HETEROZYGOTES FOR 17α-HYDROXYLASE DEFICIENCY CAN BE DETECTED WITH A SHORT ACTH TEST

A short ACTH test was performed in the six parents, and four siblings, of three cases with 17 alpha-hydroxylase deficiency. Baseline steroid levels were all normal in female heterozygotes but in males 17 alpha-hydroxyprogesterone levels were elevated. After ACTH-stimulation, plasma levels of corticosterone were elevated in five obligate heterozygotes and 18-hydroxydeoxycorticosterone levels were increased in four of them. Two of the four siblings had biochemical signs of heterozygosity. The short ACTH test appears to be an efficient method for detecting heterozygosity, but the abnormalities found are more heterogeneous than previously suggested.     

Identification and characterization of human B-cell epitopes in recombinant antigens of Leishmania aethiopica

Recombinant DNA fragments from Leishmania aethiopica that code for epitopes which react with human antibodies have been characterized by cross-hybridization studies and DNA sequence analysis. Twenty clones could be grouped into seven different groups (I–VII), probably representing seven different L. aethiopica antigens. The DNA sequences of representative clones from the seven groups have been obtained and the amino acid sequence of the respective recombinant antigens established. The recombinant antigens have been analysed by epitope scanning with patient sera, and octapeptides that contain potential B-cell epitopes have been identified in all seven recombinant antigens. These octapeptides have further been tested with additional patient sera and control sera, and three octapeptides (HAFCHEEG, YHSSVVHD and SYAPCSLK) were found to contain major epitopes recognizing specific antibodies in nine, seven and four, respectively, of the twenty sera tested. Fifteen of the twenty sera reacted with one or more of these three octapeptides.     

The Renin–Angiotensin System Mediates the Effects of Stretch on Conduction Velocity,Connexin43 Expression,and Redistribution in Intact Ventricle

Effect of Stretch on Conduction and Cx43 . Introduction: In disease states such as heart failure, myocardial infarction, and hypertrophy, changes in the expression and location of Connexin43 (Cx43) occur (Cx43 remodeling), and may predispose to arrhythmias. Stretch may be an important stimulus to Cx43 remodeling; however, it has only been investigated in neonatal cell cultures, which have different physiological properties than adult myocytes. We hypothesized that localized stretch in vivo causes Cx43 remodeling, with associated changes in conduction, mediated by the renin–angiotensin system (RAS). Methods and Results: In an open‐chest canine model, a device was used to stretch part of the right ventricle (RV) by 22% for 6 hours. Activation mapping using a 312‐electrode array was performed before and after stretch. Regional stretch did not change longitudinal conduction velocity (post‐stretch vs baseline: 51.5 ± 5.2 vs 55.3 ± 8.1 cm/s, P = 0.24, n = 11), but significantly reduced transverse conduction velocity (28.7 ± 2.5 vs 35.4 ± 5.4 cm/s, P < 0.01). It also reduced total Cx43 expression, by Western blotting, compared with nonstretched RV of the same animal (86.1 ± 32.2 vs 100 ± 19.4%, P < 0.02, n = 11). Cx43 labeling redistributed to the lateral cell borders. Stretch caused a small but significant increase in the proportion of the dephosphorylated form of Cx43 (stretch 9.95 ± 1.4% vs control 8.74 ± 1.2%, P < 0.05). Olmesartan, an angiotensin II blocker, prevented the stretch‐induced changes in Cx43 levels, localization, and conduction. Conclusion: Myocardial stretch in vivo has opposite effects to that in neonatal myocytes in vitro. Stretch in vivo causes conduction changes associated with Cx43 remodeling that are likely caused by local stretch‐induced activation of the RAS. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1276‐1283, November 2010)     

A Controlled Trial of Methionyl Growth Hormone Therapy in Prepubertal Children with Short Stature, Subnormal Growth Rate and Normal Growth Hormone Response to Secretagogues

ABSTRACT. Thirty short and slowly growing children with normal plasma growth hormone (GH) responses to standard provocation tests were randomly assigned to either a group ( n = 20) undergoing treatment with methionyl GH (somatrem), 2IU per m² body surface s.c. daily, or a control group ( n = 10). Twelve out of 18 children who completed the first year of treatment showed a height velocity increment of more than 2 cm/year. The mean (SD) growth velocity of the treatment group increased by 3.0 (1.9) cm/year over the first year, compared with -0.2 (0.7) cm/year in the control group. Neither parameters of endogenous GH secretion nor plasma IGF-I levels showed a significant correlation with the growth response. Of the auxological variables studied, pre-treatment growth velocity ( r = 0.8) and the short-term height velocity increment ( r = 0.7–0.9) showed significant correlations with the growth response in the first year of treatment. Somatrem therapy was without side effects, except in one child who developed anti-GH antibodies in combination with a poor growth response.     

