Contribution of KChIP2 to the developmental increase in transient outward current of rat cardiomyocytes

The Ca(2+)-independent, voltage-gated transient outward current (I(to)) displays a marked increase during development of cardiomyocytes. However, the molecular mechanism remained unclear. In rat adult ventricular myocytes, I(to) can be divided into a fast (I(to,f)) and a slow (I(to,s)) component by recovery process from inactivation. Voltage-gated K(+) channel-interacting proteins 2 (KChIP2) has recently been shown to modify membrane expressions and current densities of I(to,f). Here we examined the developmental change of I(to) and the putative molecular correlates of I(to,f) (Kv4.2 and Kv4.3) and KChIP2 in rat ventricular myocytes. Even in rat embryonic day 12 (E12) myocytes, we detected I(to). However, I(to) in E12 was solely composed of I(to,s). In postnatal day 10 (P10), we recorded much increased I(to) composed of two components (I(to,f) and I(to,s)), and I(to,f) was dominant. Thus, the developmental increase of I(to) from E12 to P10 can be explained by the dramatic appearance of I(to,f). Real-time RT-PCR revealed that Kv4.2 and Kv4.3 mRNA levels were slightly changed. By contrast, KChIP2 mRNA level increased from E12 to P10 by 731-fold. Therefore, the huge increase of KChIP2 expression was likely to be the cause of the great increase of I(to,f). In order to confirm that KChIP2 is crucial to induce I(to,f), we used adenoviral gene transfer technique. When KChIP2 was over-expressed in E12 myocytes, a great amplitude of I(to,f) appeared. Immunocytochemical experiments also demonstrated that KChIP2 enhanced the trafficking of Kv4.2 channels to cell surface. These results indicate that KChIP2 plays an important role in the generation of functional I(to,f) channels during development.     

Increased receptor binding by bovine (b) TSH bound to monoclonal antibody to bTSHbeta-subunit

TSH receptor (R) binding and cAMP production by bovine (b) TSH-bound to a monoclonal antibody (MoAb) or polyclonal antibody (Ab) to bTSH were examined, using TSH receptor (R) coating tube and porcine thyroid cells. (125) I-bTSH bound-to MoAbs to bTSH(alpha) or discontinuous type MoAb showed TSHR binding (10%) similar to intact (125) I-bTSH. TSHR binding was completely decreased (<2%) when (125) I-bTSH was bound by polyclonal Abs to bTSH(alpha) in Graves' patient or rabbit polyclonal Abs to bTSH. When either of the two MoAb (No. 1 and 2) to bTSH(beta) was bound to (125) I-bTSH, TSHR binding was 4 times higher (40%) compared to intact (125) I-bTSH. Binding of another MoAb (No. 3) caused no increased binding. TSHR binding of intact (125) I-bTSH was decreased from 10% to 2% by excess amounts of bTSH. Binding of (125) I-bTSH bound to MoAb to bTSH(beta) (No. 1 and 2) decreased from 40% to 30% by excess amounts of bTSH. When (125) I-bTSH bound-Fab of MoAb was used, the binding was reduced from 30 to 10% (No. 1) and from 25 to 6% (No. 2), respectively. In contrast, cAMP production by bTSH was decreased by pre-binding of all MoAbs and polyclonal Abs. Binding of (125) I-MoAb to bTSH (beta) to a synthetic peptide array of bTSH (beta) sequence was examined by the radioautography. The epitope of MoAb to bTSH(beta) was suggested to be LPK (beta 42-44) for No. 1, KLF (beta 39-41) for No. 2 and PKYA (beta 43-46) for No. 3, respectively, although the existence of discontinuous epitope could not be ruled out. The increased TSHR binding and the decreased cAMP production by bTSH bound to MoAbs may be due to the conformational change of TSH molecule or TSHR by binding of both bTSH and MoAb.     

