High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

OBJECTIVES: To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND: The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS: In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS: At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS: Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.     

Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine

Disabling orthostatic hypotension, due to insufficiency of the autonomic nervous system, is a common complication of type I familial amyloidotic polyneuropathy (FAP). We investigated whether oral treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-Dops), a noradrenaline precursor, might be of therapeutical benefit. In twenty untreated FAP patients, aged 33 to 44 years, who, because of severe orthostatic hypotension, were bedridden or constrained to a sitting life, supine and erect blood pressure (BP), plasma noradrenaline and tilting time, defined as the interval (s) between the beginning of a 60 degrees head-up tilt and the occurrence of orthostatic symptoms (dizziness, blurred vision or near syncope) were determined before and at repeated intervals during oral treatment with L-threo-Dops, 100 mg bid, for 6 months. Before treatment supine mean BP was 80 (76-85) mmHg (mean and 95% CI), supine plasma noradrenaline was low, 59 (41-77) pg/ml and tilting time ranged from 38 to 118 s. In response to tilt, mean BP immediately fell by 36 (31-41) mmHg, whereas plasma noradrenaline increased by only 11 (0-21) pg/ml (p = 0.05). After 3 to 5 days of treatment with L-threo-Dops all patients experienced marked improvement of their orthostatic tolerance as reflected by their ability to walk freely around. This effect sustained throughout the six months of treatment. Plasma noradrenaline increased moderately by 37 (11-63) pg/ml (p = 0.02) and supine mean BP increased by 8.6 (5.8-12.4) mmHg (p < 0.001) during chronic treatment. Supine or nocturnal hypertension did not develop, the fall in mean BP in response to tilt diminished by 12.5 (6.5-17.3) mmHg (p < 0.001) and tilting time became longer than 600 s in all patients. Because of its efficacy, its sustained duration of action and the lack of side effects, L-threo-Dops is advocated to improve orthostatic tolerance in patients with autonomic insufficiency due to FAP.     

Anti-B-50 (GAP-43) antibodies decrease exocytosis of glutamate in permeated synaptosomes

The involvement of the protein kinase C substrate, B-50 (GAP-43), in the release of glutamate from small clear-cored vesicles in streptolysin-O-permeated synaptosomes was studied by using anti-B-50 antibodies. Glutamate release was induced from endogenous as well as 3H-labelled pools in a [Ca(2+)]-dependent manner. This Ca(2+)-induced release was partially ATP dependent and blocked by the light-chain fragment of tetanus toxin, demonstrating its vesicular nature. Comparison of the effects of anti-B-50 antibodies on glutamate and noradrenaline release from permeated synaptosomes revealed two major differences. Firstly, Ca(2+)-induced glutamate release was decreased only partially by anti-B-50 antibodies, whereas Ca(2+)-induced noradrenaline release was inhibited almost completely. Secondly, anti-B-50 antibodies significantly reduced basal glutamate release, but did not affect basal noradrenaline release. In view of the differences in exocytotic mechanisms of small clear-cored vesicles and large dense-cored vesicles, these data indicate that B-50 is important in the regulation of exocytosis of both types of neurotransmitters, probably at stages of vesicle recycling and/or vesicle recruitment, rather than in the Ca(2+)-induced fusion step.     

Individual differences in P300 amplitude: a genetic study in adolescent twins

Three experiments, using temporal generalization and verbal estimation methods, studied judgements of durations of auditory (500-Hz tone) and visual (14-cm blue square) stimuli. With both methods, auditory stimuli were judged longer, and less variable, than visual ones. The verbal estimation experiments used stimuli from 77 to 1183 msec in length, and the slope of the function relating mean estimate to real length differed between modalities (but the intercept did not), consistent with the idea that a pacemaker generating duration representations ran faster for auditory than for visual stimuli. The different variability of auditory and visual stimuli was attributed to differential variability in the operation of a switch of a pacemaker-accumulator clock, and experimental data suggested that such switch effects were separable from changes in pacemaker speed. Overall, the work showed how a clock model consistent with scalar timing theory, the leading account of animal timing, can address an issue derived from the classical literature on human time perception.     

Elevated sinistrality in transsexuals.

