comparison of shortening with timing of wall motion in detecting regional abnormalities of the left ventricle in coronary disease

Clinical observations suggest that ischemic myocardium may demonstrate delayed wall motion while absolute shortening remains normal. Wall motion timing and percent shortening were examined in 25 patients (7 normal, 18 coronary disease) with 35 mm biplane left ventriculograms and coronary arteriography. Mean age was 63 ± 2.4 years. Of 17 males and 8 females, 13 had 3 vessel, 4 had 2 vessel, and 1 had 1 vessel disease. Left ventricular regions were analyzed using the Coronary Artery Surgery Study nomenclature and quantitative computer-based analysis as well as visual based qualitative analysis. Regional percent shortening and ejection fraction were calculated from end systolic and end diastolic frames. Regional shortening times were related to global ejection time from 30 frame/sec, frame by frame analysis. Feeder arteries were stenosed (>70%) in 135 of 225 left ventricular regions analyzed. Computer detection (shortening and timing) identified 97/225 as abnormal (P < 0.01 vs. feeder artery stenosis) while physicians identified 79/225 as abnormal (p < 0.01 vs. feeder artery stenosis). Of the 97 computer detected abnormal regions, shortening alone detected 47, timing alone detected 39, and 11 showed both abnormalities. Timing analysis increased detection of wall motion abnormalities from 58/225 (26%) to 97/225 (43%) (p < 0.001). Timing abnormalities were noted more (92%) in basal segments, while shortening abnormalities dominated (88%) in apical segments (p < 0.001). Use of temporal measurements in wall motion analysis significantly increases the likelihood of detecting abnormal left ventricular regional wall motion when compared to shortening measurements alone. © 1993 Wiley-Liss, Inc.     

Turnip yellow mosaic virus RNA-replicase contains host and virus-encoded subunits

The enzyme (RNA-replicase) involved in the synthesis of viral RNA has been purified from turnip yellow mosaic virus (TYMV)-infected chinese cabbage leaves. The RNA-replicaset contains two major subunits: one of apparent molecular weight 115,000 (115K) and the other of 45K. We have raised antisera against the purified TYMV-RNA-replicase and have demonstrated by immunoaffinity chromatography and immunoblotting that the 115K polypeptide is coded by the viral RNA but that the 45K protein is of host origin. Furthermore the TYMV RNA-replicase is clearly different from the RNA-dependent RNA polymerase that occurs in healthy as well as in infected plants.