Optimization of Shocking Lead Configuration for Transvenous Atrial Defibrillation

Optimum Electrodes for Atrial Defibrillation. Introduction : High atrial defibrillation energy requirements (ADER) in patients with chronic atrial fibrillation (AF) may limit the acceptance of transvenous atrial defibrillation. We evaluated an optimized defibrillation electrode configuration that could help to reduce the ADKR in patients with AF.
Methods and Results : We tested ten different configurations in nine dogs with AF (3.33 ± 2.92 days) induced by rapid atrial pacing. The configurations were: right atrial (RA) appendage as anode und coronary sinus (CS) as cathode; RA and innominate vein (I) as anode to CS (cathode); RA-CS (anode) to I (cathode); I-CS (anode) to RA (cathode); RA and left lateral subcutaneous patch (P) as anode to CS (cathode); RA-CS (anode) to P (cathode); P-CS (anode) to RA (cathode); superior vena cava (SVC) and CS (anode) to RA (cathode); RA-CS (anode) to SVC (cathode); and RA-SVC (anode) to CS (cathode). ADER was defined as the voltage needed to defibrillate the atria in 10% to 90% of 20 consecutive shocks. Three lead systems had ADER lower than the RA (anode) to CS (cathode) configuration, which required a mean of 143 ± 58 volts. These three were: RA-SVC (anode) to CS (cathode) 103 ± 29 V; I-CS (anode) to RA (cathode) 129 ± 39 V; and P-CS (anode) to RA (cathode) 130 ± 38 V. The remaining configurations had ADER higher than the RA (anode) to CS (cathode) configuration.
Conclusion : Adding an additional shocking electrode may reduce ADER when compared with the RA (anode) to CS (cathode) configuration. This concept could he incorporated into future implantable atrial defibrillators or used for refractory patients undergoing temporary transvenous cardioversion.     

钙离子激活性氯通道在犬心力衰竭心肌功能重塑的观察

目的观察 I_(to)第2个成分 I_(to2)即钙离子激活性氯通道(CLCA)是否参与心力衰竭(心衰)心脏的功能重塑。方法快速起搏犬右心室,诱发心衰,酶学法分离心肌细胞,以经典膜片钳全细胞记录法评价心衰时 I_(to2)电流密度的变化、I_(to2)与 L-型钙通道电流(I_(Ca-L))的关系和在恒定的细胞内钙浓度条件下 I_(to2)与膜电压的关系。用氯通道阻断剂4,4′diisothiocyanostilbene-2,2′-disulfonic acid(DIDS)200μmol 筛选出 I_(to2)。结果 I_(to2)电压-电流关系呈倒钟型,与 I_(Ca-L)的曲线成镜影关系但右移10 mV_oI_(Ca-L)密度在心衰和对照组之间差异无统计学意义。在膜电压0～40 mV 之间,I_(to2)密度在心衰组明显减小。例如膜电压为20 mV 时,对照组与心衰组 I_(to2)分别为(3.02±0.55)pA/pF(n=7)和(1.31±0.25)pA/pF(n=8),P<0.05。I_(to2)电流的衰退时间常数在两组间差异无统计学意义。当细胞内钙浓度锁定在100μmol 时,I_(to2)密度在心衰组反而比对照组增大,提示 CLCA 功能上调。结论心衰时 I_(to2)密度下降,这可能与心衰细胞兴奋释放钙浓度下降有关。I(to2)密度下降可能参与心衰时的动作电位时程延长和晚期后除极的发生,可能是心衰时心律失常的发生机制之一。     

Demonstration of calcium-activated transient outward chloride current and delayed rectifier potassium currents in Swine atrial myocytes

Cellular electrophysiology is not fully understood in the atrium of pig heart. The objective of the present study was to determine whether transient outward current (I(to)), ultra-rapid delayed rectifier potassium current (I(Kur)), and rapid and slow delayed rectifier K(+) currents (I(Kr) and I(Ks)) were present in pig atrium. The whole-cell patch technique was applied to record membrane currents and action potentials in myocytes isolated from pig atrium. It was found that an I(to) was activated upon depolarization voltage steps to between -10 and +60 mV from -50 mV in pig atrial cells, and the I(to) was sensitive to the inhibition by the blockade of L-type calcium (Ca(2+)) current, showed a "bell-shaped" I-V relationship, typical of I(to2) (i.e. I(Cl.Ca)). The I(to2) was inhibited by the chloride (Cl(-)) channel blocker anthracene-9-carboxylic acid (9-AC, 200 micromol/l) or 4,4'-diisothiocyanostilben-2,2'disulfonic acid (200 micromol/l), and by Cl(-) substitution in the superfusate. I(Kur) was found in pig atrial myocytes, and the current showed properties of weak inward rectification and use- and frequency-dependent reduction. I(Kur) was resistant to tetraethylammonium, but sensitive to inhibition by 4-aminopyridine (4-AP) (IC(50) = 71.7 +/- 3.5 micromol/l). In addition, E-4031-sensitive I(Kr) and chromanol 293B-sensitive I(Ks) were observed in pig atrial myocytes. Blockade of I(to2), I(Kur), I(Kr) or I(Ks) with corresponding blockers significantly prolonged atrial action potentials. These results indicate that Ca(2+)-activated I(to2), 4-AP-sensitive I(Kur), E-4031-sensitive I(Kr), and 293B-sensitive I(Ks) are present in pig atrial myocytes, and these currents play important roles in action potential repolarization of pig atria.     