Assessed hand preference in 44 female-to-male (FTM) and 93 male-to-female (MTF) transsexuals to test whether the frequency of left-handedness in FTM transsexuals would be higher than in the general population and whether the frequency of left-handedness in MTF transsexuals would be lower or the same as in the general population. The prevalence of left-handedness in both FTM and MTF transsexuals was nearly 2 times higher than in the general population. Data argue against abnormal prenatal testosterone exposure as a factor in the etiology of left-handedness among transsexuals and indicate that either G. Dorner's (1980) theory on the etiology of transsexuality or N. Geschwind and O. Behan's (1984) model of the genesis of left-handedness, or both, need to be revised. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A simulation study of the effects of assignment of prior identity-by-descent probabilities to unselected sib pairs, in covariance-structure modeling of a quantitative-trait locus

Sib pair-selection strategies, designed to identify the most informative sib pairs in order to detect a quantitative-trait locus (QTL), give rise to a missing-data problem in genetic covariance-structure modeling of QTL effects. After selection, phenotypic data are available for all sibs, but marker data-and, consequently, the identity-by-descent (IBD) probabilities-are available only in selected sib pairs. One possible solution to this missing-data problem is to assign prior IBD probabilities (i.e., expected values) to the unselected sib pairs. The effect of this assignment in genetic covariance-structure modeling is investigated in the present paper. Two maximum-likelihood approaches to estimation are considered, the pi-hat approach and the IBD-mixture approach. In the simulations, sample size, selection criteria, QTL-increaser allele frequency, and gene action are manipulated. The results indicate that the assignment of prior IBD probabilities results in serious estimation bias in the pi-hat approach. Bias is also present in the IBD-mixture approach, although here the bias is generally much smaller. The null distribution of the log-likelihood ratio (i.e., in absence of any QTL effect) does not follow the expected null distribution in the pi-hat approach after selection. In the IBD-mixture approach, the null distribution does agree with expectation.     

Multivariate Genetic Structure of Externalizing Behavior and Structural Brain Development in a Longitudinal Adolescent Twin Sample

Externalizing behavior in its more extreme form is often considered a problem to the individual, their families, teachers, and society as a whole. Several brain structures have been linked to externalizing behavior and such associations may arise if the (co)development of externalizing behavior and brain structures share the same genetic and/or environmental factor(s). We assessed externalizing behavior with the Child Behavior Checklist and Youth Self Report, and the brain volumes and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) with magnetic resonance imaging in the BrainSCALE cohort, which consisted of twins and their older siblings from 112 families measured longitudinally at ages 10, 13, and 18 years for the twins. Genetic covariance modeling based on the classical twin design, extended to also include siblings of twins, showed that genes influence externalizing behavior and changes therein (h² up to 88%). More pronounced externalizing behavior was associated with higher FA (observed correlation r_ph up to +0.20) and lower MD (r_ph up to −0.20), with sizeable genetic correlations (FA r_a up to +0.42; MD r_a up to −0.33). The cortical gray matter (CGM; r_ph up to −0.20) and cerebral white matter (CWM; r_ph up to +0.20) volume were phenotypically but not genetically associated with externalizing behavior. These results suggest a potential mediating role for global brain structures in the display of externalizing behavior during adolescence that are both partially explained by the influence of the same genetic factor.     

High activity of semicarbazide-sensitive amine oxidase (SSAO): an important source of errors in the determination of the concentration of dopamine in pig plasma

We noted rapid breakdown at 4 degrees and 20 degrees C of dopamine (DA) (but not of (nor)epinephrine and epinine) in pig plasma, but not in human plasma. The enzyme responsible appears to be a semicarbazide-sensitive amine oxidase (SSAO) because the breakdown can be inhibited by semicarbazide, but not by pargyline, clorgyline, EDTA, or (extra) glutathione. Among catecholamines tested, only DA and 3,4-dihydroxybenzylamine (DHBA, the internal standard of most catecholamine assays using high-performance liquid chromatography (HPLC) with electrochemical detection) were good substrates for the pig plasma SSAO. At 37 degrees C, especially after prolonged storage, all catecholamines break down. This breakdown results from autoxidation since it can be prevented by addition of extra glutathione (but not by semicarbazide) for all catecholamines except DA and DHBA. Breakdown at 37 degrees C of these two compounds cannot be prevented by addition of extra glutathione or semicarbazide, but only by addition of both. For reliable measurements of DA concentrations in pig plasma, blood should be collected in tubes containing not only glutathione, but also semicarbazide. The possibility of similarly high plasma SSAO activity in other species should be investigated further.     

Genetic and Environmental Mechanisms Underlying Stability and Change in Problem Behaviors at Ages 3, 7, 10, and 12.

Maternal ratings on internalizing (INT) and externalizing (EXT) behaviors were collected in a large, population-based longitudinal sample. The numbers of participating twin pairs at ages 3, 7, 10, and 12 were 5,602, 5,115, 2,956, and 1,481, respectively. Stability in both behaviors was accounted for by genetic and shared environmental influences. The genetic contribution to stability (INT: 43%; EXT: 60%) resulted from the fact that a subset of genes expressed at an earlier age was still active at the next time point. A common set of shared environmental factors operated at all ages (INT: 47%; EXT: 34%). The modest contribution of nonshared environmental factors (INT: 10%; EXT: 6%) could not be captured by a simple model. Significant age-specific influences were found for all components, indicating that genetic and environmental factors also contributed to changes in problem behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)