Dose-response relationship and time course of action of Org 9426

The dose-response relationship of Org 9426, its time course of action and the reversibility of the residual block by neostigmine have been investigated in 100 patients undergoing various anaesthetic techniques. The dose-response was measured immediately following induction of anaesthesia. Doses of Org 9426, required for 50% and 90% depression of the twitch height, were 202 and 328 micrograms.kg-1, respectively. The clinical duration of the maintenance doses, 150 micrograms.kg-1, ranged from 9.5 to 13.4 min and from 12.8 to 18.9 min for the first and fifth maintenance doses, respectively. Spontaneous recovery indices (25%-75%) were between 9.5 and 16.7 min; neostigmine methylsulphate administered at 25% recovery of the twitch height promptly reversed the residual block. No side effects were observed. The extent of the influence of the anaesthetic on the time course of Org 9426 appears to be fractional considering the variation of the time course within the separate groups.     

Arrhythmogenic Effects of Quinidine on Catecholamine-Induced Delayed Afterdepolarizations in Canine Atrial Fibers

Arrhythmogenic Effects of Quinidine on Catecholamine-induced Delayed Afterdepolarizations. We studied the effects of quinidine and tetrodotoxin (TTX), two drugs that block Na⁺ channels, on delayed afterdepolarizations (DAD) caused by norepinepbrine in atrial fibers of the canine coronary sinus. At long stimulus cycle lengths of 10 seconds, quinidine increased the amplitude of the afterdepolarizations and caused triggered activity within 1–2 minutes. Simultaneously, action potential duration (APD) was lengthened but upstroke velocity was not decreased. Prolonged exposure to quinidine eventually decreased upstroke velocity but DAD amplitude remained larger than control and triggered activity was still induced more easily. The effects of quinidine to increase afterdepolarizations was partially related to its prolongation of the APD since shortening APD with repolarizing current decreased DAD amplitude. However, DAD amplitude remained larger than control indicating that quinidine caused triggering by other mechanisms as well. TTX, on the other hand, which blocks Na⁺ channels but shortens APD, decreased DAD amplitude and triggered activity. Part but not all of these effects resulted from the shortening of APD by TTX since prolongation of APD with depolarizing current only partially restored DAD amplitude. Anti-arrhythmic drugs, therefore, may have effects on DADs that partly result from changes in the APD. Quinidine may cause cardiac arrhythmias by virtue of its effects to potentiate triggered activity.     

Optimized Measurement of Activation Rate at Left Atrial Sites with Complex Fractionated Electrograms During Atrial Fibrillation

Local Activation Rate in Atrial Fibrillation. Background: Complex fractionated atrial electrograms (CFAE) have become targets for catheter ablation of atrial fibrillation (AF). Frequency components of AF signals have also become important markers for identifying potential mechanisms of AF, yet inaccuracies exist, particularly in standard dominant frequency (SDF) calculations especially at CFAE sites. We developed new methodology to improve accuracy of AF rate determinations at such recording sites. Objective: To develop optimal methods for estimating activation rates in paroxysmal and persistent AF. Methods: Electrograms were obtained from one right atrial, coronary sinus, and 6 left atrial (LA) endocardial regions manifesting CFAEs in paroxysmal (N = 7) and persistent (N = 7) AF patients. SDF was measured from 8.4 s intervals and compared to (1) optimized DF (ODF) calculated by optimizing the filter coefficients which maximized dominant frequency power, (2) autocorrelation (AC), with the rate estimated as the inverse of the signal phase shift generating the largest autocorrelation coefficient, and (3) ensemble average (EA), with the rate estimated by summing successive signal segments and selecting segment length yielding maximum power. Rate measurements were compared between groups, at baseline and with additive interference, having similar frequency content to the electrograms, to test the robustness of the different methods. Results: From pooled data (N = 168 recording sites), a significantly higher LA dominant frequency was found in persistent versus paroxysmal patients using each method (P < 0.001), with a mean value for all methods of 6.23 ± 0.08 Hz versus 5.32 ± 0.10 Hz, respectively. At the highest additive interference level, the rate measurement error was significantly greater in SDF as compared with EA (P = 0.010) and ODF (P = 0.035), and at all interference levels SDF had the largest error of any method. Conclusions: SDF appears less robust to additive interference, compared to the ODF and EA methods of estimating the activation rate at CFAE sites in this small group of patients. Use of optimized filter coefficients for DF measurement, or use of correlative methods such as EA, that reinforce the signal rather than filtering the noise, may improve calculation of activation rates. (J Cardiovasc Electrophysiol, Vol. 21, pp. 133‐143, February 2010)