Changes in renal function during acute insulin-induced hypoglycaemia in patients with type 1 diabetes.

The effect of acute hypoglycaemia on renal function was examined in eight male patients with Type 1 diabetes who had normal urinary albumin excretion. Insulin was given as a bolus intravenous injection (0.125 U kg-1) and plasma glucose fell to a nadir of 1.6 (SE 0.2) mmol l-1, with all patients experiencing an acute autonomic reaction. Renal plasma flow fell from 674 (106) to 540 (198) ml min-1 during hypoglycaemia (p less than 0.01) and returned to 655 (181) ml min-1 (NS vs baseline). Glomerular filtration rate (GFR) declined from 143 (23) to 110 (36) ml min-1 during hypoglycaemia (p less than 0.02), rising to 150 (44) ml min-1 in the recovery period (NS vs baseline). The urinary flow rate and urinary albumin excretion rate both fell significantly in response to hypoglycaemia (10.6 (1.2) to 4.7 (1.1) ml min-1; p less than 0.002, and 46.2 (10.6) to 26.0 (10.5) micrograms min-1, respectively). Urinary dopamine excretion also declined, from 322 (37) to 211 (29) mumol min-1 (p less than 0.005) but sodium excretion was unchanged. Plasma adrenaline concentration (0.2 (0.03) to 1.7 (0.4) nmol l-1; p less than 0.01) and plasma renin activity (0.49 (0.13) to 1.08 (0.17) ng-Ang 1 l-1 h-1; p less than 0.01) increased during hypoglycaemia, but changes in plasma noradrenaline and angiotensin II levels did not attain significance. These acute changes in renal function, observed during hypoglycaemia in diabetic patients, may result from direct stimulation of the efferent sympathetic nerves to the kidney, complemented by the hormonal changes induced by hypoglycaemia.     

Change in specificity of antibodies to a random synthetic branched polypeptide in mice tolerant to its ordered analogs

The crossreactivity between the random synthetic polypeptide antigen, (Tyr,Glu)-poly(DLAla)- -poly(Lys), and its ordered sequence analogs, (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys) and (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys), has been studied on the level of tolerance induction. Induction of tolerance to the random (Tyr,Glu)-poly(DLAla)- -poly(Lys) affected the response of the tolerant mice to the homologous antigen as well as to (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys), which was shown previously to represent the major determinant of (Tyr,Glu)-poly(DLAla)- -poly(Lys). In contrast, these mice responded with high antibody titers to the hardly crossreacting (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys). Mice tolerant to the ordered peptide antigen (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys) did not respond to the homologous polypeptide; however, their immune response to either (Tyr-Glu)-poly(DLAla)- -poly(Lys) or (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys) was not affected. Mice that were tolerant to (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(Lys) responded well to (Tyr-Glu-Tyr-Glu)-poly(DLAla)- -poly(Lys). Furthermore, these mice produced high antibody titers after immunization with the random (Tyr,Glu)-poly(DLAla)- -poly(Lys). However, the antibodies produced were not specific to the major determinant of (Tyr,Glu)-poly(DLAla)- -poly(Lys), namely, Tyr-Tyr-Glu-Glu, but were directed to minor determinants of the random polypeptide, including Tyr-Glu-Tyr-Glu, which are not immunopotent when nontolerant mice are immunized with (Tyr,Glu)-poly(DLAla)- -poly(Lys). Thus, whereas antigenic specificity reflects itself also at the level of tolerance induction, the animals that had been made tolerant are capable of responding to previously silent antigenic determinants.     

The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium

G. Y. Oudit, Z. Kassiri, R. Sah, R. J. Ramirez, C. Zobel and P. H. Backx. The Molecular Physiology of the Cardiac Transient Outward Potassium Current (I(to)) in Normal and Diseased Myocardium. Journal of Molecular and Cellular Cardiology (2001) 33, 851-872. The Ca(2+)-independent transient outward potassium current (I(to)) plays an important role in early repolarization of the cardiac action potential. I(to)has been clearly demonstrated in myocytes from different cardiac regions and species. Two kinetic variants of cardiac I(to)have been identified: fast I(to), called I(to,f), and slow I(to), called I(to,s). Recent findings suggest that I(to,f)is formed by assembly of K(v4.2)and/or K(v4.3)alpha pore-forming voltage-gated subunits while I(to,s)is comprised of K(v1.4)and possibly K(v1.7)subunits. In addition, several regulatory subunits and pathways modulating the level and biophysical properties of cardiac I(to)have been identified. Experimental findings and data from computer modeling of cardiac action potentials have conclusively established an important physiological role of I(to)in rodents, with its role in large mammals being less well defined due to complex interplay between a multitude of cardiac ionic currents. A central and consistent electrophysiological change in cardiac disease is the reduction in I(to)density with a loss of heterogeneity of I(to)expression and associated action potential prolongation. Alterations of I(to)in rodent cardiac disease have been linked to repolarization abnormalities and alterations in intracellular Ca(2+)homeostasis, while in larger mammals the link with functional changes is far less certain. We review the current literature on the molecular basis for cardiac I(to)and the functional consequences of changes in I(to)that occur in cardiovascular disease.     

The gas phase reaction of singlet dioxygen with water: a water-catalyzed mechanism

Stimulated by the recent surprising results from Wentworth et al. [Wentworth, A. D., Jones, L. H., Wentworth, P., Janda, K. D. & Lerner, R. A. (2000) Proc. Natl. Acad. Sci. USA 97, 10930-10935] that Abs efficiently catalyze the conversion of molecular singlet oxygen ((1)O(2)) plus water to hydrogen peroxide (HOOH), we used quantum chemical methods (B3LYP density functional theory) to delineate the most plausible mechanisms for the observed efficient conversion of water to HOOH. We find two reasonable pathways. In Pathway I, (i) H(2)O catalyzes the reaction of (1)O(2) with a second water to form HOOOH; (ii) two HOOOH form a dimer, which rearranges to form the HOO-HOOO + H(2)O complex; (iii) HOO-HOOO rearranges to HOOH-OOO, which subsequently reacts with H(2)O to form H(2)O(4) + HOOH; and (iv) H(2)O(4) rearranges to the cyclic dimer (HO(2))(2), which in turn forms HOOH plus (1)O(2) or (3)O(2). Pathway II differs in that step ii is replaced with the reaction between HOOOH and (1)O(2), leading to the formation of HOO-HOOO. This then proceeds to similar products. For a system with (18)O H(2)O, Pathway I leads to a 2.2:1 ratio of (16)O:(18)O in the product HOOH, whereas Pathway II leads to 3:1. These ratios are in good agreement with the 2.2:1 ratio observed in isotope experiments by Wentworth et al. These mechanisms lead to two HOOH per initial (1)O(2) or one, depending on whether the product of step iv is (1)O(2) or (3)O(2), in good agreement with the experimental result of 2.0. In addition to the Ab-induced reactions, the hydrogen polyoxides (H(2)O(3) and H(2)O(4)) formed in these mechanisms and their decomposition product polyoxide radicals (HO(2), HO(3)) may play a role in combustion, explosions, atmospheric chemistry, and the radiation chemistry in aqueous systems.     

Bacteriophage typing and antibiotic sensitivity pattern of Staphylococcus aureus from clinical specimen in and around Solapur (South Maharashtra)

Two hundred and eighty nine strains of Staphylococcus aureus isolated from pus and wound swabs (149), blood (36), urine (28), sputum (14), stool (12), throat swab (9) and CSF (4) were subjected for bacteriophage typing and antibiotic susceptibility pattern. 113 (39.11%) strains were typable. Among the typable strains, 16 (5.53%) belonged to phage group I, 33 (11.41%) strains belonged to phages group II, 38 (13.14%) belonged to phage group III, 26 (8.99%) strains belonged to the phages which have not been allocated to any group (Miscellaneous group) 176 (60.89%) strains were untypable. Only one (0.34%) strain was sensitive to all the drugs tested. Almost all the isolates were resistant to Ampicillin and Tobramycin (99.3% each). 286 (98.96%) strains were found to be resistant to Penicillin and Erythromycin followed by Kanamycin 272 (94.11%) and Gentamicin 263 (91.3%). 113 (39.1%) strains were Methicillin resistant Staphylococcus aureus (MRSA). All MRSA strains were resistant to all drugs tested except vancomycin. Resistance to most of the commonly used antimicrobial agents indicates a need to replace these drugs with other agents and maintenance of surveillance to detect changing patterns of resistance.     

Effects of chromanol 293B on transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes

It is unclear whether chromanol 293B, a selective inhibitor of slow component of delayed rectifier K(+) current (I(Ks)), may affect other K(+) currents in human atrium. With whole-cell patch configuration, we evaluated effects of 293B on transient outward K(+) current (I(to1)) and ultra-rapid delayed rectifier K(+) current (I(Kur)) in isolated human atrial myocytes. It was found that 293B inhibited I(to1) and I(Kur) in a concentration-dependent manner. At 10 microM 293B suppressed I(to1) to 3.4 +/- 0.4 from 5.1 +/- 0.3 pA/pF (P < 0.01), and I(Kur) to 1.5 +/- 0.2 from 2.1 +/- 0.3 pA/pF (P < 0.01) at +50 mV. The inhibition of I(to1) and I(Kur) was independent of depolarizing voltage, and the concentration of 50% inhibition was 31.2 microM for I(to1), and 30.9 microM for I(Kur). 293B blocked I(to1) and I(Kur) with the same concentration range, and the significant effect was observed from the concentration of 1 microM. The maximum inhibitive effect was 88% for I(to1) and 96% for I(Kur) at 250 microM. Voltage dependence of activation and inactivation, and time-dependent recovery from inactivation of I(to1) were not altered by 293B; however, time to peak and time-dependent inactivation of I(to1) was significantly accelerated. The results indicate that 293B significantly inhibits the major repolarization K(+) currents I(to1) and I(Kur) in human atrial myocytes.     

Is alcohol ablation of the septum associated with recurrent tachyarrhythmias?

QUESTIONS UNDER STUDY: Alcohol ablation (AA) of the septum has been introduced as new therapy in hypertrophic cardiomyopathy (HCM). It was feared that iatrogenic myocardial infarction due to AA may induce re-entry tachyarrhythmias and increase sudden cardiac death. METHODS AND RESULTS: Twenty-four patients (mean age 52 years) underwent successful AA. Clinical follow-up (FU) ranged from 0.3 to 0.7 years (mean 2.8). One patient died (suicide) 4 years after AA. Left ventricular (LV) outflow gradient (peak-to-peak) decreased (median) after AA from 43 (IQR 25 to 4) mmHg to 1 (IQR 0 to 12) mmHg (rest) (p <0.001) and from 130 (IQR 75 to 165) mmHg to 13 (IQR 0 to 31) mmHg (postextrasystolic) (p <0.001). Transient AV block occurred in 22% (5/24) necessitating temporary pacing. A permanent pacemaker was implanted in 4% (1/24). NYHA-class was 2.5 (IQR 2.0 to 3.0) before and 1.5 (IQR 1.3 to 2.0) (p <0.001) after AA. During FU, 2 pacemakers were implanted due to bradycardia (no AV block). A right bundle branch block was found in 13% (2/24) before and 46 % (11/24) after AA (p = 0.003). Non-sustained ventricular tachycardia (NSVT) was observed in 13% (2/16) before and 22% (5/23) (p = 0.46) after AA. Two patients required ICD implantation. CONCLUSIONS: Long-term FU is excellent in HCM after AA. The pressure gradient drops below 25 mm Hg in 95% (23/24) of all patients. Transient AV block occurs in 22% (5/24), but permanent pacemaker implantation is rarely needed (13%, 2/24). Severe NSVT occurs in 13% (2/16) before and 22% (5/23) after AA but ICD implantation is only occasionally required.     

Efficacy of bispectral monitoring as an adjunct to nurse-administered propofol sedation for colonoscopy: a randomized controlled trial

BACKGROUND AND AIMS: Bispectral (BIS) monitoring provides an objective, non-invasive measure of the level of consciousness in sedated patients. BIS has been shown to lag behind the level of sedation during induction and emergence of sedation with propofol. In this study, we sought to determine whether BIS is a useful adjunctive maneuver to registered nurse-administered propofol sedation (NAPS) as measured by reductions in recovery time and doses of propofol administered. METHODS: A randomized controlled trial of 102 outpatients presenting for colonoscopy was performed. BIS values were recorded continuously in all subjects. Patients were randomized to receive NAPS with BIS visible to nurse and endoscopist versus BIS invisible to nurse and endoscopist. In phase 1 (47 patients), the nurse and endoscopist team were instructed to consider BIS (when visible) as only adjunctive information with regard to titrating sedation. In phase 2 (55 patients), the nurse endoscopist team was instructed to use BIS as the primary endpoint for titration of sedation, and to target BIS to greater than 60 (60-70 is deep sedation). RESULTS: In phase 1, the mean (SD) BIS value from scope-in (SI) to scope-out (SO) for BIS was 59.3 (9.9) and was not different from controls at 59.9 (10.1; p= 0.82). The mean (SD) propofol dose (mg/min) was 15.8 (5.6) and 17.2 (6.2) for BIS and controls, respectively (p= 0.45). The mean (SD) recovery time with BIS visible in phase 1 was 20.6 min (5.5) versus 19.2 min (4.5) in controls (p= 0.34). In phase 2, the mean (SD) BIS from SI to SO in those randomized to have BIS visible was 64.1 (5.4) versus 63.1 (8.5) in controls (p= 0.58). The mean (SD) dose of propofol (mg/min) was 16.1 (11.2) and 16.4 (12.3) for BIS and control groups, respectively (p= 0.92). The mean (SD) recovery time in phase 2 with BIS visible was 18.7 (3.5) versus 20.1 (5.6) in controls (p= 0.27). CONCLUSIONS: BIS did not lead to reductions in mean propofol dose or recovery time when used as an adjunct to NAPS for colonoscopy, or when used as the primary target for sedation. No clinically important role for BIS monitoring as an adjunct to NAPS has yet been established.     

Superoxo,mu-peroxo,and mu-oxo complexes from heme/O2 and heme-Cu/O2 reactivity: copper ligand influences in cytochrome c oxidase models

The O(2)-reaction chemistry of 1:1 mixtures of (F(8))Fe(II) (1; F(8) = tetrakis(2,6-diflurorophenyl)porphyrinate) and [(L(Me(2))N)Cu(I)](+) (2; L(Me(2))N = N,N-bis(2-[2-(N',N'-4-dimethylamino)pyridyl]ethyl)methylamine) is described, to model aspects of the chemistry occurring in cytochrome c oxidase. Spectroscopic investigations, along with stopped-flow kinetics, reveal that low-temperature oxygenation of 1/2 leads to rapid formation of a heme-superoxo species (F(8))Fe(III)-(O(2)(-)) (3), whether or not 2 is present. Complex 3 subsequently reacts with 2 to form [(F(8))Fe(III)-(O(2)(2-))-Cu(II)(L(Me(2))N)](+) (4), which thermally converts to [(F(8))Fe(III)-(O)-Cu(II)(L(Me(2))N)](+) (5), which has an unusually bent (Fe-O-Cu) bond moiety. Tridentate chelation, compared with tetradentate, is shown to dramatically lower the nu(O-O) values observed in 4 and give rise to the novel structural features in 5.     

Bromocriptine and Triac therapy for hyperthyroidism due to pituitary resistance to thyroid hormone.

Although a number of patients with generalized resistance to thyroid hormone have been treated with bromocriptine (Brc), only one previously reported patient with nontumoral TSH-mediated hyperthyroidism, presumably due to pituitary resistance to thyroid hormone (PRTH), has been successfully treated with bromocriptine (Brc). In addition, several studies suggested that the T3 analog 3,5,3'-triiodothyroacetic acid (Triac) may control hyperthyroidism in patients with PRTH. In the current study a patient with PRTH diagnosed at age 15 yr underwent separate therapeutic trials with Brc and Triac, during which time physical parameters, thyroid function tests, systolic time intervals (STI), and oxygen consumption (VO2) were measured. On Brc therapy (12.5 mg/day), heart rate decreased (108 to 72/min), TSH decreased (5.7 to 1.2 mU/L), T3 decreased (9.9 to 1.7 nmol/L), free T4 decreased (205 to 21 pmol/L), STI lengthened (left ventricular ejection time, 0.389 to 0.405 s), and VO2 did not change (164 to 162 mL/min). We found no significant clinical improvement with a maximal dose of Triac (2.1 mg/day), only minimal reduction in goiter size; mild decreases in T3 (9.9 to 6.7 nmol/L), free T4 (205 to 113 pmol/L), and TSH (5.7 to 5.4 mU/L); no change in STI (left ventricular ejection time, 0.389 to 0.401 sec); and an increase in O2 consumption (VO2, 164 to 209 mL/min). Thus, the results favor Brc as effective therapy for this patient with PRTH.     

Free radical scavengers improve the impaired endothelium-dependent responses in aorta and kidneys of diabetic rabbits

The effects of two endogenous antioxidants, alpha-lipoic acid and reduced gluthathione (GSH), were evaluated in the response of the renal vasculature and aortic rings ex vivo of 4-week alloxan-diabetic rabbits to the endothelium-dependent agonists bradykinin (BK) and acetylcholine (Ach) or to the endothelium-independent agonist sodium nitroprusside (SNP) and compared with age and sex-matched euglycemic rabbits. The maximal decrease in perfusion pressure (R(max)) after BK infusion in the renal vasculature from diabetic rabbits was 5.4+/-1.3% (PD(2) 8 [12.6-3.4]) compared with 34.2+/-4.2% (PD(2) 9 [11.3-6.7]) (P<0.05) attained in tissues obtained from euglycemic rabbits. The addition of 1 microM lipoic acid or GSH improved (P<0.05) the R(max) to BK to 18.3+/-2.4% (PD(2) 8.6 [12.4-4.8]) and 19.5+/-3.7% (PD(2) 9.1 [13.3-4.9]), respectively. Similarly, the maximal vasorelaxant response to Ach in kidneys from diabetic rabbits was 16+/-2.0% (PD(2) 7.3 [10.4-4.2] whilst the R(max) in kidneys from euglycemic animals was 52.7+/-4.9% (PD(2) 11.3 [16.4-6.2]). Incubation with 1 microM alpha-lipoic acid or GSH restored the R(max) to Ach to 31+/-3.9% (PD(2) 9.8 [14.3-5.3]) and to 23+/-5.4% (PD(2) 7.6 [11.4-3.8], respectively. The vasodilatory response to SNP was unaltered among tissues from diabetic and euglycemic rabbits and was also unaffected by the treatments utilized. In addition, the R(max) to Ach in aortic rings of diabetic rabbits was 28.7+/-2.4% (PD(2) 8.3 [11.7-4.9]) compared with 100% (PD(2) 7.9 [12.1-3.7]) obtained in tissues gathered from euglycemic rabbits. The pretreatment of the tissues with alpha-lipoic acid restores the R(max) to 47.4+/-4% (PD(2) 11.1 [14.3-7.9]) and the pretreatment with GSH to 52+/-3.2% (PD(2) 9.8 [12.7-6.9]). Similarly, the response to SNP was unaltered in all groups. Lipoic acid and reduced gluthatione directly improved the endothelium-dependent response of renal arterioles and aortic rings of diabetic rabbits.     

Reference values for nocturnal home pulse oximetry during sleep in primary school children

OBJECTIVE: To provide reference values for pulse oximeter saturation (SpO(2)) in primary school children, measured at home during sleep. METHODS: Recordings of SpO(2) and signal quality from 100 children were randomly selected from a larger population-based sample intended to study the prevalence of sleep-disordered breathing. Recordings were analyzed for the duration of artifact-free recording time (AFRT), minimum SpO(2) (SATmin) and median SpO(2) (SAT(50)), the SpO(2) below which the child spent 5% of AFRT (SAT(5)), and the SpO(2) below which the child spent 10% of AFRT (SAT(10)). In addition, the time in seconds with SpO(2) or= 4% per hour of AFRT (DI(4)), the number of falls in SpO(2) to 相似文献   

Ca2+ overload evokes a transient outward current in guinea-pig ventricular myocytes.

There are 2 types of transient outward currents (Ito) in the hearts of various mammals: a 4-aminopyridine (4-AP) sensitive K+ current and a 4-AP resistant Ca2+ activated current, carried by Cl-, (referred to as I(to1) and I(to2), respectively). However, the I(to) has been considered to be absent in guinea-pig ventricular myocytes and so this study tested the hypothesis that I(to1) is generally absent in guinea-pig ventricular myocytes, but I(to2) appears under the condition of Ca2+ overload. Membrane currents were recorded by the whole-cell patch-clamp technique and Ca2+ overload was achieved by adding internal, and eliminating external, Na+ with subsequent enhancement of Ca2+ influx via the Na+-Ca2+ exchange. Under physiological conditions, I(to) could not be elicited by 300 ms-test pulse from -70 mV to 0 mV (n=32). However, under Ca2+ overload, a biphasic current resulting from the overlap of the L-type Ca2+ channel current and Ito was elicited (n=38). This I(to) was resistant to 4-AP (3 mmol/L, n=30) but sensitive to both anthrancene-9-carboxylic acid (9-AC, 3 mmol/L, n=8) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (100 micromol/L, n=3). Replacing K+ with Cs+ on both sides of the membrane failed to abolish I(to) (n=38). I(to) disappeared by lowering the external Cl- (n=3). The amplitude of I(to) was dependent on that of the L-type Ca2+ channel current (n=4). Because Ca2+ release from the sarcoplasmic reticulum was prevented by caffeine (5 mmol/L), I(to) was negligible (n=6). These results suggest that I(to1) is absent, but Ca2+ overload evokes I(to2) in guinea-pig ventricular myocytes.     

Sudden death in hypertrophic cardiomyopathy: identification of high risk patients

OBJECTIVES

We sought to identify patients with hypertrophic cardiomyopathy (HCM) at high risk of sudden death (SD).

BACKGROUND

Relatively low mortality rates in HCM make conventional analysis of multiple clinical risk markers for SD problematic. This study used a referral center registry to investigate a smaller number of generally accepted noninvasive risk markers.

METHODS

We studied 368 patients (14 to 65 years old, 239 males) with HCM. There were five variables: nonsustained ventricular tachycardia (NSVT), syncope, exercise blood pressure response (BPR), family history of sudden death (FHSD) and left ventricular wall thickness (LVWT).

RESULTS

During follow-up (3.6 ± 2.5 years [range 2 days to 9.6 years]), 36 patients (9.8%) died, 22 of them suddenly. Two patients received heart transplants. The six-year SD-free survival rate was 91% (95% confidence interval [CI] 87% to 95%). In the Cox model, there was a significant pairwise interaction between FHSD and syncope (p = 0.01), and these were subsequently considered together. The multivariate SD risk ratios (with 95% CIs) were 1.8 for BPR (0.7 to 4.4) (p = 0.22); 5.3 for FHSD and syncope (1.9 to 14.9) (p = 0.002); 1.9 for NSVT (0.7 to 5.0) (p = 0.18) and 2.9 for LVWT (1.1 to 7.1) (p = 0.03). Patients with no risk factors (n = 203) had an estimated six-year SD-free survival rate of 95% (95% CI 91% to 99%). The corresponding six-year estimates (with 95% CIs) for one (n = 122), two (n = 36) and three (n = 7) risk factors were 93% (87% to 99%), 82% (67% to 96%) and 36% (0% to 75%), respectively. Patients with two or more risk factors had a lower six-year SD survival rate (95% CI) compared with patients with one or no risk factors (72% [56% to 88%] vs. 94% [91% to 98%]) (p = 0.0001).

CONCLUSIONS

This study demonstrates that patients with multiple risk factors have a substantially increased risk of SD sufficient to warrant consideration for prophylactic therapy.     

IgG immunoadsorption reduces systemic lupus erythematosus activity and proteinuria: a long term observational study

OBJECTIVE: To analyse the effects of rigorous immunoglobulin removal by immunoadsorption (IAS) on proteinuria (primary outcome variable), disease activity (SIS, SLEDAI, ECLAM), and autoantibodies to double stranded DNA (anti-dsDNA) in active systemic lupus erythematosus (SLE). METHODS: 16 patients with severe SLE and renal disease, in whom cyclophosphamide was contraindicated or failed to halt disease progression, were treated with IAS for 3 months. Patients achieving at least 20% improvement in two or more of the outcome measures were considered responders and offered a 9 months' extension period. RESULTS: Within 3 months, 14 patients responded and 11 opted for an extension. Proteinuria decreased from 6.7 (4.6) g/day (mean (SD)) at baseline to 4.3 (3.5) g/day at 3 months and 2.9 (2.4) g/day at 12 months (p<0.001). From baseline to 3 and 12 months, disease activity improved independently of scoring by SIS (15 (5) to 5 (2) and to 5 (2), p<0.0001), SLEDAI (21 (7) to 5 (4) and to 5 (4), p<0.0001), or ECLAM (7 (2) to 2 (1) and to 3 (1), p<0.0001). Anti-dsDNA fell from 391 (647) IU/ml to 146 (218) and to 53 (50) IU/ml at 3 and 12 months, respectively. Steroids could be tapered from 117 (159) mg/day at baseline to 29 (17) mg/day at 3 months and 9 (2) mg/day at 12 months. IAS was not associated with an excess of infections. However, one patient died of septicaemia after 1 month of treatment. CONCLUSION: In this negatively selected cohort of patients with SLE, IAS was associated with a significant response shown by reduced proteinuria, improved global disease activity, decreased anti-dsDNA, and lower glucocorticoid dosages, suggesting therapeutic benefit.